Author Archives: admin


Stem Cell Clinic > Articles by: admin

Bristol Myers Squibb Receives European Commission Approval for LAG-3-Blocking Antibody Combination, Opdualag (nivolumab and relatlimab), for the…

By Stem Cell Medicine

Opdualag is a first-in-class, fixed-dose dual immunotherapy combination treatment of the PD-1 inhibitor nivolumab and novel LAG-3-blocking antibody relatlimab

In RELATIVITY-047, Opdualag more than doubled median progression-free survival compared to nivolumab monotherapy

PRINCETON, N.J.--(BUSINESS WIRE)-- Bristol Myers Squibb (NYSE: BMY) today announced that the European Commission (EC) has approved the fixed-dose combination of Opdualag (nivolumab and relatlimab) for the first-line treatment of advanced (unresectable or metastatic) melanoma in adults and adolescents 12 years of age and older with tumor cell PD-L1 expression < 1%.

The ECs decision is based upon an exploratory analysis of results from the Phase 2/3 RELATIVITY-047 trial in patients with tumor cell expression < 1%, which demonstrated that treatment with the fixed-dose combination of the PD-1 inhibitor nivolumab and novel LAG-3-blocking antibody relatlimab more than doubled the median progression-free survival (PFS) compared to nivolumab monotherapy an established standard of care. No new safety events were identified with the combination when compared to nivolumab monotherapy.

Opdualag is now the first approved LAG-3-blocking antibody combination for advanced melanoma in the European Union. The RELATIVITY-047 study demonstrated the important benefit of inhibiting both LAG-3 and PD-L1 with our novel immunotherapy combination, said Samit Hirawat, M.D., executive vice president, chief medical officer, Global Drug Development, Bristol Myers Squibb. This is a continuation of our work in bringing innovative medicines to adults and adolescents living with melanoma. Thank you to all of the patients, researchers and physicians who contributed to these advancements and made todays approval possible.

The EC decision allows for the use of Opdualag for the first-line treatment of adults and adolescents 12 years of age and older with advanced melanoma and tumor cell PD-L1 expression < 1% in all European Union member states*, as well as Iceland, Liechtenstein, and Norway.

RELATIVITY -047 Efficacy and Safety Results

The indication in the European Union is based upon an exploratory analysis of the RELATIVITY-047 data in patients with tumor cell PD-L1 expression < 1%:

The RELATIVITY-047 trial also met its primary endpoint of PFS in the all-comer population.

*Centralized Marketing Authorization does not include approval in Great Britain (England, Scotland, Wales).

About RELATIVITY-047

RELATIVITY-047 is a global, randomized, double-blind Phase 2/3 study evaluating the fixed-dose combination of nivolumab and relatlimab versus nivolumab alone in patients with previously untreated metastatic or unresectable melanoma. Patients were enrolled regardless of tumor cell PD-L1 expression. The trial excluded patients with active autoimmune disease, medical conditions requiring systemic treatment with moderate or high dose corticosteroids or immunosuppressive medications, uveal melanoma, and active or untreated brain or leptomeningeal metastases. The primary endpoint of the trial is progression-free survival (PFS) determined by Blinded Independent Central Review (BICR) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1) in the all-comer population. The secondary endpoints are overall survival (OS) and objective response rate (ORR) in the all-comer population. A total of 714 patients were randomized 1:1 to receive a fixed-dose combination of nivolumab (480 mg) and relatlimab (160 mg) or nivolumab (480 mg) by intravenous infusion every four weeks until disease progression, unacceptable toxicity or withdrawal of consent.

About LAG-3

Lymphocyte-activation gene 3 (LAG-3) is a cell-surface molecule expressed on effector T cells and regulatory T cells (Tregs) and functions to control T-cell response, activation and growth. Preclinical studies indicate that inhibition of LAG-3 may restore effector function of exhausted T cells and potentially promote an anti-tumor response. Early research demonstrates that targeting LAG-3 in combination with other potentially complementary immune checkpoints may be a key strategy to more effectively potentiate anti-tumor immune activity.

Bristol Myers Squibb is evaluating relatlimab, its LAG-3-blocking antibody, in clinical trials in combination with other agents in a variety of tumor types.

About Melanoma

Melanoma is a form of skin cancer characterized by the uncontrolled growth of pigment-producing cells (melanocytes) located in the skin. Metastatic melanoma is the deadliest form of the disease and occurs when cancer spreads beyond the surface of the skin to other organs. The incidence of melanoma has been increasing steadily for the last 30 years. In the United States, 106,110 new diagnoses of melanoma and about 7,180 related deaths are estimated for 2021. Globally, the World Health Organization estimates that by 2035, melanoma incidence will reach 424,102, with 94,308 related deaths. Melanoma can be mostly treatable when caught in its very early stages; however, survival rates can decrease as the disease progresses.

Bristol Myers Squibb: Creating a Better Future for People with Cancer

Bristol Myers Squibb is inspired by a single vision transforming patients lives through science. The goal of the companys cancer research is to deliver medicines that offer each patient a better, healthier life and to make cure a possibility. Building on a legacy across a broad range of cancers that have changed survival expectations for many, Bristol Myers Squibb researchers are exploring new frontiers in personalized medicine, and through innovative digital platforms, are turning data into insights that sharpen their focus. Deep scientific expertise, cutting-edge capabilities and discovery platforms enable the company to look at cancer from every angle. Cancer can have a relentless grasp on many parts of a patients life, and Bristol Myers Squibb is committed to taking actions to address all aspects of care, from diagnosis to survivorship. Because as a leader in cancer care, Bristol Myers Squibb is working to empower all people with cancer to have a better future.

OPDUALAG U.S. INDICATION

Opdualag (nivolumab and relatlimab-rmbw) is indicated for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma.

OPDUALAG IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions (IMARs) listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

IMARs which may be severe or fatal, can occur in any organ system or tissue. IMARs can occur at any time after starting treatment with a LAG-3 and PD-1/PD-L1 blocking antibodies. While IMARs usually manifest during treatment, they can also occur after discontinuation of Opdualag. Early identification and management of IMARs are essential to ensure safe use. Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying IMARs. Evaluate clinical chemistries including liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. In cases of suspected IMARs, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if Opdualag requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose IMARs are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

Opdualag can cause immune-mediated pneumonitis, which may be fatal. In patients treated with other PD-1/PD-L1 blocking antibodies, the incidence of pneumonitis is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.7% (13/355) of patients receiving Opdualag, including Grade 3 (0.6%), and Grade 2 (2.3%) adverse reactions. Pneumonitis led to permanent discontinuation of Opdualag in 0.8% and withholding of Opdualag in 1.4% of patients.

Immune-Mediated Colitis

Opdualag can cause immune-mediated colitis, defined as requiring use of corticosteroids and no clear alternate etiology. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies.

Immune-mediated diarrhea or colitis occurred in 7% (24/355) of patients receiving Opdualag, including Grade 3 (1.1%) and Grade 2 (4.5%) adverse reactions. Colitis led to permanent discontinuation of Opdualag in 2% and withholding of Opdualag in 2.8% of patients.

Immune-Mediated Hepatitis

Opdualag can cause immune-mediated hepatitis, defined as requiring the use of corticosteroids and no clear alternate etiology.

Immune-mediated hepatitis occurred in 6% (20/355) of patients receiving Opdualag, including Grade 4 (0.6%), Grade 3 (3.4%), and Grade 2 (1.4%) adverse reactions. Hepatitis led to permanent discontinuation of Opdualag in 1.7% and withholding of Opdualag in 2.3% of patients.

Immune-Mediated Endocrinopathies

Opdualag can cause primary or secondary adrenal insufficiency, hypophysitis, thyroid disorders, and Type 1 diabetes mellitus, which can be present with diabetic ketoacidosis. Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

For Grade 2 or higher adrenal insufficiency, initiate symptomatic treatment, including hormone replacement as clinically indicated. In patients receiving Opdualag, adrenal insufficiency occurred in 4.2% (15/355) of patients receiving Opdualag, including Grade 3 (1.4%) and Grade 2 (2.5%) adverse reactions. Adrenal insufficiency led to permanent discontinuation of Opdualag in 1.1% and withholding of Opdualag in 0.8% of patients.

Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism; initiate hormone replacement as clinically indicated. Hypophysitis occurred in 2.5% (9/355) of patients receiving Opdualag, including Grade 3 (0.3%) and Grade 2 (1.4%) adverse reactions. Hypophysitis led to permanent discontinuation of Opdualag in 0.3% and withholding of Opdualag in 0.6% of patients.

Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism; initiate hormone replacement or medical management as clinically indicated. Thyroiditis occurred in 2.8% (10/355) of patients receiving Opdualag, including Grade 2 (1.1%) adverse reactions. Thyroiditis did not lead to permanent discontinuation of Opdualag. Thyroiditis led to withholding of Opdualag in 0.3% of patients. Hyperthyroidism occurred in 6% (22/355) of patients receiving Opdualag, including Grade 2 (1.4%) adverse reactions. Hyperthyroidism did not lead to permanent discontinuation of Opdualag. Hyperthyroidism led to withholding of Opdualag in 0.3% of patients. Hypothyroidism occurred in 17% (59/355) of patients receiving Opdualag, including Grade 2 (11%) adverse reactions. Hypothyroidism led to the permanent discontinuation of Opdualag in 0.3% and withholding of Opdualag in 2.5% of patients.

Monitor patients for hyperglycemia or other signs and symptoms of diabetes; initiate treatment with insulin as clinically indicated. Diabetes occurred in 0.3% (1/355) of patients receiving Opdualag, a Grade 3 (0.3%) adverse reaction, and no cases of diabetic ketoacidosis. Diabetes did not lead to the permanent discontinuation or withholding of Opdualag in any patient.

Immune-Mediated Nephritis with Renal Dysfunction

Opdualag can cause immune-mediated nephritis, which is defined as requiring use of steroids and no clear etiology. In patients receiving Opdualag, immune-mediated nephritis and renal dysfunction occurred in 2% (7/355) of patients, including Grade 3 (1.1%) and Grade 2 (0.8%) adverse reactions. Immune-mediated nephritis and renal dysfunction led to permanent discontinuation of Opdualag in 0.8% and withholding of Opdualag in 0.6% of patients.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Immune-Mediated Dermatologic Adverse Reactions

Opdualag can cause immune-mediated rash or dermatitis, defined as requiring use of steroids and no clear alternate etiology. Exfoliative dermatitis, including Stevens-Johnson syndrome, toxic epidermal necrolysis, and Drug Rash with eosinophilia and systemic symptoms has occurred with PD-1/L-1 blocking antibodies. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate non-exfoliative rashes.

Withhold or permanently discontinue Opdualag depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information).

Immune-mediated rash occurred in 9% (33/355) of patients, including Grade 3 (0.6%) and Grade 2 (3.4%) adverse reactions. Immune-mediated rash did not lead to permanent discontinuation of Opdualag. Immune-mediated rash led to withholding of Opdualag in 1.4% of patients.

Immune-Mediated Myocarditis

Opdualag can cause immune-mediated myocarditis, which is defined as requiring use of steroids and no clear alternate etiology. The diagnosis of immune-mediated myocarditis requires a high index of suspicion. Patients with cardiac or cardio-pulmonary symptoms should be assessed for potential myocarditis. If myocarditis is suspected, withhold dose, promptly initiate high dose steroids (prednisone or methylprednisolone 1 to 2 mg/kg/day) and promptly arrange cardiology consultation with diagnostic workup. If clinically confirmed, permanently discontinue Opdualag for Grade 2-4 myocarditis.

Myocarditis occurred in 1.7% (6/355) of patients receiving Opdualag, including Grade 3 (0.6%), and Grade 2 (1.1%) adverse reactions. Myocarditis led to permanent discontinuation of Opdualag in 1.7% of patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant IMARs occurred at an incidence of <1% (unless otherwise noted) in patients who received Opdualag or were reported with the use of other PD-1/PD-L1 blocking antibodies. Severe or fatal cases have been reported for some of these adverse reactions: Cardiac/Vascular: pericarditis, vasculitis; Nervous System: meningitis, encephalitis, myelitis and demyelination, myasthenic syndrome/myasthenia gravis (including exacerbation), Guillain-Barr syndrome, nerve paresis, autoimmune neuropathy; Ocular: uveitis, iritis, and other ocular inflammatory toxicities can occur. Some cases can be associated with retinal detachment. Various grades of visual impairment, including blindness, can occur. If uveitis occurs in combination with other IMARs, consider a Vogt-Koyanagi-Haradalike syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: pancreatitis including increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: myositis/polymyositis, rhabdomyolysis (and associated sequelae including renal failure), arthritis, polymyalgia rheumatica; Endocrine: hypoparathyroidism; Other (Hematologic/Immune): hemolytic anemia, aplastic anemia, hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, histiocytic necrotizing lymphadenitis (Kikuchi lymphadenitis), sarcoidosis, immune thrombocytopenic purpura, solid organ transplant rejection.

Infusion-Related Reactions

Opdualag can cause severe infusion-related reactions. Discontinue Opdualag in patients with severe or life-threatening infusion-related reactions. Interrupt or slow the rate of infusion in patients with mild to moderate infusion-related reactions. In patients who received Opdualag as a 60-minute intravenous infusion, infusion-related reactions occurred in 7% (23/355) of patients.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

Fatal and other serious complications can occur in patients who receive allogeneic hematopoietic stem cell transplantation (HSCT) before or after being treated with a PD-1/PD-L1 receptor blocking antibody. Transplant-related complications include hyperacute graft-versus-host disease (GVHD), acute GVHD, chronic GVHD, hepatic veno-occlusive disease after reduced intensity conditioning, and steroid-requiring febrile syndrome (without an identified infectious cause). These complications may occur despite intervening therapy between PD-1/PD-L1 blockade and allogeneic HSCT.

Follow patients closely for evidence of transplant-related complications and intervene promptly. Consider the benefit versus risks of treatment with a PD-1/PD-L1 receptor blocking antibody prior to or after an allogeneic HSCT.

Embryo-Fetal Toxicity

Based on its mechanism of action and data from animal studies, Opdualag can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with Opdualag for at least 5 months after the last dose of Opdualag.

Lactation

There are no data on the presence of Opdualag in human milk, the effects on the breastfed child, or the effect on milk production. Because nivolumab and relatlimab may be excreted in human milk and because of the potential for serious adverse reactions in a breastfed child, advise patients not to breastfeed during treatment with Opdualag and for at least 5 months after the last dose.

Serious Adverse Reactions

In Relativity-047, fatal adverse reaction occurred in 3 (0.8%) patients who were treated with Opdualag; these included hemophagocytic lymphohistiocytosis, acute edema of the lung, and pneumonitis. Serious adverse reactions occurred in 36% of patients treated with Opdualag. The most frequent serious adverse reactions reported in 1% of patients treated with Opdualag were adrenal insufficiency (1.4%), anemia (1.4%), colitis (1.4%), pneumonia (1.4%), acute myocardial infarction (1.1%), back pain (1.1%), diarrhea (1.1%), myocarditis (1.1%), and pneumonitis (1.1%).

Common Adverse Reactions and Laboratory Abnormalities

The most common adverse reactions reported in 20% of the patients treated with Opdualag were musculoskeletal pain (45%), fatigue (39%), rash (28%), pruritus (25%), and diarrhea (24%).

The most common laboratory abnormalities that occurred in 20% of patients treated with Opdualag were decreased hemoglobin (37%), decreased lymphocytes (32%), increased AST (30%), increased ALT (26%), and decreased sodium (24%).

Please see U.S. Full Prescribing Information for OPDUALAG.

OPDIVO U.S. INDICATIONS

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of adult patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adult patients with unresectable or metastatic melanoma.

OPDIVO (nivolumab) is indicated for the adjuvant treatment of adult patients with melanoma with involvement of lymph nodes or metastatic disease who have undergone complete resection.

OPDIVO (nivolumab), in combination with platinum-doublet chemotherapy, is indicated as neoadjuvant treatment of adult patients with resectable (tumors 4 cm or node positive) non-small cell lung cancer (NSCLC).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) whose tumors express PD-L1 (1%) as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab) and 2 cycles of platinum-doublet chemotherapy, is indicated for the first-line treatment of adult patients with metastatic or recurrent non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with metastatic non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving OPDIVO.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable malignant pleural mesothelioma (MPM).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with intermediate or poor risk advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab), in combination with cabozantinib, is indicated for the first-line treatment of adult patients with advanced renal cell carcinoma (RCC).

OPDIVO (nivolumab) is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) who have received prior anti-angiogenic therapy.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with classical Hodgkin lymphoma (cHL) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin or after 3 or more lines of systemic therapy that includes autologous HSCT. This indication is approved under accelerated approval based on overall response rate. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after platinum-based therapy.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

OPDIVO (nivolumab), as a single agent, is indicated for the adjuvant treatment of adult patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection of UC.

OPDIVO (nivolumab), as a single agent, is indicated for the treatment of adult and pediatric (12 years and older) patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) metastatic colorectal cancer (CRC) that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the treatment of adult patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

OPDIVO (nivolumab) is indicated for the treatment of adult patients with unresectable advanced, recurrent or metastatic esophageal squamous cell carcinoma (ESCC) after prior fluoropyrimidine- and platinum-based chemotherapy.

OPDIVO (nivolumab) is indicated for the adjuvant treatment of completely resected esophageal or gastroesophageal junction cancer with residual pathologic disease in adult patients who have received neoadjuvant chemoradiotherapy (CRT).

OPDIVO (nivolumab), in combination with fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).

OPDIVO (nivolumab), in combination with YERVOY (ipilimumab), is indicated for the first-line treatment of adult patients with unresectable advanced or metastatic esophageal squamous cell carcinoma (ESCC).

OPDIVO (nivolumab), in combination with fluoropyrimidine- and platinum- containing chemotherapy, is indicated for the treatment of adult patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma.

IMPORTANT SAFETY INFORMATION

Severe and Fatal Immune-Mediated Adverse Reactions

Immune-mediated adverse reactions listed herein may not include all possible severe and fatal immune-mediated adverse reactions.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue. While immune-mediated adverse reactions usually manifest during treatment, they can also occur after discontinuation of OPDIVO or YERVOY. Early identification and management are essential to ensure safe use of OPDIVO and YERVOY. Monitor for signs and symptoms that may be clinical manifestations of underlying immune-mediated adverse reactions. Evaluate clinical chemistries including liver enzymes, creatinine, adrenocorticotropic hormone (ACTH) level, and thyroid function at baseline and periodically during treatment with OPDIVO and before each dose of YERVOY. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.

Withhold or permanently discontinue OPDIVO and YERVOY depending on severity (please see section 2 Dosage and Administration in the accompanying Full Prescribing Information). In general, if OPDIVO or YERVOY interruption or discontinuation is required, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose immune-mediated adverse reactions are not controlled with corticosteroid therapy. Toxicity management guidelines for adverse reactions that do not necessarily require systemic steroids (e.g., endocrinopathies and dermatologic reactions) are discussed below.

Immune-Mediated Pneumonitis

OPDIVO and YERVOY can cause immune-mediated pneumonitis. The incidence of pneumonitis is higher in patients who have received prior thoracic radiation. In patients receiving OPDIVO monotherapy, immune-mediated pneumonitis occurred in 3.1% (61/1994) of patients, including Grade 4 (<0.1%), Grade 3 (0.9%), and Grade 2 (2.1%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 7% (31/456) of patients, including Grade 4 (0.2%), Grade 3 (2.0%), and Grade 2 (4.4%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated pneumonitis occurred in 3.9% (26/666) of patients, including Grade 3 (1.4%) and Grade 2 (2.6%). In NSCLC patients receiving OPDIVO 3 mg/kg every 2 weeks with YERVOY 1 mg/kg every 6 weeks, immune-mediated pneumonitis occurred in 9% (50/576) of patients, including Grade 4 (0.5%), Grade 3 (3.5%), and Grade 2 (4.0%). Four patients (0.7%) died due to pneumonitis.

In Checkmate 205 and 039, pneumonitis, including interstitial lung disease, occurred in 6.0% (16/266) of patients receiving OPDIVO. Immune-mediated pneumonitis occurred in 4.9% (13/266) of patients receiving OPDIVO, including Grade 3 (n=1) and Grade 2 (n=12).

Immune-Mediated Colitis

Original post:
Bristol Myers Squibb Receives European Commission Approval for LAG-3-Blocking Antibody Combination, Opdualag (nivolumab and relatlimab), for the...

This Blood Stem Cell Research Could Change Medicine of the Future – SciTechDaily

By Stell Cell Research

The microfluidic device that emulated an embryos heartbeat and blood circulation. The cell seeding channels are indicated by red food dye, while the heart ventricular contraction control channels and circulation valve control channels are indicated by blue and green food dye respectively. Credit: Jingjing Li, UNSW Sydney

New discoveries about embryonic blood stem cell creation made independently by biomedical engineers and medical researchers at the University of New South Wales (UNSW) Sydney could one day eliminate the need for blood stem cell donors.

These achievements are part of a move in regenerative medicine towards the use of induced pluripotent stem cells to treat disease. This is where stem cells are reverse engineered from adult tissue cells rather than using live human or animal embryos.

Although we have known about induced pluripotent stem cells since 2006, researchers still have plenty to learn about how cell differentiation in the human body can be mimicked artificially and safely in the lab for the purposes of delivering targeted medical treatment.

Induced pluripotent stem cells are a type of pluripotent stem cell that can be generated directly from a somatic cell. A somatic cell is any biological cell forming the body of a multicellular organism other than a gamete, germ cell, gametocyte, or undifferentiated stem cell.

UNSW researchers have recently completed two studies in this area that shine new light on not only how the precursors to blood stem cells occur in animals and humans, but how they may be induced artificially.

One study was published on September 13, 2022, in the journal Cell Reports by scientists from the UNSW School of Biomedical Engineering. They demonstrated how a simulation of an embryos beating heart using a microfluidic device in the lab led to the development of human blood stem cell precursors, which are stem cells on the verge of becoming blood stem cells.

In another article, which was recently published in Nature Cell Biology, researchers from UNSW Medicine & Health revealed the identity of cells in mice embryos responsible for blood stem cell creation.

Both studies are significant steps towards an understanding of how, when, where, and which cells are involved in the creation of blood stem cells. In the future, this knowledge could be used to help cancer patients, among others, who have undergone high doses of radio- and chemotherapy, to replenish their depleted blood stem cells.

In the study detailed in Cell Reports, lead author Dr. Jingjing Li and fellow researchers described how a 3cm x 3cm (1.2 x 1.2) microfluidic system pumped blood stem cells produced from an embryonic stem cell line to mimic an embryos beating heart and conditions of blood circulation.

She said that in the last few decades, biomedical engineers have been trying to make blood stem cells in laboratory dishes to solve the problem of donor blood stem cell shortages. But no one has yet been able to achieve it.

Part of the problem is that we still dont fully understand all the processes going on in the microenvironment during embryonic development that leads to the creation of blood stem cells at about day 32 in the embryonic development, Dr. Li said.

So we made a device mimicking the heart beating and the blood circulation and an orbital shaking system which causes shear stress or friction of the blood cells as they move through the device or around in a dish.

These systems promoted the development of precursor blood stem cells which can differentiate into various blood components white blood cells, red blood cells, platelets, and others. They were excited to see this same process known as hematopoiesis replicated in the device.

Study co-author Associate Professor Robert Nordon said he was amazed that not only did the device create blood stem cell precursors that went on to produce differentiated blood cells, but it also created the tissue cells of the embryonic heart environment that is crucial to this process.

The thing that just wows me about this is that blood stem cells, when they form in the embryo, form in the wall of the main vessel called the aorta. And they basically pop out of this aorta and go into the circulation, and then go to the liver and form whats called definitive hematopoiesis, or definitive blood formation.

Getting an aorta to form and then the cells actually emerging from that aorta into the circulation, that is the crucial step required for generating these cells.

What weve shown is that we can generate a cell that can form all the different types of blood cells. Weve also shown that it is very closely related to the cells lining the aorta so we know its origin is correct and that it proliferates, A/Prof. Nordon said.

The researchers are cautiously optimistic about their achievement in emulating embryonic heart conditions with a mechanical device. They hope it could be a step towards solving challenges limiting regenerative medical treatments today: donor blood stem cell shortages, rejection of donor tissue cells, and the ethical issues surrounding the use of IVF embryos.

Blood stem cells used in transplantation require donors with the same tissue type as the patient, A/Prof. Nordon said.

Manufacture of blood stem cells from pluripotent stem cell lines would solve this problem without the need for tissue-matched donors providing a plentiful supply to treat blood cancers or genetic disease.

Dr. Li added: We are working on up-scaling manufacture of these cells using bioreactors.

Meanwhile, and working independently of Dr. Li and A/Prof. Nordon, UNSW Medicine & Healths Professor John Pimanda and Dr. Vashe Chandrakanthan were doing their own research into how blood stem cells are created in embryos.

In their study of mice, the researchers looked for the mechanism that is used naturally in mammals to make blood stem cells from the cells that line blood vessels, known as endothelial cells.

It was already known that this process takes place in mammalian embryos where endothelial cells that line the aorta change into blood cells during hematopoiesis, Prof. Pimanda said.

But the identity of the cells that regulate this process had up until now been a mystery.

In their paper, Prof. Pimanda and Dr. Chandrakanthan described how they solved this puzzle by identifying the cells in the embryo that can convert both embryonic and adult endothelial cells into blood cells. The cells known as Mesp1-derived PDGFRA+ stromal cells reside underneath the aorta, and only surround the aorta in a very narrow window during embryonic development.

Dr. Chandrakanthan said that knowing the identity of these cells provides medical researchers with clues on how mammalian adult endothelial cells could be triggered to create blood stem cells something they are normally unable to do.

Our research showed that when endothelial cells from the embryo or the adult are mixed with Mesp1 derived PDGFRA+ stromal cells they start making blood stem cells, he said.

While more research is needed before this can be translated into clinical practice including confirming the results in human cells the discovery could provide a potential new tool to generate engraftable hematopoietic cells.

Using your own cells to generate blood stem cells could eliminate the need for donor blood transfusions or stem cell transplantation. Unlocking mechanisms used by Nature brings us a step closer to achieving this goal, Prof. Pimanda said.

References:

Mimicry of embryonic circulation enhances the hoxa hemogenic niche and human blood development by Jingjing Li, Osmond Lao, Freya F. Bruveris, Liyuan Wang, Kajal Chaudry, Ziqi Yang, Nona Farbehi, Elizabeth S. Ng, Edouard G. Stanley, Richard P. Harvey, Andrew G. Elefanty and Robert E. Nordon, 13 September 2022, Cell Reports. DOI: 10.1016/j.celrep.2022.111339

Mesoderm-derived PDGFRA+ cells regulate the emergence of hematopoietic stem cells in the dorsal aorta by Vashe Chandrakanthan, Prunella Rorimpandey, Fabio Zanini, Diego Chacon, Jake Olivier, Swapna Joshi, Young Chan Kang, Kathy Knezevic, Yizhou Huang, Qiao Qiao, Rema A. Oliver, Ashwin Unnikrishnan, Daniel R. Carter, Brendan Lee, Chris Brownlee, Carl Power, Robert Brink, Simon Mendez-Ferrer, Grigori Enikolopov, William Walsh, Berthold Gttgens, Samir Taoudi, Dominik Beck and John E. Pimanda, 28 July 2022, Nature Cell Biology. DOI: 10.1038/s41556-022-00955-3

Funding: National Health and Medical Research Council, Stem Cells Australia, Stafford Fox Medical Research Foundation, Novo Nordisk

See original here:
This Blood Stem Cell Research Could Change Medicine of the Future - SciTechDaily

Creating stem cells from minipigs offers promise for improved treatments – University of Wisconsin-Madison

By Stell Cell Research

A breed of pigs called Wisconsin Miniature Swine created by a team of UWMadison scientists will help researchers better model and understand human diseases. Photo: Jeff Miller

Cells from miniature pigs are paving the way for improved stem cell therapies.

A team led by University of WisconsinMadison Stem Cell & Regenerative Medicine Center researcher Wan-Ju Li offers an improved way to create a particularly valuable type of stem cell in pigs a cell that could speed the way to treatments that restore damaged tissues for conditions from osteoarthritis to heart disease in human patients.

In a study published in Scientific Reports, Lis team also provides insights into the reprogramming process that turns cells from one part of the body into pluripotent stem cells, a type of building block cell that can transform into any type of tissue. These new insights will help researchers study treatments for a wide range of diseases.

The researchers turned to pigs, a well-established animal model for potential human treatments, because translating research to improve human health is deeply important to Li, a professor of Orthopedics and Rehabilitation and Biomedical Engineering. He has spent much of his career studying cartilage and bone regeneration to develop innovative therapies to help people.

Li and members of his Musculoskeletal Biology and Regenerative Medicine Laboratory obtained skin cells from the ears of three different breeds of miniature pigs Wisconsin miniature swine, Yucatan miniature swine and Gttingen minipigs.

University of WisconsinMadison Stem Cell & Regenerative Medicine Center researcher Wan-Ju Li (left) shows a collagen fiber sample to Gwen Plunkett and Karen Plunkett. Funding from the Plunkett Family Foundation has contributed to research on cartilage repair therapies in UWMadisons Musculoskeletal Research Program.

The researchers reprogrammed the cells to create induced pluripotent stem cells and demonstrated that they have the capacity to become different types of tissue cells. Pluripotent stem cells are the bodys master cells, and they are invaluable to medicine since they can be used for the regeneration or repair of damaged tissues.

Findings of this study suggest that the miniature pig is a promising animal model for pre-clinical research. The team plans to use the established pig model to reproduce their recent findings of cartilage regeneration in rats as reported in Science Advances. Regenerating cartilage in animals even more alike to humans moves science one step closer to helping patients experiencing joint diseases such as osteoarthritis.

In successfully developing induced pluripotent stem cells from three different breeds of minipigs, we learned we can take somatic skin cells from these pigs that we programmed ourselves and then inject them back into the same animal to repair cartilage defects, says Li. Or we can create induced pluripotent stem cells from the skin cell that carried the gene causing cartilage diseases such as chondrodysplasia and put that into the culture dish and use that as a disease model to study disease formation.

Li says the approach can be applied to regenerative therapies targeting any organ or tissue.

The team also found that a particular protein complex involved in managing the way genes are expressed, and tied to cellular growth and survival, could influence how efficiently induced pluripotent stem cells are generated. While we successfully created induced pluripotent stem cells from the three different strains of pig, we noticed that some pigs had a higher reprogramming efficiency, says Li. So, the second part of our findings, which is significant in biology, is understanding how these differences occur and why.

These findings, he says, may directly translate to understanding differences in the effectiveness of induced pluripotent stem cell generation between individual people one study has shown cellular reprogramming efficiency varying by age and ancestry and lead to better tailored therapies.

I want to make sure that our findings in stem cell research can be used to help people, says Li. I just feel this internal drive to study this area and I feel good knowing this model carries significant weight in terms of its potential for translational stem cell research and the development of therapeutic treatments.

Interest in moving these treatments forward has grown, and while the study was funded in part by the National Institutes of Health, Li also received support from the Milwaukee-based Plunkett Family Foundation through their donation to the UW Stem Cell & Regenerative Medicine Center. After hearing of Lis research, Gwen Plunkett and her daughter Karen visited Lis lab in 2019 to learn more. They were inspired to support research into stem cells for cartilage regeneration.

Innovation in medicine sparks critical change, for the world and the survival of our species, and the Plunkett Family mission is to be a catalyst in stem cell and regenerative medicine research, says Karen Plunkett.

The donation was profoundly impactful, says Li, allowed him to further his goal of using stem cells to help patients living with osteoarthritis and other joint diseases many of whom write his lab regularly in hope of finding a clinical trial opportunity.

I have to keep saying, Wait for another two, three years, maybe well be ready for a clinical trial, Li says. But for me, its time to move on and really do our larger animal studies to fulfill our promise. At least that way, I can fill the gap between the lab and clinical trials as the larger animals must be studied before you go into a clinical trial.

This research was supported by grants from the National Institutes of Health (R01 AR064803), the Plunkett Family Foundation and UW Carbon Cancer Center.

See the original post here:
Creating stem cells from minipigs offers promise for improved treatments - University of Wisconsin-Madison

Stem Cell Therapy Market worth $558 million by 2027 Exclusive Report by MarketsandMarkets – GlobeNewswire

By Stell Cell Research

Chicago, Sept. 14, 2022 (GLOBE NEWSWIRE) -- Stem Cell Therapy Marketis projected to reach USD 558 million by 2027 from USD 257 million in 2022, at a CAGR of 16.8% during the forecast period, according to a new report by MarketsandMarkets. Key drivers of the stem cell therapy market include increase in stem cell research funding, expanding number of clinical trials related to stem cell therapies, and growing number of GMP-certified cell therapy production facilities. However, high costs associated with the development of stem cell therapy along with the ethical concerns related to embryonic stem cells are likely to hamper the market growth to a certain extent.

Download PDF Brochure: https://www.marketsandmarkets.com/pdfdownloadNew.asp?id=48

Browse in-depth TOC on "Stem Cell Therapy Market 155 Tables 43 Figures 166 Pages

The adipose tissue-derived MSCs segment dominates the cell source market in the stem cell therapy through 2020-2027.

The global stem cell therapy market is segmented into adipose tissue-derived MSCs (mesenchymal stem cells), bone marrow-derived MSCs, placenta/umbilical cord-derived MSCs, and other cell sources. Adipose-derived stem cell tissues can be obtained easily and also possess a variety of the regenerative properties similar to other mesenchymal stem cells/tissues. These cells are multipotent and are easy to isolate & harvest; these qualities have collectively rendered the adipose tissue-derived MSCs segment highest revenue in 2021.

In 2021, the musculoskeletal disorders ranked first in terms of revenue in the stem cell therapy market.

Based on therapeutic application, the global stem cell therapy market is segmented into musculoskeletal disorders, wounds & injuries, cardiovascular diseases, surgeries, inflammatory & autoimmune diseases, neurological disorders, and other therapeutic applications. In 2021, the musculoskeletal disorders application segment accounted for the largest share of the stem cell therapy market. Increasing market availability of stem cell-based therapeutic products across major markets and the growing patient preference for effective & early treatment strategies are driving the growth of this segment.

Request Sample Pages: https://www.marketsandmarkets.com/requestsampleNew.asp?id=48

The Asia Pacific region is the fastest-growing region of the stem cell therapy market in 2021.

The Asia Pacific region is estimated to grow at the highest CAGR in the stem cell therapy market during the forecast period. Japan and South Korea are the key revenue contributors of the Asia Pacific stem cell therapy market. Favorable government support for product approvals and the presence of major players in these countries are anticipated to drive the regional market growth.

The stem cell therapy market is consolidated in nature with prominent players in the stem cell therapy market include Smith+Nephew (UK), MEDIPOST Co., Ltd. (South Korea), Anterogen Co., Ltd. (South Korea), CORESTEM (South Korea), Pharmicell Co., Ltd. (South Korea), NuVasive, Inc. (US), RTI Surgical (US), AlloSource (US), JCR Pharmaceuticals Co., Ltd. (Japan), Takeda Pharmaceutical Company Limited (Japan), Holostem Terapie Avanzate Srl (Italy), Orthofix (US), Regrow Biosciences Pvt Ltd. (India), and STEMPEUTICS RESEARCH PVT LTD. (India).

Get 10% Free Customization on this Report: https://www.marketsandmarkets.com/requestCustomizationNew.asp?id=48

Related Reports:

Stem Cell Manufacturing Market by Product (Consumables, Instrument, HSCs, MSCs, iPSCs, ESCs), Application (Research, Clinical (Autologous, Allogenic), Cell & Tissue Banking), End User (Pharma & Biotech, Hospitals, Tissue Bank) - Global Forecast to 2026

Read more here:
Stem Cell Therapy Market worth $558 million by 2027 Exclusive Report by MarketsandMarkets - GlobeNewswire

Tanya Dorff, MD, Speaks to the Development of CAR T-Cell Therapy in Prostate Cancer – Cancer Network

By Stell Cell Research

At 2022 ASCO, Tanya Dorff, MD, reviewed the use of CAR T cells in the treatment of prostate cancer.

CAR T cells are typically used in the treatment of hematologic malignancies, but recent studies have shown they may also be used to combat prostate cancer. A recent panel discussion by Tanya Dorff, MD, from the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting shed light on this potential addition to the prostate cancer treatment paradigm.

Several trials are underway assessing the use CAR T cells targeted to prostate-specific membrane antigen (PSMA), prostate stem cell antigen (PSCA), and KLK2. Dorff emphasized the importance of educating oncologists who treat solid malignancies to identify adverse effects and mechanisms associated with CAR T-cell therapies that those specializing in hematologic malignancies may be more familiar with.

A big part of our education focus was just to help familiarize solid tumor oncologists with things like cytokine release syndrome and macrophage activation and the ways these present and how to manage them. Thats the long-term implementation of making sure the community is educated as a whole so these treatments can be widely accessed, Dorff, an associate professor in the Department of Medical oncology and Therapeutics Research, and section chief of the Genitourinary Disease Program at City of Hope, said in an interview with CancerNetwork.

Dorff also discussed highlights in prostate cancer from the 2022 ASCO Annual Meeting, including the use potential treatment intensification with triplet regimens up front and the efficacy of 177Lu-PSMA-617 in metastatic castration-resistant prostate cancer.

Dorff: I was part of an educational session discussing CAR T-cell therapy and bispecific T-cell engaging therapy for advanced prostate cancer. It was a case-based approach helping oncologists get a sense of how these treatments that are traditionally used in hematologic malignancies are being studied in prostate cancer, what to expect from them, how things are going, what kind of results were seeing, and where were going next with the field.

We have a long way to go to get CAR T-cell therapy into practice for prostate cancer, but weve been excited that even within the first handful of patients treated on the various trials, we are seeing responses. At the 2022 ASCO Genitourinary Symposium (ASCO GU), a poster was presented for POSEIDAs PSMA CAR T product by Susan F. Slovin, MD, PhD, of Memorial Sloan Kettering,1 showing this beautiful response in a patient and a fairly robust PSA [prostate specific antigen] response waterfall from that early experience with the CAR T-cell [study. Findings using] our PSCA-targeted CAR T from City of Hope that our scientists have developed and we produce here were also presented a ASCO GU showing, again, a robust response early on. However, the toxicity was considerable.2 Were just learning what the [adverse] effect [AE] profile will look like in [patients with] prostate cancer vs hematologic malignancies. Taking a step back, were still sorting out optimal dosing and whether were going to need adjunctive strategies or multiple doses to get a higher rate of nice, durable remissions with these therapies.

Multiple trials are open and accruing. We have 3 of them open here at City of Hope, 1 with our own PSCA-targeted CAR T-cell product. Were just finishing up phase 1 study and expect to open the phase 1b study later this summer where were going to be testing multiple dosing and radiation prior to CAR T-cell administration, which in the lab seems to augment responsiveness; a good number of patients already have been treated. The PSMA targeted CAR T from POSEIDA is still accruing. Weve treated 7 [patients] here. Its a multi-site study, so there are many other sites that have treated patients as well, and thats still ongoing. Then there's the KLK2 targeted CAR T-cell study [NCT04898634] from Janssen. Thats a little earlier along but theyve treated a fair number of patients at this point; its a multicenter study. This is already a reality in terms of clinical trials, but still far from practice.

There are 2 big topics that came out of ASCO for prostate cancer this year. One was the up-front intensification study using triplet combinations where were not only adding chemotherapy up front or an androgen targeted agent like abiraterone [Yonsa], enzalutamide [Xtandi], apalutamide [Erleda], or darolutamide [Nubeqa], but using all the above. The important message to get out is for community oncologists and urologists to act on this and implement this in their own practices. Newly diagnosed [patients with] metastatic prostate cancer should not get just castration monotherapy. They will benefit tremendously from having up-front intensification with either doublet or in some cases triplet therapy.

The other big story is the 177Lu-PSMA-617 which was recently approved by the FDA based on the [phase 3] VISION trial [NCT03511664].3 Theres a lot of information coming out at some of these meetings about differences between the VISION trial and the [phase 2] TheraP trial [NCT03392428], in which the control arm was cabazitaxel [Jevtana], which helps us benchmark the efficacy and start to think about sequencing. Also, what PSMA PET characteristics might help us optimally select patients for this treatment, because the criteria have been different [across] trials. There has been all kinds of practical and helpful information presented at ASCO and a lot of buzz and talking among attendees about those topics.

More:
Tanya Dorff, MD, Speaks to the Development of CAR T-Cell Therapy in Prostate Cancer - Cancer Network

What may have given modern humans an edge over Neanderthals, according to new research – kuna noticias y kuna radio

By Stell Cell Research

By Katie Hunt, CNN

From studying fossilized skulls, scientists know that the size of a Neanderthals brain was the same as, if not slightly bigger than, that of a modern human. However, researchers have known little about Neanderthal brain development because soft tissue doesnt preserve well in the fossil record.

Now, an intriguing study released September 8 has revealed a potential difference that may have given modern humans, or Homo sapiens, a cognitive advantage over the Neanderthals, the Stone Age hominins who lived in Europe and parts of Asia before going extinct about 40,000 years ago.

Scientists at the Max Planck Institute of Molecular Cell Biology and Genetics in Dresden, Germany, said they have identified a genetic mutation that triggered the faster creation of neurons in the Homo sapiens brain. The Neanderthal variant of the gene in question, known as TKTL1, differs from the modern human variant by one amino acid.

Weve identified a gene that contributes to making us human, said study author Wieland Huttner, professor and director emeritus at the institute.

When the two versions of the gene were inserted into mice embryos, the research team found that the modern human variant of the gene resulted in an increase in a specific type of cell that creates neurons in the neocortex region of the brain. The scientists also tested the two gene variants in ferret embryos and lab-grown brain tissue made from human stem cells, called organoids, with similar results.

The team reasoned that this ability to produce more neurons likely gave Homo sapiens a cognitive edge unrelated to overall brain size, suggesting that modern humans have more neocortex to work with than the ancient Neanderthal did, according to the study published in the journal Science.

This shows us that even though we do not know how many neurons the Neanderthal brain had, we can assume that modern humans have more neurons in the frontal lobe of the brain, where TKTL1 activity is highest, than Neanderthals, Huttner explained.

There has been a discussion whether or not the frontal lobe of Neanderthals was as large as that of modern humans, he added.

But we dont need to care because (from this research) we know that modern humans must have had more neurons in the frontal lobe and we think that that is an advantage for cognitive abilities.

Alysson Muotri, professor and director of the Stem Cell Program and Archealization Center at the University of California San Diego, said while the animal experiments revealed quite a dramatic difference in neuron production, the difference was more subtle in the organoids. He was not involved in the research.

This was only done in one cell line, and since we have huge variability with this protocol of brain organoids, it would be ideal to repeat the experiments with a second cell line, he said via email.

It was also possible the archaic version of the TKTL1 gene was not unique to Neanderthals, Muotri noted. Most genomic databases have focused on Western Europeans, and its possible human populations in other parts of the world might share the Neanderthal version of that gene.

I think it is quite premature to suggest differences between Neanderthal and modern human cognition, he said.

Archaeological finds in recent years have suggested that Neanderthals were more sophisticated than pop culture depictions of brutish cavemen might suggest. Our ancient relatives knew how to survive in cold and warm climates and used complex tools. They also made yarn, swam and created art.

Study coauthor and geneticist Svante Pbo, director of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, pioneered efforts to extract, sequence and analyze ancient DNA from Neanderthal bones.

His work led to the discovery in 2010 that early humans interbred with Neanderthals. Scientists have subsequently compared the Neanderthal genome with the genetic records of living humans today to see how our genes overlap and differ: TKTL1 is just one of dozens of identified genetic differences, while some shared genes may have implications for human health.

The-CNN-Wire & 2022 Cable News Network, Inc., a Warner Bros. Discovery Company. All rights reserved.

See the original post:
What may have given modern humans an edge over Neanderthals, according to new research - kuna noticias y kuna radio

Comparison of the Efficacy of Platelet-Rich Plasma (PRP) and Local Corticosteroid Injection in Periarthritis Shoulder: A Prospective, Randomized,…

By Platelet Rich Plasma Injections

Background

Periarthritis or frozen shoulder, also called adhesive capsulitis, is characterized by stiffness and pain along with gradual loss of active and passive movement in the glenohumeral joint. More than 2-5% of the population suffers from periarthritis with a higher incidence in the age group of 40-60 years. The various treatment modalities used for its management include simple physiotherapy, short-wave therapy, ultrasonic therapy, transcutaneous electrical nerve stimulation, hydrotherapy, analgesics, intra-articular injections, manipulation under general anesthesia (MUA), and surgical management. The application of intra-articular steroid injection has been a common and efficacious option in rapidly diminishing shoulder pain and disability. Some recent studies reported a better outcome using platelet-rich plasma (PRP) injections in frozen shoulder cases. Hence, this randomized controlled trial was conducted to compare the efficacy of intra-articular injections of PRP and triamcinolone in patients of shoulder periarthritis in a population from the eastern region of India

A total of 60 patients with periarthritis shoulder were allocated into two groups after randomization. Group A received 2 mL autologous PRP, and Group B received 2 mL of triamcinolone (40 mg/mL) intra-articular injection. Patients were followed up on the 4thweek, 12thweek, and 24thweek. The assessment of pain and function using the visual analog scale (VAS) score and the Disabilities of Arm, Shoulder, and Hand (DASH) score, respectively, was done at each follow-up. The primary analyses of both primary and secondary outcomes were conducted in the intention-to-treat (ITT) population. SPSS version 24 (IBM Corp., Armonk, NY, USA) was used for data analysis.

The mean VAS score in the PRP and triamcinolone groups was 14.33 3.79 and 31.63 7.62, respectively (p = 0.0001) after 24 weeks. The mean DASH score in the PRP and triamcinolone groups was 18.08 8.08 and 31.76 3.63, respectively (p = 0.0001), which shows significant improvement in both pain and disability scores in the PRP group after 24 weeks.

The triamcinolone group showed better short-term outcomes whereas PRP showed better long-term outcomes in reducing pain and disability scores in terms of VAS and DASH scores.

Periarthritis of the shoulder is characterized by functional loss of passive and active shoulder motion. This condition was termed by Duplay in 1896 and later substituted by the term frozen shoulder by Codman in 1932. Subsequently, Nevaiser introduced the term adhesive capsulitis [1]. This disorder is defined by the American Shoulder and Elbow Surgeons as a condition of significant restriction of both active and passive motion of the shoulder joints because of an unknown etiology that occurs without an intrinsic shoulder disorder [2].

The definite pathophysiology of periarthritis remains unclear. The progressive fibrosis causing the contracture of the glenohumeral joint capsule results in pain and stiffness [3]. Periarthritis can be primary or secondary. The primary (or idiopathic) type occurs without any known trauma or provoking event. The secondary type is often observed after periarticular trauma, fracture, or dislocation of the glenohumeral joint [4].

According to recent studies, the incidence of periarthritis is 2-5% in the general population [5,6]. The affected population includes 70% females. The idiopathic type often involves the non-dominant extremity, while 40-50% of cases have been reported as bilateral involvement. Regardless of the etiology, the condition is more prevalent in the 40-60-year age group [4,7]. The risk factors for developing periarthritis include diabetes. Patients with type I diabetes have a 40% chance of developing periarthritis. Up to 29% of individuals with type II diabetes may develop this condition. Thyroid disease, Parkinsons disease, cardiac disease, autoimmune disease, chronic obstructive pulmonary disorder, and myocardial infarction are also linked with increased incidence of periarthritis or adhesive capsulitis [3,8].

In most cases, periarthritis resolves spontaneously or it can last for up to three years [9]. Various treatment approaches have been used and explored to treat this disorder. Physical therapy individually or in combination with short-wave therapy, ultrasonic therapy, transcutaneous electrical nerve stimulation, and hydrotherapy is used [10]. Pharmacological treatment includes the use of analgesic or non-steroidal anti-inflammatory drugs, oral or intra-articular use of corticosteroids, and sodium hyaluronate injections. Other approaches to treat periarthritis include manipulation under anesthesia (MUA), dilation or distension of the capsule, and arthroscopic or open capsular release (arthroscopic capsulotomy) [3,4,11].

Platelet-rich plasma (PRP) is an emerging entity in the field of tissue engineering and regenerative medicine due to its availability, affordability, and minimally invasive procedure. Its autologous nature prevents an immunological reaction and offers good therapeutic safety. Recently, evidence in immune-mediated disorders and inflammatory processes has garnered attention due to their anti-inflammatory effects through the inhibition of nuclear factor kappa B signaling in target cells and by tissue inhibitor of matrix metalloproteinase. The creation and remodeling of the extracellular matrix also encompass a function of platelet growth factors which further supports this treatment modality [12]. The application of intra-articular steroid injection has been a common and efficacious option in rapidly diminishing shoulder pain and disability [5]. Some recent studies show a better outcome using PRP injections in frozen shoulder cases [13]. A systemic review and meta-analysis by Sun et al. described that patients taking a single steroid injection for a frozen shoulder is effective and safe and improves functional outcomes and pain scores [14].

Corticosteroid injections have been associated with prominent side effects, which have led to the conception of modalities such as PRP. This randomized trial aimed to evaluate and compare the efficacy of intra-articular injections of PRP and steroid (triamcinolone) in periarthritis. We hypothesized that PRP would prove more effective in relieving pain and improving function. Several studies have reported comparative analyses of steroids and PRP. Most of these were conducted outside India. Studies by Upadhyay et al. [15], Kothari et al. [16], and Kumar et al. [17] reported the effect of PRP versus steroids in periarthritis in the Indian population. One study from the eastern part of India with a similar intervention was conducted by Barman et al. [18], but the follow-up period was only 12 weeks. Hence, this study was conducted to analyze the comparative efficacy of PRP versus steroids in periarthritis with a follow-up duration of 24 weeks in a population from the eastern region of India.

This study was a parallel-group, prospective, randomized, open, blinded end-point (PROBE), single-center clinical study. Randomization was done in permuted blocks of varying sizes (2, 4, 6) using a sealed envelope website (computer-generated)[19]. There was central randomization, and the person doing randomization was not part of the study. The investigator assigning intervention telephonically contacted the randomizer on the recruitment of every new patient regarding the group to which the patient was assigned. Another investigator (other than the one assigning intervention) assessed the outcomes of the patients without any knowledge of the study group to which the patient belonged to. Patients were recruited to different treatment regimens following proper randomization. Unlike double-blind studies, the treatment regimens were recognizable to both physicians and patients. The trial was conducted according to the principles of the Consolidated Standards of Reporting Trials (CONSORT).

The study was conducted from December 2020 to December 2021 at the Department of Orthopaedics, Rajendra Institute of Medical Sciences (RIMS), Ranchi Jharkhand, India. Ethical approval was obtained (vide reference number: 123, dated November 23, 2020) from the Institutional Ethical Committee of RIMS, Ranchi.

A total of 60 patients from the outpatient department (OPD), Department of Orthopedics, RIMS who were clinically diagnosed to have periarthritis shoulder and willing to participate were randomized into two groups. A written informed consent regarding participation was obtained before recruitment. The complete procedure of the study was explained to all participants in their language by the investigator before recruitment. The inclusion and exclusion criteria are presented in Table1and Table2, respectively.

The sample size was calculated by OpenEpi, Version 3, an open-source calculator based on the findings of the study by Kothari et al., in which the mean VAS score for PRP and steroid group were reported [16]. The calculated sample size was 29 for each group (Table 3). Rounding off to the nearest, the total sample size was finally set as 60 (30 per group).

All information about the history, clinical features, examination findings, and treatment (if any were taken before) were recorded in a predesigned proforma. All patients were subjected to routine blood investigation and radiographic examinations of the cervical spine and ipsilateral shoulder under study.

Before administrating the injection, povidone-iodine and ethyl alcohol were applied to the skin. One milliliter of 2% lignocaine with adrenaline was injected at the injection site after administering the test dose. After 10 minutes, the proposed injection was injected. If any resistance was felt during the injection, the needle was withdrawn slightly and again injected.

The first group of patients was administered 2 mL of triamcinolone (40 mg/mL). The second group was given 2 mL autologous PRP. To prepare PRP, about 15 mL of the patients blood was drawn through a scalp vein catheter. The PRP was prepared using a differential centrifugation technique with two spins. The blood was collected in three citrate tubes having 0.9% sodium citrate as an anticoagulant. The first spin was performed at 1,500 rpm for 15 minutes using a laboratory centrifuge. This spin separated the red blood cells from the rest of the components. The upper half of the supernatant was discarded. The lower halves of the supernatant from all three tubes were transferred into another plain tube for the second spin. The second spin was performed at 2,500 rpm for 10 minutes. The upper half of the supernatant was discarded. Three milliliters of the lower half was taken into a syringe having 0.1 mL of calcium chloride. At the end of the preparation of PRP, 1 mL of obtained PRP (as a sample) was sent for platelet count, and the count was compared with the patients platelet count. Another 2 mL was used for intra-articular injection. The platelet count in the PRP preparation was 860,000 74,500 platelets per mm3which were 4.2 1.37 times higher than whole blood values. In our study, we injected freshly prepared PRP (within 30 minutes of preparation), as a study by Blajchman [20] reported that platelets may alter the shape and reduce the functional properties, including the degranulation of -granules due to prolonged storage.

All patients were advised regarding post-injection care. The possibility of pain increasing during the initial two weeks was explained to the patient. Post-injection, patients were prescribed paracetamol (650 mg BD orally for five days) for pain relief in both groups. Patients were advised to rest during the initial two weeks and avoid strenuous activities by the extremity under study after the injection. Physiotherapy was advised for both groups. Bilateral cases were injected simultaneously, and the post-injection protocol was the same.

After inclusion in the study, demographic data, baseline clinical findings, duration of pain, dominancy of the affected side, and associated comorbidities were recorded. Any relevant X-ray findings were noted. Special investigations were performed as per comorbidity present in a case. The follow-ups were done in the 4th week, 12th week, and 24th week for all patients of both groups. The assessment of pain and function through the VAS and the Disabilities of Arm, Shoulder, and Hand (DASH) score, respectively, was done at each follow-up. Any adverse effects were noted and reported. All data were documented in case report form (CRF) designed for the project and in Excel sheets for analysis.

The primary outcome of the study was the pain reduction assessed using the VAS after the injections. The DASH scores were assessed as a secondary outcome.

The primary analyses of both primary and secondary outcomes were conducted in the intention-to-treat (ITT) population (i.e., all randomized participants for whom consent was given to use data). SPSS version 24 (IBM Corp., Armonk, NY, USA) was used for data analysis. The data with categorical variables were expressed as numbers and percentages, while the continuous variables were expressed as the mean standard deviation (SD). An unpaired t-test was used for analyzing continuous variables inthe intergroup analysis. The Fishers exact test and Pearsons chi-square test were used for analyzing categorical variables. P-values of <0.05 were considered to be significant.

A total of 60 patients were recruited for the study and randomized equally into two groups. One patient from the PRP group and two patients from the triamcinolone group did not come for the last follow-up (24 weeks). However, analyses were done for a total of 60 patients as per the ITT analysis protocol (See Figure 1).

The demographic data presented in Table4 reveals that both groups were similar in characteristics.There was no significant difference between both groups in the baseline characteristics, e.g., age, gender, the dominance of the affected side, duration of symptoms, and presence of diabetes mellitus. This revealed that patient variability was not present between both groups. Moreover, the inclusion and exclusion criteria were followed strictly during patient recruitment and randomization. Therefore, the possibility of patient variability in the study groups was negligible.

The patients with frozen shoulders were aged from 33 to 67 years. The incidence of the disease was higher in the fifth decade of life (46.67%). The mean age of the patients was 47.25 8.38 years (in triamcinolone and PRP treatment groups). The incidence of the disease was higher in females (58.33%) compared to males (41.67%). In the triamcinolone group, there were 56.67% females, while in the PRP group, there were 60% females.

Among 60 patients, 30 received prolotherapy (PRP injection) and 30 received triamcinolone injection for frozen shoulder. Table 5 represents the outcome analysis of both groups. In the first follow-up (four weeks), the mean VAS score in the triamcinolone group was 46.27 8.17 while it was in 51.70 6.02 in the PRP group. This significantly shows better improvement of pain with triamcinolone injection (p = 0.0048).

In the second follow-up (12 weeks), the mean VAS score in the PRP group was 43.23 4.01 while it was 31.83 10.31 in the triamcinolone group. This significantly showed better improvement of pain with triamcinolone injection (p = 0.0001) after 12 weeks. However, in the third follow-up (24 weeks), the mean VAS score in the PRP and triamcinolone groups was 14.33 3.79 and 31.63 7.62, respectively, which showed a significantly better improvement in the VAS score in the PRP group (p = 0.0001).

For DASH scores (see Table 5), after four weeks of injection, the triamcinolone group shows somewhat better improvement, although there was no significant difference in both groups (p = 0.069). After 12 weeks of injection, the PRP group showed somewhat better improvement, although no significant difference was found between the groups (p = 0.075). At the third follow-up (24 weeks), the mean DASH score in the PRP and triamcinolone groups was 18.08 8.08 and 31.76 3.63, respectively, which showed significant improvement in the DASH score in the PRP group (p = 0.0001).

Frozen shoulder or shoulder periarthritis is the most common cause of the gradual onset of pain and stiffness with loss of active and passive movement of the glenohumeral joint[16]. Various treatment modalities are used for the management of periarthritis, e.g., physiotherapy, intra-articular injections, oral and injectable corticosteroids, MUA, hydrodilation, and surgery[1,21]. Triamcinolone is a long-acting steroid with anti-fibrotic and anti-inflammatory properties[17]. This study compares the effect of intra-articular injections of triamcinolone versus PRP.

In this study, 60 patients with shoulder periarthritis with ages ranging from 33 to 67 years were included. The incidence of the disease was higher in the fifth decade of life (46.67%). The result was similar to previous studies[16,22]. The mean ageof the patients included in the study was 47.25 8.38 years. The prevalence rate of frozen shoulder is expected to be 2-5% of the population, with the peak occurrence in persons aged 40-60 years [11,23]. Our study reported a higher incidence(46.67%) of the diseasein the fifth decade of life.

Our study reported that periarthritis mostly occurred in female patients than males, which is similar to a previous study[7]. The side of the joint affected by periarthritis was higher on the non-dominant side. A total of 38 (63.33%) patients had affected joints by periarthritis on the non-dominant side. Moreover, the majority of the studies showed a higher prevalence rate on the non-dominant side[24]. About 45% of patients with periarthritis had diabetes mellitus as comorbidity, while 8.33% of patients had hypertension.

In our study, we assessed the VAS and DASH scores at baseline, 4th,12th, and 24th weeks. We found that the VAS score showed significant improvement in the triamcinolone group (p = 0.0048 and p = 0.0001, respectively) than in the PRP group at four and 12 weeks. The DASH score was reduced in both groups in the 4th week (p = 0.0699)and 12th week (p = 0.0752), but the improvement was statistically not significant. However, in a study by Barman et al., there was no significant difference at the end of three weeks after a single dose of PRP injection or steroid injection. However, PRP was found to be more effective than corticosteroid injection at 12 weeks in pain and disability score improvement[18].

At 24 weeks, both the VAS and DASH scores showed significant improvement in the PRP group to the triamcinolone group (p = 0.0001). Our result was similar to previous studies by Kothari et al. and Kumar et al. that assessed triamcinolone and PRP[16,17]. A case study by Aslani et al. in 2016 also reported good results with PRP in the frozen shoulder[25]. Evidence of PRP administration in periarthritis is continuously emerging[26,27]. In their systematic review, Griesser et al. reported that the use of steroidssignificantly improved theforward elevation and abductiontemporarily, as well as short-term and long-term pain reduction assessed through the Shoulder Pain and Disability Index (SPADI) and VAS scores[23]. Our study has added support to this growing technique.

The study showed that at the 12th week, both the steroid and PRP groups improved the VAS and DASH scores. However, the steroid group had a better outcome in the 12th week, while in the 24th week, the PRP group showed better outcomes.

Various studies have reported that the effect of steroids gradually decreases over a long-term follow-up. Blanchard et al. [28] compared the steroid injections and physiotherapeutic interventions for adhesive capsulitis and reported a good efficacy of corticosteroid injections in the short term (six weeks) and, to a lower magnitude, in the longer term (one year). Another study by Shah and Lewis [6] found that corticosteroid injections in adhesive capsulitis improved pain and range of motion for 6-16 weeks after the first injection. A systematic review that included 12 randomized controlled trials on using corticosteroids in adhesive capsulitis reported that the intervention was beneficial, although its effect was small and not well maintained [29]. It has been suggested that the efficacy of corticosteroids on periarthritis is exerted through anti-inflammatory properties and suppressing the granulomatous response in affected tissue which leads to clinical improvement.

In contrast, a study reported that PRP releases a pool of several growth factors (transforming growth factor-, platelet-derived growth factor, vascular and epidermal endothelial growth factor) which helps in tissue repair[18]. PRP also releases hepatocyte growth factor and tumor necrosis factor-alpha, which possess potent anti-inflammatory effects [30] In this study, long-term improvements in the PRP group could be explained by the fact that PRP might have effects on improving all phases of tissue repair, e.g., inflammatory, proliferative, and remodeling phases of capsular healing in periarthritis [18]. Based on the above discussion, it can be concluded that the effect of steroid injections lasts for a shorter period, while PRP injections might have a longer effect.

In this study, the standardized techniquefor PRP preparation was used and comparisons were done with the conventionally used treatment. The actual platelet count in obtained PRP was compared to the whole blood or baseline platelet count. All intra-articular injections were administered by a single experienced clinician.Evaluation of pain and disability outcomes was done at several time points over up to 24 weeks for high-quality evidence of the effect of PRP and corticosteroid injections. Despite the carefully designed protocol for the study, there are some limitations to this study. The study did not explore cost analysis. All stages of periarthritis were included in our study; therefore, further studies are needed to compare the effect of these interventions in different stages of periarthritis. This study was conducted on single injections of steroids and PRP as most of the studies on periarthritis were based on single intra-articular injections [29]. Moreover, this is a standard protocol followed in the institution and approved by the ethical committee. Studies exploring the effect of multiple injections need to be conducted in the future.

Intra-articular injections of PRP and triamcinolone for periarthritis are effective in reducing pain and disability scores in terms of VAS and DASH scores. The triamcinolone group showed a better effect in short-term outcomes (12th-week analysis) whereas PRP showed better results in long-term outcomes (24th-week analysis). A large sample size study to enhance the power of the study with robust design must be conducted in the future that compares single versus multiple injections as well as both steroid and PRP injections simultaneously.

Go here to see the original:
Comparison of the Efficacy of Platelet-Rich Plasma (PRP) and Local Corticosteroid Injection in Periarthritis Shoulder: A Prospective, Randomized,...

Implanting a Patient’s Own Reprogrammed Stem Cells Shows Early Positive Results for Treating Dry AMD – Everyday Health

By Stem Cell Medical Center

Specially treated stem cells derived from a single individual have been successfully implanted into that same individuals eyes in a first-of-its-kind clinical trial testing ways to treat advanced dry age-related macular degeneration (AMD).

The therapy, currently in its first phase of testing to ensure that its safe for humans, involves harvesting and processing a persons blood cells and using them to replace the persons retinal cells that had succumbed to AMD, a leading cause of vision loss globally.

The procedure was performed by researchers from the National Eye Institute (NEI), a branch of the National Institutes of Health in Bethesda, Maryland, and from the Wilmer Eye Institute at Johns Hopkins School of Medicine in Baltimore. The NIH researchers have been working on the new treatment for a decade.

The scientists, who previously demonstrated the safety and effectiveness of the therapy in rats and pigs, took blood cells from the patient and, in the laboratory, converted them into patient-derived induced pluripotent stem (iPS) cells. These immature, undifferentiated cells have no assigned function in the body, which means they can assume many forms. The researchers programmed these particular iPS cells to become retinal pigment epithelial (RPE) cells, the type that die in AMD and lead to late-stage dry AMD.

In healthy eyes, RPE cells supply oxygen to photoreceptors, the light-sensing cells in the retina at the back of the eyeball. The death of RPE cells virtually dooms the photoreceptors, resulting in vision loss. The idea behind the new therapy is to replace dying RPE cells with patient-derived induced iPS ones, strengthening the health of the remaining photoreceptors.

Before being transplanted, the iPS-derived cells were grown in sheets one cell thick on a biodegradable scaffold designed to promote their integration into the retina. The researchers positioned the resulting patch between atrophied host RPE cells and the photoreceptors using a specially created surgical tool.

The patient received the transplanted cells during the summer and will be followed for a year as researchers monitor overall eye health, including retina stability, and whether any inflammation or bleeding develop, says Kapil Bharti, PhD, a senior investigator at the NEI and for the clinical trial.

Safety data are critical for any new drug, says Gareth Lema, MD, PhD, a vitreoretinal surgeon at New York Eye & Ear Infirmary, a division of the Mount Sinai Health System. Stem cells have added complexity in that they are living tissue, Dr. Lema says. Precise differentiation is necessary for them to fulfill their intended therapeutic effect and not cause harm."

This therapy also requires a surgical procedure to implant the cells, Lema says, adding that its an exquisitely elegant surgery, but introduces further risk of harm. For those reasons, he says, Patients must know that ocular stem cell therapies should only be attempted within the regulated environment of a nationally registered clinical trial.

The rules of a clinical trial dont generally allow specifics to be discussed this early in the process, says Dr. Bharti. Announcing that we were able to successfully transplant the cells now hopefully allows us to recruit more patients, since we can take up to 12 in this phase, he says. We also hope that it will give some optimism to patients with dry AMD and to researchers studying it.

It took seven months to develop the implanted cells, says Bharti, and although the federal Food and Drug Administration (FDA) approved the clinical trial in 2019, the onset of the COVID-19 pandemic delayed the start by two years, he says.

Macular degeneration comprises several stages of disease within the macula, the critical portion of the retina responsible for straight-ahead vision. Aging causes retinal cells to deteriorate, generating debris, or drusen, within the macula, setting the stage for early (aka dry) AMD. Geographic atrophy represents a more advanced stage. If the disease progresses to the relatively rare wet AMD, so named for the leaking of blood into the macula, central vision can be snuffed out.

Risk of AMD increases with age, particularly among people who are white, have a history of smoking, or have a family history of the disease.

Treatment to slow wet AMDs progression includes eye injections with anti-VEGF (or VEGF-A for vascular endothelial growth factor antagonists), a medication that halts the growth of unstable, leaky blood vessels in the eye. Some people may undergo photodynamic therapy, which combines injections and laser treatments.

Currently, there is no cure for dry AMD; it cant be reversed. Nor are there treatments to reliably stop its onset or progression for everyone at every stage of the disease. (Research has confirmed that a specialized blend of vitamins and minerals, available over the counter as AREDS, or Age-Related Eye Disease Studies supplements, reduces the risk of AMDs progression from intermediate to advanced stages.)

There are other, ongoing clinical trials for the treatment of dry AMD. Regenerative Patch Technologies, in Menlo Park, California, for example, is a little further along in testing a different stem cell treatment. Patients have been followed for three years, and 27 percent have shown vision improvement, says Jane Lebkowski, PhD, the companys president. There are a number of AMD clinical trials ongoing in the U.S., and patients should ask their ophthalmologists about trials that might be appropriate.

ClinicalTrials.gov, the NIHs clinical trials database, lists close to 300 AMD clinical trials at various stages in the United States.

Ferhina Ali, MD, MPH, a retinal specialist at the Westchester Medical Center in Valhalla, New York, who isnt involved in the trial, describes the newest stem cell therapy as elegant and pioneering. These are early stages but there is tremendous potential as a first-in-kind surgically implanted stem cell therapy and as a way to achieve vision gains in dry macular degeneration, Dr. Ali says.

Bharti says that in laboratory animals the implanted cells behaved as retinal cells should maintaining the retinas integrity. Over the next few years, he and his colleagues will determine whether they function effectively in humans.

Does that mean, however, that the same AMD disease process that destroyed the original retinal cells could destroy the transplanted ones? It takes 40 to 60 years to damage human cells, Bharti says, and if we get that long with the transplanted cells, well take it.

See original here:
Implanting a Patient's Own Reprogrammed Stem Cells Shows Early Positive Results for Treating Dry AMD - Everyday Health

BrainStorm Cell Therapeutics Announces Peer Reviewed Publication of Results from the NurOwn Phase 2 Progressive MS Trial in Multiple Sclerosis Journal…

By Stem Cell Medical Center

NEW YORK, Sept. 15, 2022 /PRNewswire/ -- BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leading developer of cellular therapies for neurodegenerative diseases, today announced the peer reviewed publication of data from the Phase 2 trial of NurOwn in progressive multiple sclerosis (MS) in Multiple Sclerosis Journal. The publication, entitled "Evaluation of neurotrophic factor secreting mesenchymal stem cells in progressive multiple sclerosis", can be found here.

Results from the Phase 2, single-arm, open-label study demonstrated NurOwn's safety and provided preliminary evidence of its efficacy in people with progressive MS. Additionally, biomarker analyses confirmed NurOwn's proposed mechanism of action by showing consistent treatment effects in neuroinflammation and neuroprotection pathways.

Twenty participants were enrolled into the Phase 2 trial, with seventeen receiving all three scheduled NurOwn treatments. The mean age of study participants was 47 years with a mean expanded disability status scale (EDSS) score of 5.4 at screening. Results from the trial were compared to 48 matched control patients who were selected from the from the Comprehensive Longitudinal Investigation of Multiple Sclerosis (CLIMB) registry (Brigham and Women's Hospital and the Ann Romney Center for Neurologic Diseases) at the beginning of the trial.

Treatment with NurOwn resulted in large, clinically meaningful improvements in some patients, as defined by response criteria, across all endpoints measured. These endpoints included timed 25-foot walk speed (T25FW), 9-hole peg test (9HPT), multiple sclerosis walking scale (MSWS), symbol digit modality test (SDMT), and low contrast letter acuity (LCLA). These observed improvements diverged from what was seen in matched patients with progressive MS from the CLIMB registry. Key data from the trial, as well as relevant comparisons to the matched CLIMB registry patients, are shown below.

Across all participants, improvements in function as measured by LCLA, SDMT and MS Functional Composite (MSFC) were observed. Mean improvements from baseline of 3.3 points in the LCLA binocular (2.5% contrast), 3.8 points on the SDMT, and 0.18 points in MSFC were observed in treated trial participants. The corresponding changes in matched CLIMB registry patients estimated at 28 weeks showed declines in function on the LCLA and MSFC. The average change in function decline as measured by T25FW, 9HPT, and EDSS across all treated trial participants demonstrated stabilization of functional decline, with similar or slightly worse findings observed in the matched CLIMB registry patients for the same endpoints.

There were no adverse events related to worsening of MS disease and no clinically significant changes in safety lab results/vital signs, confirming NurOwn's favorable safety profile. Two patients developed symptoms of low back and leg pain, consistent with arachnoiditis, occurring in one of three treatments in both participants.

Treatment also consistently resulted in increases in cerebrospinal fluid neuroprotective factors (VEGFA, HGF, NCAM-1, Follistatin, LIF and FetuinA) and reductions in inflammatory biomarkers (MCP-1, sCD27, SDF-1, and Osteopontin), confirming NurOwn's proposed mechanism of action in progressive MS.

"We were pleased that the study's initial results showed efficacy in patients with progressive MS," said Jeffrey Cohen, M.D., Hazel Prior Hostetler Endowed Chair Professor, Cleveland Clinic Lerner College of Medicine, Director, Experimental Therapeutics, Mellen Center for MS Treatment and Research, and the paper's lead author. "There are both promising biological and preliminary clinical signals of a treatment effect that will require confirmation in a randomized trial."

"There is a high unmet need for better treatments for progressive forms of MS and we congratulate the Brainstorm Cell Therapeutics team for the successful completion and publication of this important study. We look forward to future studies that will help to fully understand the potential of NurOwn and other cell-based therapies for this hard-to-treat form of disease" said Bruce Bebo, EVP Research National MS Society.

Chaim Lebovits, Chief Executive Officer, BrainStorm Cell Therapeutics stated, "Having these data peer reviewed and published in the prestigious Multiple Sclerosis Journal is an important step in the evaluation of NurOwn in progressive MS. We appreciate the expertise and commitment of the study investigators and contributions of study participants to advance our understanding of NurOwn's cellular technology platform. Thanks to their efforts and those of the BrainStorm team, we believe we are closer to providing a meaningful treatment option for those with progressive MS".

Ralph Kern, M.D., MHSc, President and Chief Medical Officer of BrainStorm Cell Therapeutics and co-author of the paper commented, "This publication provides preliminary evidence of NurOwn's potential to modify functional outcomes in progressive MS, which we believe warrants further study. In addition, consistent changes in cerebrospinal fluid neuroinflammation and neuroprotection biomarkers reveal how NurOwn may impact disease mechanisms in progressive MS and are complementary to biomarker results observed in our Phase 3 ALS trial. These observations provide further support for NurOwn as a platform technology with potential broad applications and will bolster BrainStorm's efforts to bring much needed solutions to patients with progressive MS, ALS, and other neurodegenerative diseases."

Study Design

The Phase 2 study (BCT-101) was designed to evaluate the safety, efficacy, and biomarker effects of three intrathecal administrations of NurOwn (MSC-NTF cells), given at two-month intervals, to adults with progressive MS. The trial was conducted at four MS centers of excellence: Cleveland Clinic Mellen Center for MS, Icahn School of Medicine at Mount Sinai, Keck School of Medicine of the University of Southern California, and Stanford University School of Medicine. Twenty participants ages 18-65 with progressive MS were enrolled and 17 received all three treatments and were followed for up to 28 weeks. Participants had baseline EDSS scores of between 3.0 and 6.5, were able to walk 25 feet in 60 seconds or less and had not experienced an MS relapse in the 6 months prior to study enrollment.

The primary efficacy outcome was pre-specified improvement (25%) in T25FW or 9-HPT. Additional efficacy endpoints included pre-specified improvements in EDSS, SDMT, LCLA, and MSWS-12. The efficacy outcomes were compared to a pre-specified matched group of progressive MS patients from CLIMB registry (n=48) (Tanuja Chitnis, M.D. Brigham and Women's Hospital and the Ann Romney Center for Neurologic Diseases). The study was sponsored by Brainstorm Cell Therapeutics with additional financial support for biomarker analyses received from the National Multiple Sclerosis Society, Fast-Forward Commercial Research Funding Program. For more information on the trial, visit https://clinicaltrials.gov/ct2/show/NCT03799718.

About NurOwn

The NurOwn technology platform (autologous MSC-NTF cells) represents a promising investigational therapeutic approach to targeting disease pathways important in neurodegenerative disorders. MSC-NTF cells are produced from autologous, bone marrow-derived mesenchymal stem cells (MSCs) that have been expanded and differentiated ex vivo. MSCs are converted into MSC-NTF cells by growing them under patented conditions that induce the cells to secrete high levels of neurotrophic factors (NTFs). Autologous MSC-NTF cells are designed to effectively deliver multiple NTFs and immunomodulatory cytokines directly to the site of damage to elicit a desired biological effect and ultimately slow or stabilize disease progression.

About BrainStorm Cell Therapeutics Inc.

BrainStorm Cell Therapeutics Inc. is a leading developer of innovative autologous adult stem cell therapeutics for debilitating neurodegenerative diseases. The Company holds the rights to clinical development and commercialization of the NurOwn technology platform used to produce autologous MSC-NTF cells through an exclusive, worldwide licensing agreement. Autologous MSC-NTF cells have received Orphan Drug designation status from the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of amyotrophic lateral sclerosis (ALS). BrainStorm has completed a Phase 3 pivotal trial in ALS (NCT03280056); this trial investigated the safety and efficacy of repeat-administration of autologous MSC-NTF cells and was supported by a grant from the California Institute for Regenerative Medicine (CIRM CLIN2-0989). BrainStorm completed under an investigational new drug application a Phase 2 open-label multicenter trial (NCT03799718) of autologous MSC-NTF cells in progressive MS and was supported by a grant from the National MS Society (NMSS).

Safe-Harbor Statement

Statements in this announcement other than historical data and information, including statements regarding future clinical trial enrollment and data, constitute "forward-looking statements" and involve risks and uncertainties that could cause BrainStorm Cell Therapeutics Inc.'s actual results to differ materially from those stated or implied by such forward-looking statements. Terms and phrases such as "may," "should," "would," "could," "will," "expect," "likely," "believe," "plan," "estimate," "predict," "potential," and similar terms and phrases are intended to identify these forward-looking statements. The potential risks and uncertainties include, without limitation, BrainStorm's need to raise additional capital, BrainStorm's ability to continue as a going concern, prospects for future regulatory approval of BrainStorm's NurOwn treatment candidate, the success of BrainStorm's product development programs and research, regulatory and personnel issues, development of a global market for our products and services, the ability to secure and maintain research institutions to conduct our clinical trials, the ability to generate significant revenue, the ability of BrainStorm's NurOwn treatment candidate to achieve broad acceptance as a treatment option for ALS or other neurodegenerative diseases, BrainStorm's ability to manufacture and commercialize the NurOwn treatment candidate, obtaining patents that provide meaningful protection, competition and market developments, BrainStorm's ability to protect our intellectual property from infringement by third parties, heath reform legislation, demand for our services, currency exchange rates and product liability claims and litigation; the impacts of the COVID-19 pandemic on our clinical trials, supply chain, and operations; and other factors detailed in BrainStorm's annual report on Form 10-K and quarterly reports on Form 10-Q available at http://www.sec.gov. These factors should be considered carefully, and readers should not place undue reliance on BrainStorm's forward-looking statements. The forward-looking statements contained in this press release are based on the beliefs, expectations, and opinions of management as of the date of this press release. We do not assume any obligation to update forward-looking statements to reflect actual results or assumptions if circumstances or management's beliefs, expectations or opinions should change, unless otherwise required by law. Although we believe that the expectations reflected in the forward-looking statements are reasonable, we cannot guarantee future results, levels of activity, performance, or achievements.

CONTACTS

Investor Relations: John Mullaly LifeSci Advisors, LLC Phone: +1 617-429-3548 jmullaly@lifesciadvisors.com

Media: Lisa Guiterman lisa.guiterman@gmail.com

Logo - https://mma.prnewswire.com/media/1166536/BrainStorm_Logo.jpg

View original content:https://www.prnewswire.com/news-releases/brainstorm-cell-therapeutics-announces-peer-reviewed-publication-of-results-from-the-nurown-phase-2-progressive-ms-trial-in-multiple-sclerosis-journal-301625167.html

SOURCE BrainStorm Cell Therapeutics Inc.

Company Codes: NASDAQ-SMALL:BCLI

Read the original:
BrainStorm Cell Therapeutics Announces Peer Reviewed Publication of Results from the NurOwn Phase 2 Progressive MS Trial in Multiple Sclerosis Journal...

Health care workers appeal dismissal of lawsuit over Maine’s vaccine mandate – Kennebec Journal and Morning Sentinel

By Stem Cell Medical Center

Attorneys for a group of former Maine health care workers who sued the state over its vaccine requirements last summer are asking a panel of judges in Boston to revive their case.

Last month, U.S. District Judge Jon Levy dismissed the groups lawsuit, which argued they have a religious right to refuse the vaccine overtheir belief that fetal stem cells from abortions were used to develop it. They also argued that the state mandate was discriminatory by allowing for medical exemptions, but not religious ones.

Levy ultimately disagreed.

Exempting individuals whose health will be threatened if they receive a COVID-19 vaccine is an essential, constituent part of a reasoned public health response to the COVID-19 pandemic. It does not express or suggest a discriminatory bias against religion, Levy wrote in his order on Aug. 18.

Attorneys have a month to file a brief to the 1st Circuit Court of Appeals in Boston, outlining their reasons for an appeal.

The plaintiffs worked for MaineHealth, Genesis Healthcare, Northern Light Eastern Maine Medical Center and MaineGeneral Health. All are named as defendants in the complaint, along with Gov. Janet Mills, Maine CDC Director Nirav Shah and Commissioner Jeanne Lambrew of the Maine Department of Health and Human Services.

Nine plaintiffs originally sued in August 2021, all anonymously.

The Portland Press Herald, Kennebec Journal, Morning Sentinel and Sun Journal filed a motion last November challenging the groups right to anonymity. The newspapers argued that the plaintiffs alleged fear of harm no longer outweighs the publics interest in open legal proceedings.

Both Levy and the 1st Circuit Court of Appeals agreed, ordering the group to file a new complaint that included their names in July.

Plaintiffs named in the dismissal document are Alicia Lowe, formerly an employee of MaineHealth; Debra Chalmers and Garth Berenyi, formerly of Genesis Health; Jennifer Barbalias, Natalie Salavarria and Adam Jones, formerly of Northern Light Eastern Maine Medical Center; and Nicole Giroux, formerly of MaineGeneral Health.

They are represented by Maine attorney Steve Whiting, and lawyers from Liberty Counsel, a conservative, religious law firm based in Florida that has participated in several lawsuits against Maine and other states over COVID-19 vaccine mandates and restrictions. Theyve also opposed safe and legal access to abortions and same-sex marriage, leading the Southern Poverty Law Center to identify the firm as a hate group.

Federal judges at every level the U.S. District Court,the 1st U.S. Circuit Court of Appeals in Boston andthe U.S. Supreme Court refused to block Maines COVID-19 vaccine mandate from taking effect while the courts considered the merits of the lawsuit.

The mandate took effect in October, and major health care providers reported that most workers decided to get their shots.

Invalid username/password.

Please check your email to confirm and complete your registration.

Use the form below to reset your password. When you've submitted your account email, we will send an email with a reset code.

Previous

Next

Continue reading here:
Health care workers appeal dismissal of lawsuit over Maine's vaccine mandate - Kennebec Journal and Morning Sentinel

→←