Blood, sweat, and many miles for cellular therapy – Martha’s Vineyard Times

From the left, Theresa Janeczek (Edgartown), Cathy Mayone (Edgartown), Lisa Conroy Murphy (Edgartown), Jacki Reich, Bob Falkenberg, Chuck Klaniecki, and Matt Berg (right) at a rest stop. Stefanie Cronin

The team met at the Steamship Authority in Vineyard Haven in the morning to get ready to ride. Natalie Aymond

The team of bikers who met in the morning (left to right): Bruce Rayvid (Cycling Club of MV), Bob Falkenberg, Elle Crofton, Chuck Klaniecki, Jacki Reich, Matt Berg, Cathy Mayone, Harry Crofton, Roger Moffat (Cycling Club of MV), and Lisa Conroy Murphy (Cycling Club of MV). Natalie Aymond

Harry Crofton (left) and Bob Falkenberg arriving at the Edgartown Memorial Wharf. Natalie Aymond

Roger Moffat (left), Harry Crofton, Elle Crofton, and Bob Falkenberg cheering on the rest of the team as they arrive. Natalie Aymond

Matt Berg (left), Bob Falkenberg, Elle Crofton, Harry Crofton, Cathy Mayone (right), and Theresa Janeczek (below) at the Edgartown Memorial Wharf. Natalie Aymond

Bob Falkenberg receiving his transplant through Be The Match. Be The Match

Bob Falkenberg, a 13-year leukemia survivor, is just one example of a transplant recipient that Be The Match (BTM) has been able to treat and save by connecting him with a blood marrow donor. But while Falkenberg is a face of success in matching patients with a donor, the 12,000 patients diagnosed with life-threatening blood cancers or other blood cell diseases each year are not always as easily treated, especially with financial barriers and a disparity in match rates for non-white patients.

Just two years after his transplant, and with a push from a 100-mile bike ride challenge from his friend, Falkenberg has been biking to raise money and awareness for the need for transplant donors for the past 11 years. He and his team of nine riders took to the Island July 20 to continue this support for Be The Match, part of their month-long East Coast ride event, Tour De TC. This annual bike ride raises critical funds for Be The Match, with this years ride aimed at raising enough funds to financially support 25 families in need of treatment.

In his past years of biking for Be The Match, Falkenberg has embarked on rides from Boston to Key West, Vancouver to San Francisco, and Vancouver to Florida. His hope is to hit all 50 states with future rides. For the second half of this years July tour, the crew has already gone from Boston to the Cape and Marthas Vineyard, but will continue on via ferry to Rhode Island and Connecticut. From there, the crew will ferry to the east end of Long Island and into New York City to meet people from the transplant center there. Finally, the riders will head to the childrens hospital in Philadelphia.

In past years, the rides have been more family and friends oriented, according to Falkenberg. But this year, he said that the rides have been more open to participation. From this, he added, they have gotten a larger response and have already raised $100,000 for this year, three times as much as last years raised funds. This is just the start, as he expects they will double all raised funds from this year next year.

Funds raised go toward adding more donors to the Be The Match registry, research to ease the safety of transplant procedures, as well as financial assistance for families and patients in need of transplants and in post-transplant recovery. For adding donors, there is a cost to do the human leukocyte antigen (HLA) tests in order to add donors to the registry and match them to patients. Funds for researching the transplant procedures include identifying and preventing issues that can impact chance of survival, which has increased from 30% to closer to 50% in the past 13 years, according to Falkenberg. For many people, the journey of treatment and recovery can even be such a financial toll it can prevent patients from moving forward with potentially life-saving procedures if careers are put on hold, decreasing household income, says BTM in an information sheet.

Leukemia is the number one childhood cancer, so a lot of this is for kids. When the parents travel, they have to stay there for a long time sometimes, Falkenberg says, which takes time away from work and puts financial strain on family support. There are also financial grants through BTM that increase this family and patient support while covering costs that insurance will not.

Money is not the only thing that decreases the success of patient survival, as there has grown to be a disparity in the diversity of donors. According to BTM, out of almost 300,000 potential U.S. donors added to the registry last year, only 31% were ethnically diverse. Falkenberg commented on this issue saying, Theres about 20 million people on the registry, but if youre Black you only have about a 29% chance right now of finding a single donor on the registry because there just arent enough Black donors and its tied to your DNA and ethnicity. Falkenberg also said that there is a similar struggle for Asian or Pacific Islander patients, Hispanic or Latino patients, and Native American patients, though not quite as bad as the odds for Black or African American patients.

Elle Crofton, a first year rider diagnosed with a blood cancer nine years ago, works as an advocate for BTM alongside Falkenberg and spoke to The Times about this issue of ethnic disparity in donors. Like Falkenberg, Crofton was able to find multiple full matches on the BTM registry that allowed her to get a transplant seven years ago, but said, For people who are not white, they have a lot less likelihood of finding a match. She added that the team is trying to get the word out to get more people of color on the registry saying, We hope we can make the need for everyone to have that equal ability to find a match smaller.

Beyond volunteering and riding, Falkenberg and Crofton have begun legislative advocacy work, lobbying congress to provide legal support to donors. The two reached out to Joe Neguse, the U.S. representative for Colorados 2nd congressional district for support. Falkenberg and Crofton had a virtual meeting surrounding their current work on a Life Saving Leave Act, to which Neguse co-sponsored the next day. The act would work to allow 40 hours of non-consecutive time off of work and protect workers from being fired while undergoing the donation process. This process includes a physical exam and an injection to increase stem cell production, for which the travel and donation can take up to two days to complete. So while not a paid leave, the act would mitigate the fear for potential donors to lose their job.

Alongside the act, Be The Match reimburses for associated costs with the donation process. Its common sense stuff, just not the law right now, Falkenberg said and added, Unfortunately, the people that are more likely to say Im worried about losing my job also line up with the groups underrepresented on the registry. So, every donor that donates matters.

To donate, become a donor and join the registry, or find out other ways to support the organization visit BeTheMatch.org. Eligibility to become a donor is met if you meet the health guidelines and are between 18 and 40 years old. For registration, completion of a health history form and a swab of cheek cells is needed. The swab kit is mailed to the registrants home.

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Blood, sweat, and many miles for cellular therapy - Martha's Vineyard Times

Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor | Signal Transduction and Targeted Therapy – Nature.com

Human samples

Rapid harvesting of cadaveric pancreatic tissues was obtained with informed consent from next of kin, from heart-beating, brain-dead donors, with research approval from the Human Research Ethics Committee at St Vincents Hospital, Melbourne. Pancreas from individuals without and with diabetes, islet, acinar and ductal samples were obtained as part of the research consented tissues through the National Islet Transplantation Programme (at Westmead Hospital, Sydney and the St Vincents Institute, Melbourne, Australia), HREC Protocol number: 011/04. The donor characteristics of islet cell donor isolations are presented in Table 1.

Islets were purified by intraductal perfusion and digestion of the pancreases with collagenase AF-1.24 (SERVA/Nordmark, Germany) followed by purification using Ficoll density gradients.25 Purified islets, from low-density gradient fractions and acinar/ductal tissue, from high-density fractions, were cultured in Miami Media 1A (Mediatech/Corning 98021, USA) supplemented with 2.5% human serum albumin (Australian Red Cross, Melbourne, VIC, Australia), in a 37C, 5% CO2 incubator.

Total RNA from human ex vivo pancreatic cells was isolated using TRIzol (Invitrogen) and RNeasy Kit (QIAGEN) including a DNase treatment. First-strand cDNA synthesis was performed using a high-capacity cDNA Reverse Transcription Kit (Applied Biosystems) according to the manufacturers instructions. cDNA primers were designed using oligoperfect designer (Thermo Fisher Scientific), as shown in Table 2. Briefly, quantitative RT-PCR analyses were undertaken using the PrecisionFast 2 qPCR Master Mix (Primerdesign) and primers using Applied Biosystems 7500 Fast Real-Time PCR System. Each qPCR reaction contained: 6.5l qPCR Master Mix, 0.5l of forward and reverse primers, 3.5l H2O and 2l of previously synthesised cDNA, diluted 1/20. Expression levels of specific genes were tested and normalised to 18s ribosomal RNA housekeeping gene.

Modification of Histone H3 and histone-associated Ezh2 protein signals were quantified in human pancreatic ductal epithelial cells (AddexBio) by the LI-COR Odyssey assay. The cells were treated with 5 or 10M of GSK 126 (S7061, Selleckchem) for 48h. Histones and their associated proteins were examined using an acid extraction and immunoblotting as described previously.18 Protein concentrations were determined using Coomassie Reagent (Sigma) with BSA as a standard. Equal amounts (3g) of acid extract were separated by Nu-PAGE (Invitrogen), transferred to a PVDF membrane (Immobilon-FL; Millipore) and then probed with antibodies against H3K27me3 (07449, Millipore), H3K27ac (ab4729, Abcam), H3K9me3 (ab8898, Abcam), H3K9me2 (ab1220, Abcam), H3K4me3 (39159, Active Motif), Ezh2 (#4905, Cell Signaling Technology), and total histone H3 (#14269, Cell Signaling Technology). Protein blotting signals were quantified by an infra-red imaging system (Odyssey; LI-COR). Modification of Histone H3 and histone-associated Ezh2 signals were quantified using total histone H3 signal as a loading control.

Chromatin immunoprecipitation assays in human exocrine cells were performed previously described.26,27 Cells were fixed for 10min with 1% formaldehyde and quenched for 10min with glycine (0.125M) solution. Fixed cells were resuspended in sodium dodecyl (lauryl) sulfate (SDS) lysis buffer (1% SDS, 10mM EDTA, 50mM Tris-HCl pH 8.1) including a protease inhibitor cocktail (Roche Diagnostics GmBH, Mannheim, Germany) and homogenised followed by incubation on ice for 5min. Soluble samples were sonicated to 200600bp and chromatin was resuspended in ChIP Dilution Buffer (0.01% SDS, 1.1% Triton X-100, 1.2mM EDTA, 16.7mM Tris-HCl pH 8.0, and 167mM NaCl) and 20l of Dynabeads Protein A (Invitrogen, Carlsbad, CA, USA) was added and pre-cleared. H3K27me3 antibody was used for immunoprecipitation of chromatin and incubated overnight at 4C as previously described.28 Immunoprecipitated DNA were collected by magnetic isolation, washed low salt followed by high salt buffers and eluted with 0.1M NaHCO3 with 1% SDS. Protein-DNA cross-links were reversed by adding Proteinase K (Sigma, St. Louis, MO, USA) and incubation at 62C for 2h. DNA was recovered using a Qiagen MinElute column (Qiagen Inc., Valencia, CA, USA). H3K27me3 content at the promoters of the INS, INS-IGF2, NGN3 and PDX1 genes were assessed by qPCR using primers designed from the integrative ENCODE resource.29 ChIP primers are shown in Table 3.

Insulin and glucagon localisation in human islets were assessed using paraffin sections (5m thickness) of human pancreas tissue fixed in 10% neutral-buffered formalin and stained with hematoxylin and eosin (H&E) or prepared for immunohistochemistry. Insulin and glucagon were detected using Guinea Pig anti-insulin (1/100, DAKO) or mouse anti-glucagon (1/50) mAbs (polyclonal Abs, Sigma-Aldrich).

Pharmacological inhibition of EZH2, human pancreatic exocrine cells were kept untreated or stimulated with 10M GSK-126 (S7061, Selleckchem) at a cell density of 1105 per well for 24h. After 24h of treatment, fresh Miami Media was added to the cells, which were treated again with 10 GSK-126 and cultured for a further 24h. All cell incubations were performed in Miami Media 1A (Mediatech/Corning 98-021, USA) supplemented with 2.5% human serum albumin (Australian Red Cross, Melbourne, VIC, Australia), in a cell culture incubator at 37C in an atmosphere of 5% CO2 for 48h using non-treated six-well culture plates (Corning).

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Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor | Signal Transduction and Targeted Therapy - Nature.com

Bristol Myers Squibb Receives Positive CHMP Opinion Recommending Approval for LAG-3-Blocking Antibody Combination Opdualag (nivolumab and relatlimab)…

PRINCETON, N.J.--(BUSINESS WIRE)--Bristol Myers Squibb (NYSE: BMY) today announced that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has recommended approval of the fixed-dose combination of 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 European Commission (EC), which has the authority to approve medicines for the European Union (EU), will now review the CHMP opinion.

We are very proud of the role we have played in progressing the treatment of advanced melanoma over the years. As part of our mission to deliver new medicines for patients, we have continued to develop new dual immunotherapy combinations, said Paul Basciano, development lead, relatlimab, Bristol Myers Squibb. This positive CHMP opinion marks the first step toward the potential approval of the first LAG-3 blocking antibody combination and the third distinct checkpoint inhibitor for BMS for advanced melanoma patients in the EU.

The positive opinion is based upon efficacy and safety results from the Phase 2/3 RELATIVITY-047 trial. The trial showed that treatment with the fixed-dose combination of nivolumab and relatlimab more than doubled the median progression-free survival (PFS), including in patients with tumor cell PD-L1 expression < 1%, when compared to nivolumab monotherapy an established standard of care. The proposed indication for the EU is based upon an exploratory analysis of the data in patients with tumor cell PD-L1 expression < 1%. No new safety events were identified with the combination when compared to nivolumab monotherapy.

On March 18, 2022, the U.S. Food and Drug Administration (FDA) approved the fixed-dose combination of nivolumab and relatlimab as Opdualag (nivolumab and relatlimab-rmbw) for the treatment of adult and pediatric patients 12 years of age or older with unresectable or metastatic melanoma. Please see important safety information from the U.S. prescribing information below.

Bristol Myers Squibb thanks the patients and investigators involved in the RELATIVITY-047 trial.

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

OPDIVO and YERVOY can cause immune-mediated colitis, which may be fatal. A common symptom included in the definition of colitis was diarrhea. Cytomegalovirus (CMV) 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. In patients receiving OPDIVO monotherapy, immune-mediated colitis occurred in 2.9% (58/1994) of patients, including Grade 3 (1.7%) and Grade 2 (1%). Inpatients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated colitis occurred in 25% (115/456) of patients, including Grade 4 (0.4%), Grade 3 (14%) and Grade 2 (8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated colitis occurred in 9% (60/666) of patients, including Grade 3 (4.4%) and Grade 2 (3.7%).

Immune-Mediated Hepatitis and Hepatotoxicity

OPDIVO and YERVOY can cause immune-mediated hepatitis. In patients receiving OPDIVO monotherapy, immune-mediated hepatitis occurred in 1.8% (35/1994) of patients, including Grade 4 (0.2%), Grade 3(1.3%), and Grade 2 (0.4%). In patients receiving OPDIVO 1 mg/kg with YERVOY 3 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 15% (70/456) of patients, including Grade 4 (2.4%), Grade 3 (11%), and Grade 2(1.8%). In patients receiving OPDIVO 3 mg/kg with YERVOY 1 mg/kg every 3 weeks, immune-mediated hepatitis occurred in 7% (48/666) of patients, including Grade 4 (1.2%), Grade 3 (4.9%), and Grade 2 (0.4%).

OPDIVO in combination with cabozantinib can cause hepatic toxicity with higher frequencies of Grade 3 and 4ALT and AST elevations compared to OPDIVO alone. Consider more frequent monitoring of liver enzymes as compared to when the drugs are administered as single agents. In patients receiving OPDIVO and cabozantinib, Grades 3 and 4 increased ALT or AST were seen in 11% of patients.

Immune-Mediated Endocrinopathies

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Bristol Myers Squibb Receives Positive CHMP Opinion Recommending Approval for LAG-3-Blocking Antibody Combination Opdualag (nivolumab and relatlimab)...

Krabbe disease, which mostly affects newborns causes, symptoms, and treatment – CNBCTV18

Krabbe disease is one of many hundreds of inherited metabolic disorders. Named after the Danish neurologist Knud Krabbe, the disease causes progressive damage to the nervous system, eventually resulting in the death of the individual. The disease is common in newborns before they reach six months of age and treatment must start at the earliest. Most newborns affected by Krabbe disease do not reach the age of two.

Krabbe disease is caused due to genetic mutation on the 14th chromosome in an infant. A child needs to inherit two copies of the abnormal genome from both its parents, after which it has a 25 percent chance of inheriting both the recessive genes and developing the disease.

On inheriting the defective genome, the body doesnt produce enough of the enzyme galactosylceramidase (GALC). Galactosylceramidase is essential for breaking down unmetabolised lipids like glycosphingolipid and psychosine in the brain. These unmetabolised lipids are toxic to some of the non-neuron cells present in the brain.

Late-onset Krabbe disease, however, can be caused by a different genetic mutation which leads to a lack of a different enzyme, known as active saposin A.

Symptoms between early-onset and late-onset Krabbe disease differ slightly. Infants suffering from early-onset Krabbe disease suffer from symptoms like excessive irritability, difficulty swallowing, vomiting, unexplained fevers, and partial unconsciousness. Other common neuropathic symptoms include hypersensitivity to sound, muscle weakness, slowing of mental and motor development, spasticity, deafness, optic atrophy, optic nerve enlargement, blindness, and paralysis.

Late-onset Krabbe disease emerges with symptoms like the development of cross-eyes, slurred speech, slow development, and loss of motor functions.

The disease is diagnosed after a physician conducts a primary physical exam. A blood or skin tissue biopsy can test for GALC levels in the body and low levels can indicate the presence of Krabbe disease. Further testing through imaging scans (MRI), nerve conduction studies, eye examination, genetic testing and amniocentesis can also help diagnose the disease.

There is no cure for Krabbe disease. Treatment is mostly palliative in nature with a focus towards dealing with symptoms and providing supportive care. Experimental trials using hematopoietic stem cell transplant (HSCT), bone marrow transplantation, stem cell therapy, and gene therapy have seen some results in the small number of patients that they have been used on.

(Edited by : Shoma Bhattacharjee)

First Published:Jul 15, 2022, 06:32 AM IST

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Krabbe disease, which mostly affects newborns causes, symptoms, and treatment - CNBCTV18

Gut bacteria nurture the immune system for cancer patients, a diverse microbiome can protect against dangerous treatment complications – The…

One promising treatment for patients with blood cancers is stem cell transplantation. Doctors completely eliminate the patients immune system by aiming chemotherapy, radiation or both at their bone marrow before replacing it with a donors immune system. Because the bone marrow produces blood and immune cells, completely substituting cancerous bone marrow with healthy cells could help the body reestablish a functioning immune system and replace cancerous blood cells.

This procedure is not without risks. A key complication hematologists like me worry about is graft-versus-host disease, where the donors immune system recognizes the patients body as foreign and launches an attack. Up to 50% of patients who receive a stem cell transplant develop graft-versus-host disease.

One unexpected part of the body that may play a key role in protecting transplant patients from complications, however, is their gut bacteria.

Alongside my colleagues Hana Andrlova and Marcel van den Brink, I study how the composition of your microbiome, or the microorganisms living in your body, can affect how well cancer treatments work. While previous studies have shown that disruptions to the diversity of organisms in the gut microbiome is linked to a higher risk of death after transplantation, the precise reasons for this are not clear.

In our recently published study, we found that gut bacteria help the immune system recover from stem cell transplants by nurturing two special types of immune cells that protect against complications.

To explore the relationship between gut bacteria and the immune system, we first needed to identify the types of bacteria present in a given microbiome. So we sequenced all the bacterial genes in the stool samples of 174 stem cell transplant patients. We then took blood samples from the same patients to identify which types of immune cells were circulating and how they were functioning.

We learned that a diverse intestinal microbiome after transplantation is associated with expansion of a particular type of cell called MAIT, or mucosal-associated invariant T cells. MAIT cells are linked to improved transplant outcomes like a lower risk of graft-versus-host disease and longer survival in both mice and people. We found that the more MAIT cells patients had in their blood after transplant, the longer they survived and the fewer their complications. Patients with the highest levels of MAIT cells had the lowest incidence of graft-versus-host disease.

The precise mechanism behind the protective effects of MAIT cells is unclear. But researchers do know that these cells require molecules that come from the process of producing riboflavin, or vitamin B2, in the body to develop and multiply. Turns out, these riboflavin derivatives are produced by the microbes in the gut.

We also found that high MAIT cell numbers were linked to the presence of another special population of T cells, V-delta-2, that are also stimulated by bacterial byproducts. Above-average levels of these cells were also associated with better survival and less graft-versus-host disease in transplant patients.

These findings suggest that one of the reasons why a healthy, diverse microbiome is linked to good results for stem cell transplant recipients could be that gut bacteria support the development of immune cells that protect against transplant complications like graft-versus-host disease.

Our next step was to figure out how these special T cells protect against transplant complications. We took blood samples from five patients who had high numbers of MAIT and V-delta-2 cells. We then used a technique called single-cell RNA sequencing to analyze thousands of individual cells and explore all the potential functions any particular cell type may have in the body.

When we compared the MAIT and V-delta-2 cells of transplant patients and healthy people, our findings were very surprising. We had originally hypothesized that genes linked with tissue repair would be active in these T cells that would explain why patients with high numbers of these cells do better after such intense treatment thats so tough on the body. Instead, we found that these cells had highly expressed genes involved in inflammatory processes with the capacity to induce cell damage sometimes necessary to fight off infections when the patients immune system is still recovering. This suggests that MAIT and V-delta-2 cells may be protecting patients from transplant complications in ways that we havent previously been aware of or understood.

Its possible that T cells that are activated by the microbiome like MAIT and V-delta-2 help reduce transplant complications by killing infected cells or cells involved in graft-versus-host disease. While we arent able to confirm this hypothesis with our study, future work may help scientists better understand the important links between the microbiome, the immune system and successful stem cell transplants for cancer patients.

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Gut bacteria nurture the immune system for cancer patients, a diverse microbiome can protect against dangerous treatment complications - The...

Global Induced Pluripotent Stem Cell (iPSC) Market Report 2022: Rising Applications of iPSCs Fueling Industry Growth – ResearchAndMarkets.com -…

DUBLIN--(BUSINESS WIRE)--The "Global Induced Pluripotent Stem Cell (iPSC) Industry Report, 2022" report has been added to ResearchAndMarkets.com's offering.

Since the discovery of induced pluripotent stem cell (iPSC) technology in 2006, significant progress has been made in stem cell biology and regenerative medicine. New pathological mechanisms have been identified and explained, new drugs identified by iPSC screens are in the pipeline, and the first clinical trials employing human iPSC-derived cell types have been initiated.

iPSCs can be used to explore the causes of disease onset and progression, create and test new drugs and therapies, and treat previously incurable diseases.

Other applications of iPSCs include their use as research products, as well as their integration into 3D bioprinting, tissue engineering, and clean meat production. Technology allowing for the mass-production and differentiation of iPSCs in industrial-scale bioreactors is also advancing at breakneck speed.

iPSC Derived Clinical Trials

The first clinical trial using iPSCs started in 2008, and today, that number has surged worldwide. Most of the current clinical trials do not involve the transplant of iPSCs into humans, but rather, the creation and evaluation of iPSC lines for clinical purposes. Within these trials, iPSC lines are created from specific patient populations to determine if these cell lines could be a good model for a disease of interest.

The therapeutic applications of induced pluripotent stem cells (iPSCs) have also surged in recent years. Since the discovery of iPSCs in 2006, it took only seven years for the first iPSC-derived cell product to be transplanted into a human patient in 2013. Since then, iPSC-derived cells have been used within a rapidly growing number of preclinical studies, physician-led studies, and formal clinical trials worldwide.

Key Topics Covered:

1. Report Overview

2. Introduction

3. Current Status of iPSC Industry

3.1 Progress Made in Autologous Cell Therapy Using iPSCs

3.2 Manufacturing Timeline for Autologous iPSC-Derived Cell Products

3.3 Cost of iPSC Production

3.4 Automation in iPSC Production

3.5 Allogeneic iPSCs Gaining Momentum

3.6 Share of iPSC-Based Research Within the Overall Stem Cell Industry

3.7 Major Focus Areas of iPSC Companies

3.8 Commercially Available iPSC-Derived Cell Types

3.9 Relative Use of iPSC-Derived Cell Types in Toxicology Testing Assays

3.10 Currently Available iPSC Technologies

4. History of Induced Pluripotent Stem Cells (iPSCs)

5. Research Publications on iPSCs

6. iPSC: Patent Landscape Analysis

6.1 Legal Status of iPSC Patents

6.2 Patents by Assignee Organization Type

6.3 Ownership of Patent Families by Assignee Type

6.4 Top Inventors of iPSC Patents

6.5 Top Ten iPSC Inventors

6.6 Most Cited Five iPSC Patents

6.7 Leading Patent Filing Jurisdictions

6.8 Number of Patent Families by Year of Filing

6.9 Patents Representing Different Disorders

6.10 iPSC Patents on Preparation Technologies

6.11 Patents on Cell Types Differentiated from iPSCs

6.12 Patent Application Trends Disease-Specific Technologies

7. iPSC: Clinical Trial Landscape

7.1 Literature and Database Search

7.2 Number of iPSC Clinical Trials by Year

7.3 iPSC Study Designs

7.4 iPSC-Based Clinical Trials With Commercialization Potential

8. Research Funding for iPSCs

8.1 Value of NIH Funding for iPSC Research

8.2 Partial List of NIH Funded iPSC Research Projects in 2022

9. M&A, Collaborations & Funding Activities in iPSC Sector

10. Generation of Induced Pluripotent Stem Cells: An Overview

10.1 Reprogramming Factors

10.2 Integrating iPSC Delivery Methods

10.3 Non-Integrative Delivery Systems

10.4 Comparison of Delivery Methods for Generating iPSCs

10.5 Genome Editing Technologies in iPSC Generation

11. Human iPSC Banking

11.1 Cell Sources for iPSC Banking

11.2 Reprogramming Methods Used in iPSC Banking

11.3 Factors Used in Reprogramming in Different Banks

11.4 Workflow in iPSC Banks

11.5 Existing iPSC Banks

12. Biomedical Applications of iPSCs

12.1 iPSCs in Basic Research

12.2 iPSCs in Drug Discovery

12.3 iPSCs in Toxicology Studies

12.4 iPSCs in Disease Modeling

12.5 iPSCs in Cell-Based Therapies

12.6 Other Novel Applications of iPSCs

12.7 iPSCs in Animal Conservation

13. Market Overview

Companies Mentioned

For more information about this report visit https://www.researchandmarkets.com/r/mg6l5h

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Global Induced Pluripotent Stem Cell (iPSC) Market Report 2022: Rising Applications of iPSCs Fueling Industry Growth - ResearchAndMarkets.com -...

Ola Landgren, MD, PhD, Highlights How DETERMINATION Trial Results Inform Use of RVd/Transplant in Newly Diagnosed Myeloma – Cancer Network

C. Ola Landgren, MD, PhD, a professor and leader of Experimental Therapeutics and Myeloma Service at the Sylvester Comprehensive Cancer Center, University of Miami Health System, in an interview with CancerNetwork highlighted key efficacy findings from the phase 3 DETERMINATION trial (NCT01208662) assessing the use of lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd) plus autologous stem cell transplant vs RVd alone, both with continuous lenalidomide maintenance, in patients with newly diagnosed multiple myeloma.1 Moreover, he highlights how the findings compare with similar research such as the phase 3 IFM/DFCI2009 trial (NCT01191060) which previously assessed RVd alone or with high-dose transplant followed by 1 year of lenalidomide maintenance in newly diagnosed multiple myeloma.2

Patients treated on DETERMINATION who received RVd alone had a median progression-free survival (PFS) of 46.2 months compared with 67.5 months in the transplant group (HR, 1.53; 95% CI, 1.23-1.91; P <.0001). The rates of partial response or better were 95.0% and 97.5% in each respective group. No overall survival benefit was noted in either arm (HR, 1.10; 95% CI, 0.73-1.65; P = .99).

Transcript:

The DETERMINATION study showed very similar [findings to the phase 3 IFM/DFCI2009 trial in] that there is a progression-free survival benefit following bone marrow transplant; it was found to be around 21 months. Thats a quite long time. But also, they showed that there is no survival difference [between the 2 treatment arms]. The follow-up time is only around 5 years in the DETERMINATION trial, which is slightly shorter [than IFM/DFCI2009] but confirms very similar results.

Another very important difference between the 2 studies was that in the DETERMINATION study, of the patients on the non-transplant arm [who progressed], a much lower proportion of those patients went to transplant [vs IFM/DFCI2009]. In the DETERMINATION study, it was in the range of 20% to 25% while in the IFM/DFCI2009 study it was 70% to 80%. Despite the fact that there were fewer patients who went to transplant at the time of relapse in the non-transplant up-front arm, you still see no survival difference. Of course, this raises the question [as to whether] you need to do a transplant upfront, do you need to delay it, or do you never need to do the transplant?

This is exactly what Joseph Mikhael, MD, [of the Translational Genomics Research Institute], talked about as the discussant at ASCO. He made a very good, balanced, and fair evaluation when he said that you can make a case for transplant. If you want to extend PFS, you can make a case against the transplant not showing survival difference. There were a lot of other nuances, [such as] the onset of second malignancies. There were 10 cases of [acute myeloid leukemia and myelodysplastic syndrome] in the transplant arm and none in the non-transplant arm. There were quality-of-life differences in favor of no transplant; patients had several months of worsening as expected of their quality of life [following] transplant. Mikhael summarize saying, Welcome to the future of myelomathe era of choice. It is no longer mandatory for patients to do transplant. And I agree with that.

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Ola Landgren, MD, PhD, Highlights How DETERMINATION Trial Results Inform Use of RVd/Transplant in Newly Diagnosed Myeloma - Cancer Network

CAR T-Cell Therapy Appeared Safe, With No Signs of GVHD in Patients With T-Cell Lymphoma/Leukemia – DocWire News

A study presented at the 2022 American Society of Clinical Oncology Annual Meeting found that an autologous CD7 chimeric antigen receptor (CAR) T-cell therapy was effective for patients with relapsed/refractory T-cell acute lymphoblastic leukemia and lymphoma (ALL/LBL), with no signs of graft-versus-host disease (GVHD) reported.

The phase I study included patients with CD7+ relapsed/refractory T-cell ALL/LBL with no leukemic cells in the peripheral blood. Following a 3+3 dose escalation process, the CD7 CAR construct included an endoplasmic reticulum anchor domain fused to a CD7 binding domain to prevent CD7 expression on cell surface, which contributed to minimizing CAR T-cell fratricide. CAR T product was checked to ensure lack of tumor contamination before infusion.

Between September 2021 and January 2022, 5 patients (median age, 3.8 years; range, 1.9-13.0 years) were enrolled in the study. Of those patients, 1 had mediastinal mass and blasts in pleural fluid, 1 had central nervous system-3 status, and 3 had marrow disease with a median burden of 1.35% (range, 0.07%-7.31%).

Patients received CAR T-cell therapy at the following doses: 5 105 cells/kg (n = 3) and 1 106 cells/kg (n = 1). One patient received cells below the target dose.

A total of 3 patients had cytokine release syndrome (CRS), and 1 patient experienced grade 3 CRS. Median onset to CRS was 5 days (range, 1-9 days), with a median duration of 4 days (range, 3-14 days). There were no reports of neurotoxicity, GVHD, or infection.

All patients experienced grade 3/4 hematologic toxicities, which recovered to grade 2 within 30 days.

At 1 month post-infusion, 4 patients achieved complete remission, and 1 patient still had leukemia cells in the cerebrospinal fluid. At a median follow-up of 62 days (range, 35-136 days), 1 patient underwent hematopoietic stem cell transplantation (HSCT) at 2.9 months post-infusion and had a CD7 relapse at 1.4 months post-HSCT. The other 3 patients who experienced a response were in minimal residual disease-negative complete remission.

In the 4 patients who received target dose, the median peak CAR T-cell count in peripheral blood was 4.27 102/L (range, 2.49-5.61) by flow cytometry. All patients had detectable CAR transgene by polymerase chain reaction at their last visits.

Longer follow-up with more patients is needed to further evaluate this CAR T-cell therapy, the researchers noted.

Zhao L, Pan J, Tang K, et al. Autologous CD7-targeted CAR T-cell therapy for refractory or relapsed T-cell acute lymphoblastic leukemia/lymphoma. Abstract #7035. Presented at the 2022 American Society of Clinical Oncology Annual Meeting; June 3-7, 2022; Chicago, IL.

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CAR T-Cell Therapy Appeared Safe, With No Signs of GVHD in Patients With T-Cell Lymphoma/Leukemia - DocWire News

New cancer treatment changing outlook for those with blood cancers – WBAL TV Baltimore

Ten percent of all diagnosed cancers in the United States are blood cancers and they can be deadly. There are exciting new treatments and research happening in Baltimore that are giving patients hope."These therapies cure the patients that have no other treatment options. It's been a remarkable breakthrough," Dr. Aaron Rapoport, of the University of Maryland School of Medicine, said.Cutting-edge technology in cancer treatment will treat many types of cancers such as leukemia, lymphoma, and myeloma. Traditional treatments include chemotherapy, radiation, and stem cell therapy, but what if those treatments don't work? Now there is an immunotherapy for aggressive blood cancers that is seeing remarkable results.Chip Baldwin has a big laugh and immense love for his grandchildren."This is Kyle, he's about 3 1/2 years old and he lives in Florida. (My) granddaughter Maple. She and her family live in Fells Point. And this is (my) granddaughter Rosemary and she's a doll, and they call me Pop-pop," Baldwin said.Baldwin almost never met two of his grandchildren. In January 2018, he was told chemotherapy was no longer working to treat his lymphoma. He thought it was the end."Leaving (my wife) Angela and leaving the family, trying to figure out how they're going to get by," Baldwin said. He was out of options, or so he thought. Not willing to give up, his wife, Angela Baldwin, began researching and came across a promising new treatment."Probably the last treatment that I could have received. Had I not received it and had it not been positive to put me in remission, I probably wouldn't be talking to you today," Baldwin said.The treatment he received had just been approved by the U.S. Food and Drug Administration (FDA) months earlier. It's called "CAR T-cell Therapy." It uses the patient's own, re-engineered, immune cells to kill cancer. Rapoport helped pioneer the development of CAR T-cell at the University of Maryland Greenebaum Comprehensive Cancer Center. Baldwin was just the second patient here to receive it."The notion that one could perhaps harness the immune system, or educate the immune system, to better protect us from cancer, but also to recognize and fight against cancer, has been a goal for decades - centuries really," Rapoport said.It appears that goal has been reached. Here's how it works: The medical team extracts immune cells, called T-cells, out of the patient's blood. The cells are sent to a special lab in California, where scientists change the cells' DNA to put receptors on them called "CAR" - Chimeric Antigen Receptors. They enable the immune cells to recognize, hunt down and kill the cancer cells. The California lab then sends the now-re-engineered immune cells back to the Greenebaum Comprehensive Cancer Center."These are CAR T-cells growing in the flask here. These are CAR T-cells that were made in the lab," Dr. Djordje Atanackovic of the University of Maryland Medical Center, said. Under a microscope you can see spots on a cancer cell - those spots are the killer CAR T-cells. "You could use these right now to treat a patient, actually," Atanackovic said.For the final step, patients are admitted to the hospital and the medical team puts the T-cells back into the patient, where they multiply by the millions and destroy the cancer. For Baldwin, that was the day after Easter 2018."And, then about four months later, they determined that all the cancer cells had died, " Baldwin said."Being told that their scans are negative is a really overwhelming experience, not just for the patients, but for the families and also the nurses and physicians. The team members that are involved in their care," Rapoport said.When looking at CT scan images of two other lymphoma patients, you see black areas in the images on one is extensive cancer. The other image shows the same patient after CAR T-cell therapy and the cancer is gone. Right now, CAR T-cell Therapy is approved to treat aggressive blood cancers Lymphoma, B-cell Leukemia and Myeloma. But Atanackovic believes that's just the beginning."I'm pretty optimistic that in 10 years from now we'll have novel immunotherapies that we can't even imagine at this point for everyone, or at least most of our patients with cancer," Atanackovic said.Four years after his treatment and Baldwin is still in remission. He doesn't like the word "cure" because he's afraid it's bad luck. The word he keeps coming back to is: "Unbelievable. And even to this day, I kind of can't believe I'm in remission and I'm able to live my life. Since then, I've had two grandchildren and it's been wonderful. Had it not been for the University and the treatment, I would never have seen the two kids," Baldwin saidSo far, 250 patients have been treated with CAR T-cell Therapy at the University of Maryland, but it's not perfect and researchers are still working to improve it. The success rate for patients with aggressive lymphoma for example is 50% and some patients have side effects like flu-like symptoms, so they typically stay in the hospital for days or even weeks.Many may be wondering is this covered by insurance? The answer is yes. Keep in mind, right now it is approved by FDA as a second-line therapy, so you do have to try a different treatment first. But, immunotherapy like CAR-T is the future of cancer treatment and you're going to see more of it.

Ten percent of all diagnosed cancers in the United States are blood cancers and they can be deadly. There are exciting new treatments and research happening in Baltimore that are giving patients hope.

"These therapies cure the patients that have no other treatment options. It's been a remarkable breakthrough," Dr. Aaron Rapoport, of the University of Maryland School of Medicine, said.

Cutting-edge technology in cancer treatment will treat many types of cancers such as leukemia, lymphoma, and myeloma. Traditional treatments include chemotherapy, radiation, and stem cell therapy, but what if those treatments don't work? Now there is an immunotherapy for aggressive blood cancers that is seeing remarkable results.

Chip Baldwin has a big laugh and immense love for his grandchildren.

"This is Kyle, he's about 3 1/2 years old and he lives in Florida. (My) granddaughter Maple. She and her family live in Fells Point. And this is (my) granddaughter Rosemary and she's a doll, and they call me Pop-pop," Baldwin said.

Baldwin almost never met two of his grandchildren. In January 2018, he was told chemotherapy was no longer working to treat his lymphoma. He thought it was the end.

"Leaving (my wife) Angela and leaving the family, trying to figure out how they're going to get by," Baldwin said.

He was out of options, or so he thought. Not willing to give up, his wife, Angela Baldwin, began researching and came across a promising new treatment.

"Probably the last treatment that I could have received. Had I not received it and had it not been positive to put me in remission, I probably wouldn't be talking to you today," Baldwin said.

The treatment he received had just been approved by the U.S. Food and Drug Administration (FDA) months earlier. It's called "CAR T-cell Therapy." It uses the patient's own, re-engineered, immune cells to kill cancer.

Rapoport helped pioneer the development of CAR T-cell at the University of Maryland Greenebaum Comprehensive Cancer Center. Baldwin was just the second patient here to receive it.

"The notion that one could perhaps harness the immune system, or educate the immune system, to better protect us from cancer, but also to recognize and fight against cancer, has been a goal for decades - centuries really," Rapoport said.

It appears that goal has been reached. Here's how it works:

The medical team extracts immune cells, called T-cells, out of the patient's blood. The cells are sent to a special lab in California, where scientists change the cells' DNA to put receptors on them called "CAR" - Chimeric Antigen Receptors. They enable the immune cells to recognize, hunt down and kill the cancer cells. The California lab then sends the now-re-engineered immune cells back to the Greenebaum Comprehensive Cancer Center.

"These are CAR T-cells growing in the flask here. These are CAR T-cells that were made in the lab," Dr. Djordje Atanackovic of the University of Maryland Medical Center, said.

Under a microscope you can see spots on a cancer cell - those spots are the killer CAR T-cells.

"You could use these right now to treat a patient, actually," Atanackovic said.

For the final step, patients are admitted to the hospital and the medical team puts the T-cells back into the patient, where they multiply by the millions and destroy the cancer. For Baldwin, that was the day after Easter 2018.

"And, then about four months later, they determined that all the cancer cells had died, " Baldwin said.

"Being told that their scans are negative is a really overwhelming experience, not just for the patients, but for the families and also the nurses and physicians. The team members that are involved in their care," Rapoport said.

When looking at CT scan images of two other lymphoma patients, you see black areas in the images on one is extensive cancer. The other image shows the same patient after CAR T-cell therapy and the cancer is gone.

Right now, CAR T-cell Therapy is approved to treat aggressive blood cancers Lymphoma, B-cell Leukemia and Myeloma. But Atanackovic believes that's just the beginning.

"I'm pretty optimistic that in 10 years from now we'll have novel immunotherapies that we can't even imagine at this point for everyone, or at least most of our patients with cancer," Atanackovic said.

Four years after his treatment and Baldwin is still in remission. He doesn't like the word "cure" because he's afraid it's bad luck.

The word he keeps coming back to is: "Unbelievable. And even to this day, I kind of can't believe I'm in remission and I'm able to live my life. Since then, I've had two grandchildren and it's been wonderful. Had it not been for the University and the treatment, I would never have seen the two kids," Baldwin said

So far, 250 patients have been treated with CAR T-cell Therapy at the University of Maryland, but it's not perfect and researchers are still working to improve it.

The success rate for patients with aggressive lymphoma for example is 50% and some patients have side effects like flu-like symptoms, so they typically stay in the hospital for days or even weeks.

Many may be wondering is this covered by insurance? The answer is yes. Keep in mind, right now it is approved by FDA as a second-line therapy, so you do have to try a different treatment first. But, immunotherapy like CAR-T is the future of cancer treatment and you're going to see more of it.

Excerpt from:
New cancer treatment changing outlook for those with blood cancers - WBAL TV Baltimore

Innovative Therapies, Care Equity Highlight 2022 ASCO Annual Meeting – Targeted Oncology

After a meeting like the 2022 ASCO Annual Meeting, one cannot help but be reinvigorated to continue advancing cancer care and feel optimistic about the future of oncology, says John M. Burke, MD.

After seeing all the amazing presentations at the American Society of Oncology (ASCO) Annual Meeting, I cannot help but reflect on how far our field has come over the course of my 20-year career.

In 2000, I moved from San Francisco, California, to New York, New York, to begin my fellowship at Memorial Sloan Kettering Cancer Center. My first rotation was on the inpatient myeloma, lymphoma, and autologous stem cell transplant service, where I encountered patients with myeloma and painful bone lesions causing fractures and spinal cord compressions. We treated patients with myeloma with chemotherapy and autologous stem cell transplant. Thalidomide (Thalomid) was starting to make a splash by showing strong efficacy in myeloma trials, and bortezomib (Velcade) emerged during those years, as well.

Nevertheless, the state of the art was exemplified by an article in the New England Journal of Medicine in 2003, describing the results of an Intergroupe Francophone du Mylome (IFM) trial. Myeloma patients were treated with vincristine, doxorubicin, and dexamethasone induction followed by single or double autologous stem cell transplant. The median event-free survival was 2 years and the median overall survival was 4 years, which seem grim by modern standards.

Fast forward about 20 years to the Plenary Session of the 2022 ASCO Annual Meeting, at which we saw the results of modern therapy in the DETERMINATION trial (NCT01208662). Patients treated with the modern standard regimen of lenalidomide (Revlimid), bortezomib, and dexamethasone followed by autologous stem cell transplant achieved a median progression-free survival of 5.5 years. In the IFM trial 20 years ago, approximately 50% of patients were alive at 4 years. In DETERMINATION, 85% of patients were alive at 4 years. Weve come a long way.

DETERMINATION represents only an infinitesimal fraction of the degree of innovation demonstrated at the ASCO meeting: an antibody-drug conjugate besting conventional chemotherapy in patients with low expression of the HER2 target in breast cancer; a KRAS inhibitor demonstrating marked activity in KRAS-mutated nonsmall cell lung cancer; a bispecific antibody redirecting T cells to suppress diffuse large B-cell lymphoma; an antibody-drug conjugate added to chemotherapy, extending survival in Hodgkin lymphoma compared with the decades-old standard-of-care regimen; and a checkpoint inhibitor rendering mismatch repairdeficient rectal cancer completely helpless.

After a meeting like this, one cannot help but be reinvigorated to continue advancing cancer care and feel optimistic about the future of oncology. We have a lot of progress to celebrateand a lot more to accomplish.

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Innovative Therapies, Care Equity Highlight 2022 ASCO Annual Meeting - Targeted Oncology