Stem Cell Clinic

From asthma to cancer to infertility, the new treatments, jabs and meds making us healthier… – The Sun

WHEN it comes to health, the news in recent times has been sombre.

It has been another rollercoaster year battling Covid, with the UK emerging from a third lockdown in spring.

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Millions of people have since had their jabs, and boosters are being rolled out as winter looms large.

But Covid is not the only big health story to come out of the past two years.

Behind the scenes, scientists around the world have been working on medical trials in the hope of finding cures for major illnesses.

And there have been dozens of major breakthroughs that could save billions of lives and change the way diseases are treated forever.

Just this month it emerged the vaccine for the human papillomavirus virus (HPV) could eradicate cervical cancer within the next few years.

From asthma to Alzheimers and cancer to infertility, CLARE OREILLY looks at the new treatments, vaccines and medicines that could put an end to some of the most common and deadly conditions.

CERVICAL cancer kills more than two women every day in the UK, claiming around 850 lives every year.

Yet a new study has found the disease could soon be a thing of the past.

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Kings College London scientists found the human papillomavirus (HPV) vaccine cut cases by 90 per cent.

The jab, which was first rolled out to teenage girls in the UK in 2008 then to boys in 2019, prevents HPV, which is responsible for nearly all cases of cervical cancer.

The study, in the Lancet, tracked women who received some of the first doses and found it prevented an estimated 17,200 pre-cancers and 450 cases in women in their twenties.

Cancer Research UKs chief executive Michelle Mitchell said: Its a historic moment to see the first study showing that the HPV vaccine has and will continue to protect women from cervical cancer.

A NEW antibody-based treatment developed by scientists in the UK and Germany could soon yield a vaccine to prevent Alzheimers.

The degenerative condition is thought to be caused by a type of protein that sticks to brain cells.

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The scientists were able to trigger the immune system to make antibodies, which targeted the protein before it was deposited.

Professor Mark Carr, who led a team at the University of Leicester, said: It has the real potential to provide an effective treatment for Alzheimers using a therapeutic antibody and highlights the potential of a simple vaccine.

Meanwhile, a year-long study has started in Norway where Alzheimers patients will receive a transfusion of blood taken from runners.

It is hoped the chemicals released in the blood after running have a rejuvenating effect to slow disease progression.

THREE new drugs are being put through trials in the hope they could end the misery of hot flushes for menopausal women.

Hot flushes are thought to be caused by changes in hormone levels affecting the bodys temperature control.

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But the medicines fezolinetant, elinzanetant and pavinetant can block the receptors which are responsible for the common symptom.

London GP Dr Zoe Watson says it could be years before the treatment is available on the NHS, though.

She says: It looks interesting in theory, but there are question marks over its efficacy, its side-effect profile and its cost.

Certainly if it does this well then it could be extremely useful for women whose most troubling menopausal symptom is hot flushes.

However, menopause is much more than just hot flushes and halting periods."

A BRAND new injection could reverse spinal cord injuries and allow patients to walk again just four weeks after treatment.

Developed by a team at Northwestern University in the US, the jab encourages nerves to regrow.

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It gave paralysed mice the ability to walk and human trials are expected to begin next year.

For decades, this has remained a major challenge for scientists because our bodys central nervous system, which includes the brain and spinal cord, doesnt have any significant capacity to repair itself after injury.

Professor Samuel Stupp said: Our research aims to find a therapy that can prevent individuals from becoming paralysed after major trauma or disease.

We are going straight to the FDA [the US Food and Drug Administration] to get this approved for use in patients.

DEMENTIA affects around 850,000 people in the UK and costs 26.3billion a year, but scientists at Durham University have made a breakthrough.

They are working on a treatment that could boost memory and muscle control in patients with the killer disease.

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Using infrared light to zap the brain improved the memory and thought processing in trials of healthy people.

And the next step is to enlist dementia patients to test the therapy.

Its delivered by a specially equipped helmet, which beams invisible light waves into the brain and forces cells to boost levels, improving blood flow too.

Dr Paul Chazot, who led the study, said: While more research is needed, there are promising signs that therapy involving infrared light might also be beneficial for people living with dementia and this is worth exploring.

ANYONE with asthma knows how debilitating it can be to receive a diagnosis.

Yet more than five million people in the UK are asthmatic. But a brand new drug, already approved for use on the NHS, is set to transform the lives of many with the condition, making attacks less frequent and less severe.

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Dupilumab is prescribed to treat eczema and rhinosinusitis a type of sinusitis where the nasal cavity as well as sinuses become inflamed.

Its from a family of drugs used to treat Covid.

Currently only patients with very serious asthma who have had at least four severe asthma attacks in the last year and are ineligible for other biological treatments will be considered for a prescription.

But the drug is set to change the lives of many asthma sufferers across the country.

HALF of us will get cancer at some point in our lives. But new jab Survivin could change the landscape dramatically, scientists say.

The first clinical trials are already under way, and the injection works to boost the bodys immune system. It supercharges the immune cells, helping them seek out and destroy cancerous cells while leaving healthy cells alone.

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Currently there are 36 terminally ill patients taking part in the trials, which are focused on ovarian, prostate and lung cancers.

Michelle Mitchell, chief executive of Cancer Research UK, said: Just this month we heard the HPV vaccine has likely prevented hundreds of women from developing cervical cancer.

This is a new and exciting frontier in cancer medicine and if this trial and others are successful, we could see thousands more lives saved.

AROUND seven per cent of all men are affected by infertility.

And while treatments currently focus on solutions rather than cures, scientists at the University of Georgia, in the US, are looking to reverse male infertility altogether.

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The researchers have used primate embryonic stem cells the building blocks of all cells in the body to grow sperm cells in the earlier stages of development in a petri dish.

These spermatids, which lack a head and tail for swimming, were capable of fertilising a rhesus macaque egg in vitro.

Lead researcher and associate professor Dr Charles Easley says: This is a major breakthrough towards producing stem cell-based therapies to treat male infertility in cases where the men do not produce any viable sperm cells.

It is the first step that shows this technology is potentially translatable.

GETTING through the blood/brain barrier to target treatments for brain cancer is complex.

But now a team of scientists in Toronto, Canada, have found a way to use ultrasound beams.

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They help open the barrier and can help facilitate drug delivery, which could change the way the disease is treated.

A trial this year saw four women with breast cancer that had spread to their brains treated with magnetic resonance-guided focused ultrasound (MRgFUS).

It allowed the antibody therapy herceptin to pass into their brain tissue, and caused the tumours to shrink without damaging any healthy tissue.

Dr Nir Lipsman, who led the study, said: It has long been theorised that focused ultrasound can be used to enhance drug delivery, but this is the first time we have shown we can get drugs into the brain.

A DRUG taken in pill form is to be trialled to combat the deadliest form of cancer. Auceliciclib is already used to treat brain tumours.

But now scientists hope it can help fight pancreatic cancer, which is often first diagnosed when it is at a late stage.

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Professor Shudong Wang and her team at the University of South Australia are also working on new ways to detect the disease.

She said: Pancreatic cancer is extremely difficult to diagnose at an early stage because there are very few symptoms.

If it is caught early the malignant tumour can be surgically removed, but once it spreads into other organs it is lethal.

Chemotherapy and radiotherapy only buy patients a little extra time.

The team hopes the drug will be more effective and with fewer side-effects than current treatment options.

THE heroic scientists who developed the Covid vaccine did not stop there.

The team at the University of Oxford has also developed a malaria jab that will save billions of lives.

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A trial showed 77 per cent of volunteers who were vaccinated stayed malaria-free over the following 12 months.

More than 100 malaria vaccines have been developed in recent decades, but the Oxford jab is the first to have such a high success rate.

Halidou Tinto, professor of parasitology and the principal investigator on the trial, said: These are very exciting results showing unprecedented efficacy levels from a vaccine that has been well-tolerated in our trial programme.

We look forward to the upcoming phase III trial to demonstrate large-scale safety and efficacy data for a vaccine that is greatly needed.

A DRUG that repairs cancerous cells could revolutionise the way breast cancer is treated.

Patients given olaparib as part of a two-and-a-half year trial were 42 per cent less likely to see their cancer return.

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There was also a 43 per cent dEcrease in the risk of the disease spreading.

Until the breakthrough earlier this year, the drug was mainly used for late-stage cancers, but the new findings suggest it is effective as an early treatment.

Professor Andrew Tutt, professor of oncology at the Institute of Cancer Research who led the study, said: Women with early-stage breast cancer who have inherited BRCA1 or BRCA2 mutations are typically diagnosed at a younger age.

Up to now, there has been no treatment that specifically targets the unique biology of these cancers to reduce the rate of recurrence, beyond initial treatment such as surgery.

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From asthma to cancer to infertility, the new treatments, jabs and meds making us healthier... - The Sun

New hope for bowel cancer patients as fresh partnership between Carina Biotech and CellVec enables advancement of clinical trials. – Bio-IT World

SINGAPORE, 10 November 2021 Singapore-based viral vector CDMO CellVec announces today that it has been selected as the manufacturer of choice for Australian cell therapy immuno-oncology company Carina Biotech, undertaking the production of GMP-compliant lentivirus constructs for its LGR5 CAR-T. The partnership is slated to advance clinical trials for a treatment designed for patients with advanced colorectal (bowel) cancer.

CellVec is a certified GMP gene therapy contract development and manufacturing organisation that provides an advanced lentiviral vector platform to upscale production of viral vectors and develop novel gene transfer technologies to advance therapies to clinical application. Its strategic offering of bespoke manufacturing services will enable the clinical grade lentivirus to be produced under GMP standards while using Carinas proprietary manufacturing process, progressing the production of LGR5 CAR-T cells for a first in-human clinical trial in H2 2022.

The partnership with Carina Biotech marks a significant milestone for us to facilitate the furtherance of gene therapies. It attests to our capabilities to effectively scale bespoke viral vector manufacturing processes, enabling the advancement of different clinical therapies from bench to bedside that will benefit more patients across the world. We look forward to supporting Carina in the successful development of its LGR5 CAR-T cells, said Dr Ang Peng Tiam, Chairman of CellVec and Medical Director of Parkway Cancer Centre, the largest private oncology service provider in the region.

We are delighted to be working with CellVec because of their outstanding track record and expertise, said Professor Simon Barry, VP of CAR-T Manufacturing Research and Development and the co-inventor of Carinas lead CAR-T cell. Their flexibility and willingness to incorporate Carinas proprietary manufacturing process was an important consideration in the selection of CellVec as our service provider.

Leveraging its advanced CellVec Vector Platform, CellVecs efficacious manufacturing processes will scale the production of high-titre, high yield lentivirus constructs in an accelerated timeline (6 to 8 months) for the project. The LGR5 CAR-T cell targets the LGR5 cancer stem cell marker that is highly expressed on advanced colorectal cancer and some other cancers, resulting in durable tumour suppression and the prevention of relapses commonly seen in patients with colorectal cancer.

We are continuing to see fantastic results with our LGR5 CAR-T cell in pre-clinical testing. Colorectal cancer is Australias second deadliest cancer and its incidence is rising in people under the age of 50 with many of these people being diagnosed with advanced disease and a very poor prognosis, said Dr Deborah Rathjen, CEO of Carina Biotech.

After our recent successful capital raise and welcoming new impact investors to our company, we are on track for a pre-IND submission in Q2 of 2022 and an IND submission to the FDA in the second half of 2022 and the initiation of a Phase I/II clinical trial in patients with advanced colorectal cancer.

Commenting on the potential of the partnership, Dr Gayatri Sharma, Chief Commercial Officer of CellVec said, Carinas work in LGR5 CAR-T therapy aligns strongly with our mission of innovating for patient benefit. Our manufacture of the required lentivirus constructs will accelerate the clinical application and adoption of the therapy, bringing it to more patients around the world and ultimately reduce the incidence and mortality of colorectal cancer. We are pleased to be part of this journey with Carina and are extremely excited for what this will bring to the colorectal cancer community.

CellVec boasts a GMP-certified pharmaceutical quality system (PQS) and facility, awarded by the Health Sciences Authority of Singapore under current PIC/S guidance annexes for medicinal products. These are designed in alignment with US FDA, EU GMP and TGA (Australia) regulations and industry expectations. With a strategic location in Singapore, the regions biotech hub, CellVec is able to facilitate on-time delivery of quality viral vectors across the world, including to the US and the UK.

-ENDS-

About CellVec

CellVec is the first CDMO in Southeast Asia GMP-certified for the production of viral vectors for gene therapy as an active pharmaceutical ingredient. Its manufacturing facility is built to comply with PIC/S, US FDA and EU GMP specifications for viral vectors, upholding quality standards of viral vector production. Specialising in lentiviral vectors, CellVec is a specialist provider of custom viral vectors for pre-clinical and clinical applications. In its commitment towards innovating for patient benefit, CellVec also offers end-to-end project management support to see therapeutics ideas from bench to bedside. For more information, visit http://www.cellvec.com.

About Carina Biotech

Adelaide-based Carina Biotech is developing CAR-T and other adoptive cell therapies for the treatment of solid cancers. As well as its LGR5-targeted CAR-T cell for advanced colorectal cancer, Carina has a deep pipeline of CAR-T programs.

Using its proprietary chemokine receptor platform, Carina aims to improve access to and infiltration of solid cancers by CAR-containing cells resulting in more potent and specific cancer killing and reduced off-target effects in a number of cancers.

Carina also has a fully integrated, proprietary manufacturing process that has both reduced manufacturing time and improved CAR-T cell quality, capable of delivering robust serial-killing CAR-T cells to patients.

About LGR5

LGR5 is acancer stem cell markerthat is highly expressed on advanced colorectal cancer and some other cancers. In colorectal cancer patients,LGR5+ expression has been correlated with a particularly poor prognosis.

Cancer stem cells are a small sub-population of cells within a tumour with the ability to self-renew, differentiateinto the many cell types of a tumour, initiatenew tumours, and resistchemotherapy and radiotherapy (leading to relapses).

By targeting cancer stem cells, it is hoped that this therapy will reduce the tumours ability to generate new cancer cells, resulting in durable tumour suppression and preventing the relapses that are very common in patients with colorectal cancer.

Carinas pre-clinical studies of the LGR5-targeted CAR-T cell have shown highly promising results with complete tumour regression and no tumour recurrence. They have also demonstrated impressive tumour access and prolonged CAR-T cell survival.

Original post:
New hope for bowel cancer patients as fresh partnership between Carina Biotech and CellVec enables advancement of clinical trials. - Bio-IT World

FDA Approves Merck’s KEYTRUDA (pembrolizumab) as Adjuvant Therapy for Certain Patients With Renal Cell Carcinoma (RCC) Following Surgery – Business…

KENILWORTH, N.J.--(BUSINESS WIRE)--Merck (NYSE: MRK), known as MSD outside the United States and Canada, today announced that the U.S. Food and Drug Administration (FDA) has approved KEYTRUDA, Mercks anti-PD-1 therapy, for the adjuvant treatment of patients with renal cell carcinoma (RCC) at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions. The approval is based on data from the pivotal Phase 3 KEYNOTE-564 trial, in which KEYTRUDA demonstrated a statistically significant improvement in disease-free survival (DFS), reducing the risk of disease recurrence or death by 32% (HR=0.68 [95% CI, 0.53-0.87]; p=0.0010) compared to placebo. Median DFS has not been reached for either group.

Despite decades of research, limited adjuvant treatment options have been available for earlier-stage renal cell carcinoma patients who are often at risk for recurrence. In KEYNOTE-564, pembrolizumab reduced the risk of disease recurrence or death by 32%, providing a promising new treatment option for certain patients at intermediate-high or high risk of recurrence, said Dr. Toni K. Choueiri, director, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, and professor of medicine, Harvard Medical School. With this FDA approval, pembrolizumab may address a critical unmet treatment need and has the potential to become a new standard of care in the adjuvant setting for appropriately selected patients.

Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue and can affect more than one body system simultaneously. Immune-mediated adverse reactions can occur at any time during or after treatment with KEYTRUDA, including pneumonitis, colitis, hepatitis, endocrinopathies, nephritis, dermatologic reactions, solid organ transplant rejection, and complications of allogeneic hematopoietic stem cell transplantation. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions. Early identification and management of immune-mediated adverse reactions are essential to ensure safe use of KEYTRUDA. Based on the severity of the adverse reaction, KEYTRUDA should be withheld or permanently discontinued and corticosteroids administered if appropriate. KEYTRUDA can also cause severe or life-threatening infusion-related reactions. Based on its mechanism of action, KEYTRUDA can cause fetal harm when administered to a pregnant woman. For more information, see Selected Important Safety Information below.

KEYTRUDA is foundational for the treatment of patients with certain advanced cancers, and this approval marks the fourth indication for KEYTRUDA in earlier stages of cancer, said Dr. Scot Ebbinghaus, vice president, clinical research, Merck Research Laboratories. KEYTRUDA is now the first immunotherapy approved for the adjuvant treatment of certain patients with renal cell carcinoma. This milestone is a testament to our commitment to help more people living with cancer.

In RCC, Merck has a broad clinical development program exploring KEYTRUDA, as monotherapy or in combination, as well as other investigational products across multiple settings and stages of RCC, including adjuvant and advanced or metastatic disease.

Data Supporting the Approval

KEYTRUDA demonstrated a statistically significant improvement in DFS in patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions compared with placebo (HR=0.68 [95% CI, 0.53-0.87]; p=0.0010). The trial will continue to assess overall survival (OS) as a secondary outcome measure.

In KEYNOTE-564, the median duration of exposure to KEYTRUDA was 11.1 months (range, 1 day to 14.3 months). Serious adverse reactions occurred in 20% of these patients receiving KEYTRUDA. Serious adverse reactions (1%) were acute kidney injury, adrenal insufficiency, pneumonia, colitis and diabetic ketoacidosis (1% each). Fatal adverse reactions occurred in 0.2% of those treated with KEYTRUDA, including one case of pneumonia. Adverse reactions leading to discontinuation occurred in 21% of patients receiving KEYTRUDA; the most common (1%) were increased alanine aminotransferase (1.6%), colitis and adrenal insufficiency (1% each). The most common adverse reactions (all grades 20%) in the KEYTRUDA arm were musculoskeletal pain (41%), fatigue (40%), rash (30%), diarrhea (27%), pruritus (23%) and hypothyroidism (21%).

About KEYNOTE-564

KEYNOTE-564 (ClinicalTrials.gov, NCT03142334) is a multicenter, randomized, double-blind, placebo-controlled Phase 3 trial evaluating KEYTRUDA as adjuvant therapy for RCC in 994 patients with intermediate-high or high risk of recurrence of RCC or M1 no evidence of disease (NED). Patients must have undergone a partial nephroprotective or radical complete nephrectomy (and complete resection of solid, isolated, soft tissue metastatic lesion[s] in M1 NED participants) with negative surgical margins for at least four weeks prior to the time of screening. Patients were excluded from the trial if they had received prior systemic therapy for advanced RCC. Patients with active autoimmune disease or a medical condition that required immunosuppression were also ineligible. The major efficacy outcome measure was investigator-assessed DFS, defined as time to recurrence, metastasis or death. An additional outcome measure was OS. Patients were randomized (1:1) to receive KEYTRUDA 200 mg administered intravenously every three weeks or placebo for up to one year until disease recurrence or unacceptable toxicity.

About Renal Cell Carcinoma (RCC)

Renal cell carcinoma is by far the most common type of kidney cancer; about nine out of 10 kidney cancer diagnoses are RCCs. Renal cell carcinoma is about twice as common in men than in women. Most cases of RCC are discovered incidentally during imaging tests for other abdominal diseases. Worldwide, it is estimated there were more than 431,000 new cases of kidney cancer diagnosed and more than 179,000 deaths from the disease in 2020. In the U.S., it is estimated there will be more than 76,000 new cases of kidney cancer diagnosed and almost 14,000 deaths from the disease in 2021.

About Mercks Early-Stage Cancer Clinical Program

Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in earlier disease states, with approximately 20 ongoing registrational studies across multiple types of cancer.

About KEYTRUDA (pembrolizumab) Injection, 100 mg

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the bodys immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industrys largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient's likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Selected KEYTRUDA (pembrolizumab) Indications in the U.S.

Melanoma

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.

KEYTRUDA is indicated for the adjuvant treatment of patients with melanoma with involvement of lymph node(s) following complete resection.

Non-Small Cell Lung Cancer

KEYTRUDA, in combination with pemetrexed and platinum chemotherapy, is indicated for the first-line treatment of patients with metastatic nonsquamous non-small cell lung cancer (NSCLC), with no EGFR or ALK genomic tumor aberrations.

KEYTRUDA, in combination with carboplatin and either paclitaxel or paclitaxel protein-bound, is indicated for the first-line treatment of patients with metastatic squamous NSCLC.

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with NSCLC expressing PD-L1 [tumor proportion score (TPS) 1%] as determined by an FDA-approved test, with no EGFR or ALK genomic tumor aberrations, and is:

KEYTRUDA, as a single agent, is indicated for the treatment of patients with metastatic NSCLC whose tumors express PD-L1 (TPS 1%) as determined by an FDA-approved test, with disease progression on or after platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving KEYTRUDA.

Head and Neck Squamous Cell Cancer

KEYTRUDA, in combination with platinum and fluorouracil (FU), is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent head and neck squamous cell carcinoma (HNSCC).

KEYTRUDA, as a single agent, is indicated for the first-line treatment of patients with metastatic or with unresectable, recurrent HNSCC whose tumors express PD-L1 [combined positive score (CPS 1)] as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic HNSCC with disease progression on or after platinum-containing chemotherapy.

Classical Hodgkin Lymphoma

KEYTRUDA is indicated for the treatment of adult patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

KEYTRUDA is indicated for the treatment of pediatric patients with refractory cHL, or cHL that has relapsed after 2 or more lines of therapy.

Primary Mediastinal Large B-Cell Lymphoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with refractory primary mediastinal large B-cell lymphoma (PMBCL), or who have relapsed after 2 or more prior lines of therapy. KEYTRUDA is not recommended for treatment of patients with PMBCL who require urgent cytoreductive therapy.

Urothelial Carcinoma

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma (mUC):

Non-muscle Invasive Bladder Cancer

KEYTRUDA is indicated for the treatment of patients with Bacillus Calmette-Guerin-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

Microsatellite Instability-High or Mismatch Repair Deficient Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with MSI-H central nervous system cancers have not been established.

Microsatellite Instability-High or Mismatch Repair Deficient Colorectal Cancer

KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic MSI-H or dMMR colorectal cancer (CRC).

Gastric Cancer

KEYTRUDA, in combination with trastuzumab, fluoropyrimidine- and platinum-containing chemotherapy, is indicated for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Esophageal Cancer

KEYTRUDA is indicated for the treatment of patients with locally advanced or metastatic esophageal or GEJ (tumors with epicenter 1 to 5 centimeters above the GEJ) carcinoma that is not amenable to surgical resection or definitive chemoradiation either:

Cervical Cancer

KEYTRUDA, in combination with chemotherapy, with or without bevacizumab, is indicated for the treatment of patients with persistent, recurrent, or metastatic cervical cancer whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS 1) as determined by an FDA-approved test.

Hepatocellular Carcinoma

KEYTRUDA is indicated for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Merkel Cell Carcinoma

KEYTRUDA is indicated for the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma (MCC). This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials.

Renal Cell Carcinoma

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

KEYTRUDA is indicated for the adjuvant treatment of patients with RCC at intermediate-high or high risk of recurrence following nephrectomy, or following nephrectomy and resection of metastatic lesions.

Tumor Mutational Burden-High Cancer

KEYTRUDA is indicated for the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [10 mutations/megabase] solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options. This indication is approved under accelerated approval based on tumor response rate and durability of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. The safety and effectiveness of KEYTRUDA in pediatric patients with TMB-H central nervous system cancers have not been established.

Cutaneous Squamous Cell Carcinoma

KEYTRUDA is indicated for the treatment of patients with recurrent or metastatic cutaneous squamous cell carcinoma (cSCC) or locally advanced cSCC that is not curable by surgery or radiation.

Triple-Negative Breast Cancer

KEYTRUDA is indicated for the treatment of patients with high-risk early-stage triple-negative breast cancer (TNBC) in combination with chemotherapy as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment after surgery.

KEYTRUDA, in combination with chemotherapy, is indicated for the treatment of patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (CPS 10) as determined by an FDA-approved test.

Selected Important Safety Information for KEYTRUDA

Severe and Fatal Immune-Mediated Adverse Reactions

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the PD-1 or the PD-L1, blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of antiPD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. 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 KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA 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 adverse reactions are not controlled with corticosteroid therapy.

Immune-Mediated Pneumonitis

KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.

Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.

Immune-Mediated Colitis

KEYTRUDA can cause immune-mediated colitis, which may present with 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 colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.

Hepatotoxicity and Immune-Mediated Hepatitis

KEYTRUDA as a Single Agent

KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.

KEYTRUDA with Axitinib

KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT 3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT 3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT 3 ULN subsequently recovered from the event.

Immune-Mediated Endocrinopathies

Adrenal Insufficiency

KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Hypophysitis

KEYTRUDA can cause immune-mediated hypophysitis. 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 indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Thyroid Disorders

KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.

Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism.

Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis

Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.

Immune-Mediated Nephritis With Renal Dysfunction

KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.

Immune-Mediated Dermatologic Adverse Reactions

KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with antiPD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.4% (38/2799) of patients receiving KEYTRUDA, including Grade 3 (1%) and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 40% (15/38) of patients. These reactions led to permanent discontinuation in 0.1% (2) and withholding of KEYTRUDA in 0.6% (16) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 6% had recurrence. The reactions resolved in 79% of the 38 patients.

Other Immune-Mediated Adverse Reactions

The following clinically significant immune-mediated adverse reactions occurred at an incidence of <1% (unless otherwise noted) in patients who received KEYTRUDA or were reported with the use of other antiPD-1/PD-L1 treatments. Severe or fatal cases have been reported for some of these adverse reactions. Cardiac/Vascular: Myocarditis, 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 immune-mediated adverse reactions, consider a Vogt-Koyanagi-Harada-like syndrome, as this may require treatment with systemic steroids to reduce the risk of permanent vision loss; Gastrointestinal: Pancreatitis, to include increases in serum amylase and lipase levels, gastritis, duodenitis; Musculoskeletal and Connective Tissue: Myositis/polymyositis, rhabdomyolysis (and associated sequelae, including renal failure), arthritis (1.5%), polymyalgia rheumatica; Endocrine: Hypoparathyroidism; 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

KEYTRUDA can cause severe or life-threatening infusion-related reactions, including hypersensitivity and anaphylaxis, which have been reported in 0.2% of 2799 patients receiving KEYTRUDA. Monitor for signs and symptoms of infusion-related reactions. Interrupt or slow the rate of infusion for Grade 1 or Grade 2 reactions. For Grade 3 or Grade 4 reactions, stop infusion and permanently discontinue KEYTRUDA.

Complications of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT)

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Mum with brain fog and pins and needles in hands devastated by ‘ticking time bomb’ MS – Mirror.co.uk

The 36-year-old often suffers from "brain fog" forgetting the names of objects and getting confused during conversations along with several physical symptoms

Image: Tracey Harland)

A mum with a young daughter has opened up about living in constant anxiety with her multiple sclerosis (MS) as she aims to raise 45,000 to go towards her treatment.

Mum-of-one Tracey Harland from Houghton-le-Spring, near Sunderland, was diagnosed with MS in January 2019 after living with strange symptoms like pins and needles in her hands for years.

The 36-year-old would also often suffer from "brain fog" forgetting the names of objects and getting confused during conversations along with several physical symptoms, reports Chronicle Live.

Tracey, who described her MS as a "ticking time bomb", has since opened up on living with the fear one day she will wake up and not be able to walk.

The mum wants to be able to treat her MS to secure a better future for herself, partner Reece, 43, and four-year-old daughter Esme.

She explained: "I could start to lose the function of my hands, lose my sight, end up in a wheelchair.

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"When you have MS, you're constantly thinking about waking up and wondering if you'll be able to walk that day.

"There is no warning sign, you can't prepare for it. One day I will just be walking and my vision will go a bit wobbly, it's really scary.

"I have symptoms I deal with on a daily basis but I have this constant anxiety.

"I don't want to be a burden to my daughter."

Tracey lived with her symptoms for so long she believed "everyone suffered from them" and believed they were down to a problem with her back.

But as her symptoms got more worrying, Tracey believed she had MS and this was confirmed in January 2019 when she got an MRI scan.

The mum explained: "I used to get a stabbing pain in my foot and pins and needles in my hands and arms. I have got cognitive issues and I used to get tingling down my spine.

"I would get brain fog so I'd forget the names of things and if we were talking I'd forget what you said at the beginning and get confused about where the conversation was going.

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"When my daughter was born, about nine months later I got numbness on the right side of my face and it went down my neck and down my arm.

"I would go to my osteopath and in a couple of weeks, it would go away. I thought it was all down to issues with my back.

"I went to my GP who said: 'I think this is stress, you've just had a baby, you've returned to work' and they were really pushing anti-depressants.

"I said it doesn't feel quite right, I don't feel like this is what you think it is."

After her diagnosis, Tracey realised her symptoms made sense adding: "That's when I realised a lot of my symptoms I had been dealing with all these years, that I thought were normal were down to my MS.

"When my symptoms flared up I thought I overdid it with my back. All these years, I thought it was normal and everybody had these."

Tracey said MS is a progressive, silent disease that is still progressing in the background.

It is likely she will progress to secondary progressive MS which is when the bigger issues begin like losing speech and mobility.

Tracey is now hoping to raise enough money to get stem cell treatment (HSCT) at a clinic in Clinica Ruiz in Mexico, Monterrey which is 85% effective at halting the disease and could possibly reverse previous damage.

The HSCT treatment is available in the UK but Tracey said the NHS criteria is extremely strict and she is not eligible for it currently.

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The mum will stay at the clinic for 28 days where she will receive chemotherapy to kill her rouge immune system.

Although MS medication to slow down the progress is available on the NHS, Tracey believes the HSCT treatment is the best option.

She said: "I'm 36-year-old I have a four-year-old daughter I don't want to be slowing down the progression I want it to go away.

"This should be the first line of treatment, why take all these drugs to slow down the progression and wait to see how much worse it gets when you can potentially stop it."

Tracey's best friend Kirsty Spence set up a Go Fund Me page in a bid to raise the 45,000 needed.

She said: "The thought of not being able to push her child on a swing, chase her around the garden or just do a simple thing or go for a walk with her daughter and soon-to-be husband is a constant worry for Tracey.

"As MS is just a ticking time bomb with no cure, she has described it as living with a shadow over her life, constantly living with the fear that one relapse could change her whole world forever.

"Tracey is a beautiful soul, who never asks for anything from anyone. She is selfless, loving, and the strongest woman I know.

"She is a wonderful partner, daughter, sister, granddaughter, niece, and friend and a truly amazing mother to her daughter.

"To give her this chance of a healthy life would be the greatest gift anyone could offer."

If you would like to donate, you can do so here.

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Mum with brain fog and pins and needles in hands devastated by 'ticking time bomb' MS - Mirror.co.uk