Category Archives: Cell Medicine

The COVID-19 pandemic is what historians refer to as an "inflection point," ora singleevent that has a dramatic and sweeping effect on the human story. In the case of this particular event, itchanged the way we work, raised awareness about public health policy, contributed to the toppling of a president and, in the field of medicine, resulted in a leap forward for vaccine technology. Indeed,one of the great unsung achievements amid the pandemicwas how scientists from around the world worked together to create multipleeffective vaccines in less than a year.

Yet what may provemost historicisthe biotechnologythat emerged from the pandemic. Specifically,the vision of an mRNA vaccine went from dream to reality. And the successful creation of a viable mRNA vaccine couldhave repercussions for the way diseases are treated for centuries.

That technology, whose development was quickened by the pandemic, is already being studied to treatother diseases.Earlier this month, scientists at Yale Universitycreated a prototype mRNA vaccinethat protected guinea pigs from tick-borne diseases by training their immune systems to recognize and fight proteins found in tick saliva. They hope that, with some further development, this could be used to help humans avoid developing Lyme disease if a tick bites them.

Yet this is merely one example of mRNA vaccines'potential, revealing howthey have far more utility than merely fighting COVID-19. Indeed, mRNA vaccines are something of a holy grail of medical innovation and researchers believe thatmRNA vaccines and their underlying biotechnology could be used tofight diseases like HIV, cancer, and influenza.

The promise of mRNA vaccines

As their name suggests, mRNA vaccines depend on the nucleic acid known asRNA.RNA isa molecule similar to DNA, but it is single-stranded (DNA is double-stranded)and plays a large number of roles in keeping your cells alive and healthy. But don't think they are unique to humans: They are found in all living things. There are alsocertain types ofviruses like SARS-CoV-2, which causes COVID-19 that could be characterized as little more than RNA strands surrounded by protein shells. Like all viruses, theytake over cells and force them to churn out other copies of themselves, the worst kind of mooch you can imagine.

Yet RNA and mRNA are not precisely the same thing.mRNA refers to "messenger RNA," a specific type of RNA that (as indicated by its name) transmits information from genetic codes in the nucleus to the cytoplasm where proteins are manufactured.

This hints at how mRNA vaccines work, which is essentially by giving your cells a blueprint of a part of a virus, and then having them manufacture what they need on their own. Previously,vaccines contained either a dead or weakened version of a pathogen, which the immune system would then learn to recognize. But mRNA vaccines don't actually contain any of a live or dead virus; instead, they contain a set of instructions (in mRNA) that infects some of the host's cells and makes them spit out a piece of protein associated with a pathogen. One's cells never manufacture the actual virus; only a piece of its "shell," say. Those pieces are then detected by the immune system and identified and destroyed. It would be a bit like learning the presence of a criminal by identifying the look of their clothing, rather than the criminal themselves.

In the case of the mRNA vaccines manufactured by Pfizer and Moderna, the mRNA contains instructions for one's cells on how to create the spike protein. The spike proteins are the little points that emerge out of the coronavirus, like spines jutting from a sea urchin,and they are what the SARS-CoV-2 virus uses to enter your cells and get you sick with COVID-19.The mRNA vaccineshave been extraordinarily successful in protecting the vaccinated; even though they have not entirely thwartedbreakthrough cases, they significantly reduce the likelihood of getting sick, and the people who do develop infectionswith evasivemutant variants rarely become seriously ill. Most notably, mRNA vaccines were the first ones to be released on the market, with Pfizer/BioNTech and Moderna winning the vaccine race exactly one year ago this month.

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The next mRNA vaccines

In terms of their world-changing potential,mRNA vaccines have two key characteristics: They are quick to make, as demonstrated by the speed with which Pfizer/BioNTech and Moderna came out with their products, and by their very nature they are versatile.

As the Association of American Medical Colleges (AAMC) wrote in March, mRNA vaccine technology has the potential to treat diseases like malaria and cystic fibrosis, tuberculosis and hepatitis B. All scientists will have to do is modify RNA strands as needed to account for the different antigens (foreign substancesrecognized by the immune system as threats) produced by each pathogen.Instead of making do with the materials immediately available to them, mRNA vaccines make it possible for scientists to create more specialized weapons based on detailed knowledge of their enemies'specific characteristics.

Take the influenza epidemic. Oneso-called "holy grail"of immunology is a universal influenza vaccine. Right now there are four influenza viruses in circulation, all of which evolve so quickly that vaccines which were effective in one year may be obsolete by the next. This puts manufacturers in a crunch, as it takes at least six months to create the conventional vaccinationswith attenuated viruses grown inside chicken eggs. The final product, though almost always safe, has a very hit-and-miss rate ofeffectiveness. An mRNA vaccine, by contrast, could in theory be designed to effectively fight all four strains and be quickly modified as necessary when they evolve. In addition, while conventional vaccine platforms have to hit a precise target in order to destroy a givenintruder,an mRNA vaccine couldtargetmultiple parts of an influenza virus at once, overwhelming it with a full-body assault that can't be easily shaken off.

In fact, we already know that the early stages of mRNA flu vaccines were effective because scientists used that research to help develop their COVID-19 vaccines. This speaks to how malleable the platform is: While conventional vaccine platforms require patients to hope that the pathogen injected into their body is similar enough to a possible flu infection to be effective, mRNA vaccines could be precisely designed to meet the specific characteristics of each new strain as it emerges.

There will be challenges to pulling this off, of course. Anna Blakney, an RNA bioengineer at the University of British Columbia, told the journal Nature that there is no guarantee mRNA will be an effective vehicle for transportinghaemagglutinin glycoproteins, the protein that flu vaccines use to fight the different bugs. As Blakney put it,"Did we just get really incredibly lucky with COVID vaccines because of the antigen design and the immunodominancy of that protein? Or have we stumbled on something that's functional for other viral glycoproteins as well?"

In addition to aiding in the war against influenza, mRNA vaccines could also be a game-changer in the fight against cancer. In the pre-mRNA vaccine world, the mere notion of a "cancer vaccine" would have seemed ludicrous; vaccines work by protecting your body against a foreign invader, and cancers (as far as we know) are caused by your own body producing mutated cells. Yet just as an mRNA vaccine can help your immune system recognize and destroy proteins associated with dangerous pathogens, they could in theory be developed to identify and eliminate proteins associated with cancer cells and, of course, the cancer cells themselves.

"A successful therapeutic cancer vaccine should induce strong T cell responses, particularly with CD8+ T cells, which have a known capacity to kill malignant cells," Dr. Norbert Pardi, whose research led to the develop of the Pfizer and Moderna vaccines, explained to the University of Pennsylvania. "Therapeutic cancer vaccines would be given to cancer patients with the hope that those vaccine-induced cytotoxic T cells would clear tumor cells."

HIV mRNA vaccines are theorized to be possible, though there are massive hurdles to be overcome. The challenge so far has been that none of the vaccine candidates developed up to this point have produced broadly neutralizing antibodies, which are vital to blocking HIV in target cells. Scientists hope that an mRNA vaccine would create an immunogen (an antigen that induces an immune response) that resembles the HIV virus and can help the body develop those broadly neutralizing antibodies against it. Unfortunately, researchers are still very early in working through this, and it seems like a HIV vaccine using this technology is not in the near future.

"We certainly think that an HIV vaccine will be far and away the most complicated vaccine that we've ever had to put into the population," Derek Cain of Duke University's Human Vaccine Institute told The Guardian. "We don't expect it to work 100% or 90% like the Covid vaccines, but even if we can get to 50-60% that would be a success; 70% would be amazing."

What comes next

The future for mRNA technology is not one of unbounded promise. As the AAMC noted, each virus poses its own individual puzzle, which makes it unlikely that other ailments can be treated with the rapid success that occurred when fighting COVID-19. Similarly, although the COVID-19 vaccines have so far not caused widespread serious side effects, this may not be true for other mRNA vaccines; more research will definitely be needed. In addition, the COVID-19 pandemic was such an overwhelmingand serious crisis that the international community collaborated in fruitful ways that may not repeat themselves if a future outbreakseemsless urgent.

There are also logistical factors to take into consideration. The supply chain breakdowns prompted by the pandemic are poised to get worse due to climate change, and experts are already concerned that mRNA vaccines will get destroyed as they are transported because they must be kept in very clean and ultra-cold conditions. It is hard to imagine that the impendingsupply chain deteriorations won't exacerbate that problem, as will the ongoing disease of misinformation. Since anti-vaccine advocates can alter their baseless beliefs as easily as viruses change their genetic composition, some of this misinformation specifically targets mRNA platforms. One particularly prevalent myth right now is that mRNA vaccines change your DNA, even though (as the above explanation makes clear) this betrays a deep ignorance about how vaccines, viruses, cellular biology and the immune system actually work.

Finally, as with all biotechnology, governments and businesses will have to adequately invest.

"Despite the promise of mRNA vaccines, we caution that they are far from a silver bullet for future pandemics," Michael J. Hoganand Norbert Pardiwrite in anAnnual Review of Medicine article."Comprehensive pandemic preparedness requires significant new investments in viral surveillance, proactive clinical testing of vaccines for pandemic-potential viruses, new diagnostic technologies, broad-spectrum antiviral treatments, and stockpiling of materials."

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mRNA vaccines changed the course of the pandemic. Now, they could cure all kinds of other diseases - Salon

The new technique, which was developed at the Washington University School of Medicine in St Louis, was shown to convert human stem cells into cells producing insulin. The natural hormone is produced in the pancreas and allows the body to use glucose (sugar) from food for energy. People who suffer from diabetes struggle to produce enough insulin, which leads to a build-up of sugar in the bloodstream.

The St Louis researchers, however, believe their new technique can be used to effectively control blood sugar levels using converted stem cells.

The technique has so far been successfully tested on mice injected with the converted cells.

According to a report that is due to be published on February 24 in the online edition of the journal Nature Biotechnology, the mice were "functionally cured" for nine months.

Dr Jeffrey R. Millman, the principal investigator and assistant professor of medicine and of biomedical engineering, said: "These mice had very severe diabetes with blood sugar readings of more than 500 milligrams per deciliter of blood levels that could be fatal for a person and when we gave the mice the insulin-secreting cells, within two weeks their blood glucose levels had returned to normal and stayed that way for many months."

The same team of researchers has previously discovered how to convert human stem cells into so-called pancreatic beta cells to make insulin.

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When these cells are injected into the bloodstream, they secret the much-needed hormone.

However, the technique was found to have its limitations and was not proven to effectively control the disease in mice.

Their new research has now proven to be much more efficient and effective.

Embryonic stem cells are a type of cell that can be instructed to develop into all sorts of specialised cells.

These can range from simple tissue and muscle cells, to even brain cells.

Scientists worldwide believe stem cell research could unlock many new therapies for ailments such as Alzheimer's disease and HIV.

Dr Millman said: "A common problem when youre trying to transform a human stem cell into an insulin-producing beta cell or a neuron or a heart cell is that you also produce other cells that you dont want."

"In the case of beta cells, we might get other types of pancreas cells or liver cells."

Pancreas and liver cells do not cause any harm when injected into mice but they do not fight the disease either.

Dr Millman added: "The more off-target cells you get, the less therapeutically relevant cells you have.

"You need about a billion beta cells to cure a person of diabetes.

"But if a quarter of the cells you make are actually liver cells or other pancreas cells, instead of needing a billion cells, youll need 1.25 billion cells.

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"It makes curing the disease 25 percent more difficult."

With their new technique, the researchers found fewer off-target cells were produced and the beta cells that were created had improved.

The technique specifically targets the cell's so-called internal scaffolding or cytoskeleton.

The cytoskeleton is what gives cells their shape and allows them to interact with their environment.

Dr Millman said: "Its a completely different approach, fundamentally different in the way we go about it.

"Previously, we would identify various proteins and factors and sprinkle them on the cells to see what would happen.

"As we have better understood the signals, weve been able to make that process less random."

Although the study's results are promising, the expert added there is a long way to go before the technique can be developed into a treatment for humans.

The converted cells will need to be tested over longer periods of time and in bigger animals.

According to Diabetes UK, some 5.5 million people are estimated to have diabetes in the UK by 2030.

Right now, more than 4.9 million people are affected by the disease and 13.6 million people are at increased risk of type 2 diabetes.

About 90 percent of people with the disease have type 2 diabetes, and only about eight percent have type 1 diabetes.

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Diabetes breakthrough: Revolutionary stem cell technique treated 'severe' disease in study - Daily Express

Titilope Fasipe, MD, PhD, Assistant Professor of Pediatric Hematology-Oncology, Baylor College of Medicine, served as the opening plenary speaker at the National Organization for Rare Disease (NORD) summit.

In her presentation, Fasipe shed some light on the history of sickle cell disease; she also shared about her personal experience being a doctor and a patient of the rare disease.

Sickle cell disease is a rare disease in the US, but, it's not a rare disease worldwide, Fasipe explained. Millions of people are affected by it around the world compared to under 200,000 people in the US.

"You end up seeing 2 different ways of experiencing the disease," Fasipe said. "I had the experience of having both, because I was born in Nigeria, and then I came to the United States and I've been raised in both places."

During her presentation, Fasipe shared her journey, what led her to medical school, and how she found her advocacy voice.

It was important to her to leave the audience with an understanding of sickle cell disease that included the social determinants of health.

For sickle cell in the US, that includes long-standing historical neglect, systemic racism injustices, poor access to healthcare for many of individuals, as well as decreased community awareness that's seen with all rare diseases, Fasipe explained.

"The good news is, coming together does make things count," she said. "And that was the theme of the session, and so I felt like it was appropriate to show how I see a light at the end of the tunnel even though there's challenges, and part of that is working together with others."

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Titilope Fasipe, MD, PhD, Shares Her Presentation from the NORD Summit - MD Magazine

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)

Read more from the original source:
FDA Approves Merck's KEYTRUDA (pembrolizumab) as Adjuvant Therapy for Certain Patients With Renal Cell Carcinoma (RCC) Following Surgery - Business...

SAN DIEGO--(BUSINESS WIRE)--Third paragraph, sixth sentence of release should read: CNSide detected CSF tumor cells in all eleven measurements taken, compared to six of eleven using cytology. (instead of CNSide detected CSF tumor cells in all nine measurements taken, compared to five of nine using cytology.)

The updated release reads:

BIOCEPTS CNSIDE CEREBROSPINAL FLUID ASSAY AIDS IN MONITORING TREATMENT RESPONSE AND DETECTS ACTIONABLE BIOMARKERS IN PATIENTS WITH METASTATIC BREAST CANCER

Case series poster to be presented at the Society for Neuro-Oncology Annual Meeting

Biocept, Inc. (Nasdaq: BIOC), a leading provider of molecular diagnostic assays, products and services, today announced the presentation of a multi-institutional case series showing that its CNSide cerebrospinal fluid assay helps physicians monitor treatment response and detects actionable mutations in patients with metastatic breast cancer and leptomeningeal disease (LMD). The poster will be presented virtually at the Society for Neuro-Oncology Annual Meeting in Boston, Nov. 19, 2021, from 7:30-9:30 p.m. ET, and Biocept will be exhibiting at booth #303.

Breast cancer is one of the most common cancers associated with LMD, a devastating complication in which cancer spreads to the membrane surrounding the brain and spinal cord. The current standard of care for diagnosing LMD is through clinical evaluation, imaging and cytology, which have limited sensitivity. Median survival after a diagnosis of LMD is just two to three months.

The case series included four breast cancer patients, ages 32 to 57, with suspected LMD who were treated at four different institutions. CNSide and cytology were used in parallel to detect tumor cells in the cerebrospinal fluid at diagnosis and throughout treatment. CNSide was also used to determine tumor cell counts and the presence of HER2 amplification to help guide therapy. At diagnosis, CNSide detected cancer cells in three of three patients, compared with two of three patients for cytology. (The fourth patient was diagnosed before CNSide was available.) CNSide detected CSF tumor cells in all eleven measurements taken, compared to six of eleven using cytology. Throughout treatment, CNSide showed a decrease in CSF tumor cells in all four patients, ranging from 99.7% to 100%, corresponding with an improved clinical response.

Having a quantitative assay that provides tumor cell counts, rather than just a positive or negative result, is a major advance in the management of patients with leptomeningeal disease, said Priya Kumthekar, M.D., Neuro-Oncologist and Associate Professor of Neurology at Northwestern Medicines Feinberg School of Medicine, who will present the case series poster. A positive cytology result may suggest that the patient is not responding to treatment, which could lead to therapy being stopped or changed. As this case series shows, CNSides quantitative results may show that, in fact, the tumor cell count has dropped dramatically, indicating that the patient is responding, and therapy should be continued.

These cases illustrate the value of CNSide in treatment response monitoring and identification of targets for therapy that can produce a sustained response in leptomeningeal disease, said Michael Dugan, M.D., Chief Medical Officer and Medical Director of Biocept. CNSide has the potential to allow clinicians to have more confidence in their treatment decisions, improving the clinical management of leptomeningeal disease in a way that may help patients see improvement in symptoms and live significantly longer lives.

The case series was completed by neuro-oncologists from Smilow Cancer Hospital at Yale New Haven Health, Lou and Jean Malnati Brain Tumor Institute at Northwestern Medicine, UT Southwestern Medical Center and Barrow Neurological Institute. The abstract (#BIOM-05), titled Case Series of Multi-Institutional Utility of CNSide to Manage Leptomeningeal Disease in Patients with Metastatic Breast Cancer, can be accessed here.

About Biocept

Biocept, Inc., develops and commercializes molecular diagnostic assays that provide physicians with clinically actionable information to aid in the diagnosis, treatment and monitoring of patients with cancer. In addition to its broad portfolio of blood-based liquid biopsy tests, the company has developed the CNSide cerebrospinal fluid assay, designed to diagnose cancer that has metastasized to the central nervous system. Biocept also is leveraging its molecular diagnostic capabilities to offer nationwide RT-PCR-based COVID-19 testing and services to support public health efforts during this unprecedented pandemic. For more information, visit http://www.biocept.com. Follow Biocept on Facebook, LinkedIn and Twitter.

Forward-Looking Statements Disclaimer

This release contains forward-looking statements that are based upon current expectations or beliefs, as well as a number of assumptions about future events. Although Biocept believes that the expectations reflected in the forward-looking statements and the assumptions upon which they are based are reasonable, Biocept can give no assurance that such expectations and assumptions will prove to have been correct. Forward-looking statements are generally identifiable by the use of words like "may," "will," "could," "expect," or "believe" or the negative of these words or other variations on these words or comparable terminology. To the extent that statements in this release are not strictly historical, including without limitation statements regarding the capabilities and potential benefits of Biocepts CNSide assay and the ability of Biocepts assays to provide physicians with clinically actional information, such statements are forward-looking, and are made pursuant to the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. The reader is cautioned not to put undue reliance on these forward-looking statements, as these statements are subject to numerous risks and uncertainties, including the risk that Biocepts products and services may not perform as expected. These and other risks are described in greater detail under the "Risk Factors" heading of Biocepts Quarterly Report on Form 10-Q for the quarter ended September 30, 2021, filed with the Securities and Exchange Commission (SEC) on November 15, 2021. The effects of such risks and uncertainties could cause Biocepts actual results to differ materially from the forward-looking statements contained in this release. Biocept does not plan to update any such forward-looking statements and expressly disclaims any duty to update the information contained in this press release except as required by law. Readers are advised to review Biocepts filings with the SEC, which can be accessed over the Internet at the SEC's website located at http://www.sec.gov.

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CORRECTING and REPLACING Biocept's CNSide Cerebrospinal Fluid Assay Aids in Monitoring Treatment Response and Detects Actionable Biomarkers in...

COVID-19 vaccine booster doses may be needed to strengthen immunity among cancer patients, a new study finds. File photo by Debbie Hill/UPI | License Photo

Nov. 17 (UPI) -- Booster doses of the COVID-19 vaccine provide vital additional immunity to cancer survivors and those receiving treatment for the disease, according to a study published Wednesday by the journal Cancer Cell.

One group of cancer patients with detectable antibodies, which are proteins produced by the immune system to fight off infections, saw their levels decline four to six months after receiving their second dose of either the Moderna or Pfizer-BioNTech vaccine, the data showed.

In a second group, 64% had detectable antibodies, while the remainder did not, the researchers said.

However, after all patients in the study received a booster dose of a COVID-19 vaccine, 80% had antibody levels that were higher than before they received their booster shot.

In addition, 56% of those who previously had no detectable antibodies after standard vaccination had them after receiving their booster shot, they said.

"We've been learning how devastating COVID-19 can be not just for the general population, but in particular for our cancer patients," study co-author Dr. Lauren Shapiro told UPI in a phone interview.

"These patients responded incredibly well to the booster vaccination, even those who had no detectable antibodies after their initial round of vaccination," said Shapiro, a third-year hematology/oncology fellow at Montefiore Medical Center and Albert Einstein College of Medicine in New York City.

This means that these patients have "some protection" against COVID-19, she said.

The Food and Drug Administration in October announced that booster doses of the COVID-19 vaccines are recommended for people in certain at-risk groups, including people with cancer and those under treatment for the disease.

Cancer can weaken the body's immune system as can some forms of chemotherapy, which is among drugs used to treat the disease.

As a result, many cancer survivors and cancer patients in treatment are considered "immunocompromised," so they may be more susceptible to COVID-19 and need additional doses of the vaccines to fight off the virus, Shapiro said.

Earlier studies have shown that the vaccines are safe for people with cancer.

For this study, Shapiro and her colleagues assessed the antibody response in 187 cancer patients at Montefiore who were fully vaccinated against COVID-19.

Participants underwent blood testing for antibodies against the virus immediately after becoming fully vaccinated and again four to six months later, the researchers said.

More than three-fourths of the participants were undergoing cancer treatment at the time of the study.

Of the participants, 88 received a booster dose of the vaccine at least 28 days after their second dose of either the Moderna or Pfizer-BioNTech vaccines, both of which require two shots, or one dose of the Johnson & Johnson vaccine.

Among participants, 70% were vaccinated with the Pfizer-BioNTech vaccine, 25% with Moderna and 5% with Johnson & Johnson, the researchers said.

Participants who received the booster were an average age of 69 and almost evenly split between men and women. In addition, 65% had blood cancer and 35% had a solid tumor.

Cancer survivors and those undergoing treatment may want to check in with the oncologists before getting vaccinated against COVID-19 or receiving a booster dose, but previous studies suggest there is no reason for them to avoid the shots, Shapiro said.

An oncologist may "recommend specific timing for their booster vaccination depending on each patient's specific situation," Shapiro said.

"Our study does show, however, that booster vaccination is both safe and efficacious even in the majority of patients on active cancer directed therapy and therefore we would advocate for timely booster vaccination in coordination with their providers," she said.

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COVID-19 vaccine booster effective in people with cancer, study finds - UPI.com

Broadcast Date:December 16, 2021Time:9:00 am PT, 12:00 am ET, 18:00 CET

The retina is a multilayered, highly heterogeneous neuronal tissue with intricate cellular interactions. Single-cell multiomics allows us to take steps toward understanding the biology of this complex tissue through the ability to identify and characterize all cell subtypes. Thus, a single cell transcriptomic and epigenomic atlas of the retina can be a valuable resource in opening new opportunities for future mechanistic studies.

In this GEN webinar, our distinguished presenter, Dr. Rui Chen, will discuss how his team at Baylor College of Medicine took on the complexity of gene expression and regulation in the human retina by generating a multiomic cell atlas at single-cell resolution. snRNA-seq data from over 250,000 nuclei and snATAC-seq data from over 150,000 nuclei were combined to form a highly comprehensive atlas, resulting in the identification of over 60 different cell types at a sensitivity of 0.01%. In addition, integrative analysis of this data showed 70,000 distal cis-element gene pairs, a majority of which were cell type-specific and had been overlooked in the previous investigation via bulk profiling. eQTLs from the bulk analysis were combined with the multiomic single-cell atlas to yield candidate causal variants for targeted genes within the context of cell-type data. Taken together, this comprehensive single-cell atlas enables systematic, in-depth molecular characterization of cell subtypes in the human retina.

A live Q&A session will follow the presentations, offering you a chance to pose questions to our expert panelists.

Read more:
Single Cell Multiomic Atlas of the Human Retina: An Integrative Analysis - Genetic Engineering & Biotechnology News

Lynn M. Matrisian, PhD, MBA, and Allison Rosenzweig, PhD, from Pancreatic Cancer Action Network, review advances in the pancreatic cancer setting for World Pancreatic Cancer Awareness Day.

The Pancreatic Cancer Setting

Cancer of the pancreas is relatively rare in the United States (U.S.), ranking eleventh in cancer incidence with 60,000 cases estimated in 2021.1 Despite the low incidence, pancreatic cancer is becoming much more widely knownand fearedas a result of high-profile cases, including singer Aretha Franklin, Supreme Court Justice Ruth Bader Ginsburg, Jeopardy host Alex Trebek, and Representative John Lewis. It is known as a disease that strikes rapidly and aggressively, with minimal treatment options and short survival times. This impression is justified since pancreatic cancer holds the distinction of being the deadliest of the major cancers tracked by the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program as determined by the lowest 5-year relative survival rate.1

The combination of being rare and deadly complicates the treatment of pancreatic cancer in the community setting, where most patients with cancer in the U.S. are seen. Based on the estimate of 13,146 oncologists engaged in patient care in 2021,2 an oncologist on average would see 4 to 5 cases of pancreatic cancer per year, and only 1 would be alive a year later (35% 1-year survival, SEER-18 2000-2018). Unless substantial changes occur soon, the situation will worsen. In contrast to the trend for a continued decrease in mortality from cancer in general, the number of deaths from pancreatic cancer is increasing and are projected to surpass colorectal cancer deaths to become second only to lung cancer before 2030.3 These projections are a wake-up call that a significant commitment to advancing the management of pancreatic cancer now is required to avoid the burden of pancreatic cancer deaths predicted by current trends.

The exceptionally poor survival rate from pancreatic cancer can be attributed to factors such as the ambiguity of symptoms and aggressive nature of the pancreatic adenocarcinoma (PDAC) form of the disease. Fifty-two percent of cases of newly diagnosed PDAC present with distant metastases, 30% with regional lymph node involvement, and only 11% have tumors that are localized solely within the pancreas (SEER-18 2011-2017). Survival rates are stage-dependent: 42% for localized disease, 14% regional, and 3% metastatic make up the overall 5-year relative survival rate of 10.8% (SEER-18 2011-2017). These stark numbers explain the 2 major areas of research focus within the pancreatic cancer field: identifying better chemotherapeutic treatments to extend the lives of patients with metastatic disease and developing a strategy to detect pancreatic cancer earlier when it is localized to the pancreas and can be surgically resected.

Symptoms and Advances in the Early Detection of Pancreatic Cancer

If the stage distribution at the time of diagnosis of PDAC could be reversed so that more than 50% of individuals present with localized disease and only 10% are already metastatic, survival would be more than doubled without any additional improvements in therapy.4 For this reason, considerable effort has gone into research to identify individuals at risk of pancreatic cancer and developing surveillance programs and biomarkers to find pancreatic cancer earlier.

Between 10% to 15% of PDAC cases are found in individuals with an elevated risk based on an inherited gene. In some cases, there is a strong family history of pancreatic cancer. The risk of familial pancreatic cancer, defined as a family with at least 1 first-degree relative pair (parent/child or sibling/sibling), varies depending on the number of affected individuals in the family and degree of relatedness but is increased on average approximately 9-fold over the general population.5 In some cases, the gene responsible for familial PDAC is known and can include those involved in hereditary breast and ovarian, melanoma, and colon cancer syndromes. However, there are cases of PDAC in individuals who are found to carry a hereditary predisposition gene and have no known relative with PDAC but may have relatives with other cancer types.6 This realization resulted in changing in National Comprehensive Cancer Network (NCCN) and American Society of Clinical Oncology (ASCO) guidelines to indicate all patients diagnosed with PDAC should receive genetic testing for hereditary syndromes.7,8 Cascade testing of family members of patients with a predisposition gene helps determine their risk of developing the disease, which varies depending on the affected gene.

Most PDAC cases are sporadic, with no indication of inherited risk. Symptoms of pancreatic cancer are often vague and likely to be attributed to changes in daily activities, including abdominal or mid-back pain, unexplained weight loss, loss of appetite, indigestion, and changes in stool. The development of jaundice is more likely to be recognized as a worrisome symptom and evoke imaging follow-up. New-onset diabetes is an often-unrecognized symptom of pancreatic cancer that is providing an opportunity to develop cohorts of individuals at risk of sporadic PDAC and validate biomarker and algorithm-based approaches to improving the early detection of PDAC.9PDAC arises from benign precursors referred to as pancreatic intraepithelial neoplasms (PanIN), as well as from subsets of pancreatic cysts. Pancreatic cysts are common, and mucinous cystic neoplasm and intraductal papillary mucinous neoplasms have varying malignant potential; their detection and clinical management is addressed by guidelines from several organizations.10

Surveillance programs for high-risk individuals relies on imaging by endoscopic ultrasonography and/or MRI/magnetic resonance cholangiopancreatography.11 Results following 16 years of follow-up of individuals with genetic factors or family history of PDAC enrolled in the Cancer of the Pancreas Screening (CAPS) study revealed that most PDAC detected during surveillance were resectable with significantly improved survival relative to those who had PDAC detected outside of surveillance.12

There are several commercially developed screening assays that provide encouragement that breakthroughs in the early detection of pancreatic cancer will occur sooner rather than later. The IMMray PanCan-d blood test for protein biomarkers was released in 2021 for the early detection of PDAC in individuals at high risk for familial or hereditary pancreatic cancer. The Galleri multicancer blood test for methylated circulating DNA includes pancreatic cancer and is recommended for the general population of adults age 50 or older.13 There are also tests of cyst fluid to distinguish cysts with low vs high risk of progression to pancreatic cancer, including CompCyst,14 PancreaSeq,15 and Pancragen.16 None of these tests are FDA approved or acknowledged by the U.S. Preventive Services Task Force as being of sufficient clinical utility for use in screening for pancreatic cancer but represent an advance and an opportunity for further studies to reach that goal.

Advances in the Treatment of Pancreatic Adenocarcinoma

Chemotherapies

Advances in the treatment of PDAC in the U.S. have arisen from the testing of regimens that were successful in other cancer types as well as from clinical research leading to FDA approval for new treatment entities. Progress has historically been slow, with less than 10% of phase 3 trials for the first-line treatment of PDAC resulting in a clinically meaningful advance.17 Currently, the 4-drug regimen FOLFIRINOX (folinic acid, fluorouracil [5-FU], oxaliplatin, irinotecan) and the combination of gemcitabine and nab-paclitaxel are standard therapies for metastatic pancreatic cancer, with gemcitabine alone often used for individuals with low performance status. The first approved second line treatment for patients with metastatic PDAC who received gemcitabine in the first line occurred in 2015 and consists of 5-FU + nal-irinotecan.18

The success of gemcitabine- and FOLFIRINOX-based regimens for metastatic disease resulted in their testing and use for adjuvant treatment for earlier stage PDAC.19,20 Still under debate is the relative benefit of chemotherapy or radiation therapy in the preoperative vs postoperative setting and the agents of choice for neoadjuvant therapy for those diagnosed with resectable or borderline resectable disease. Neoadjuvant therapy is used in many U.S. institutions based on reports of clinical trials from Asia21,22 and Europe23 as the results from ongoing U.S. clinical trials are awaited.

Interestingly, there has been an improvement in survival with standard-of-care chemotherapies over time. The median overall survival (OS) with gemcitabine treatment reported in phase 3 trials between 1993 and 2000 was 5.5 months; between 2001 and 2006, 6.2 months; and 2007 and 2012, 8.1 months.17 The combination gemcitabine plus nab-paclitaxel resulted in an 8.5-month median OS in a trial that completed in 201224 and 10.8 months in the control arm of a trial that completed in 2018.25 Presumably this increase reflects experience with the drugs and improvements in supportive care measures.

Precision medicine

The success of precision medicine in cancer in general has benefited subsets of patients with pancreatic cancer. Enthusiasm for a precision medicine approach in PDAC was initially dampened by the difficulty and risk in obtaining sufficient tissue and the presence of KRAS mutations in over 90% of cases. However, studies indicated approximately 25% of PDAC tumors contained molecular alterations that suggested potential benefit from investigational or approved therapeutic agents.26-29 The Pancreatic Cancer Action Networks Know Your Tumor program, which provides biomarker testing for patients throughout the U.S., reported that individuals with molecular alterations who received targeted therapy had an OS 1 year longer than those who did not receive targeted therapy or with no molecular alteration (2.58 vs 1.51 and 1.32 years median OS, respectively).30 The holy grail of PDAC precision medicine would be targeting the common KRAS G12D, G12V, or G12R mutations (41%, 34%, and 16% of PDAC, respectively).31 The recent approval of sotorasib (Lumakras) for KRAS G12C mutant nonsmall cell lung cancer provides hope that such agents are forthcoming.32

Alterations in BRCA1/2 are currently the most common targetable molecular alteration and are identified in 5% to 10% of PDAC.33 Olaparib (Lynparza), a PARP inhibitor, has been approved in the maintenance setting for patients with PDAC with germline alterations in BRCA1/2 genes.34 Results from the ASCO Targeted Agent and Profiling Utilization Registry (TAPUR) study indicate olaparib efficacy in patients in PDAC with either germline or tumor specific BRCA1/2 inactivating mutations.35 The advent of FDA tissue-agnostic approvals of targeted therapies for biomarker-identified cancers plays an important role in patients with pancreatic cancer realizing the benefits of precision medicine. Although NTRK fusions (<1%)36 and microsatellite instability-high/mismatch repair-deficient alterations (~1%)37 are found only rarely in pancreatic cancer, the existence of these FDA-approved treatment options for these individuals justified NCCN guideline changes to recommend genetic testing for inherited mutations of all patients with pancreatic cancer and biomarker testing of tumor tissue of those with pancreatic cancer seeking treatment.8

Immunotherapy

PDAC has the reputation of being an immunologically cold tumor and non-responsive to single-agent checkpoint inhibitors. The exception is a small subset of molecularly-defined PDAC with microsatellite instability, mismatch repair deficiency, or high tumor mutational burden.38,39 There has been a substantial increase over the past decade in clinical trials testing hypotheses related to the influence of PDAC-associated desmoplasia in excluding T-cells and the presence of abundant immunosuppressive cells.40 Immunotherapy trials now make up 30% of the approximately 150 total PDAC clinical trials open in the U.S. at any one time.41 The complexity of these trials has increased over time; trials in 2011 and 2012 tested a vaccine or an immune modulating agent alone or in combination with gemcitabine; between 2013 and 2015, trials included a checkpoint inhibitor; and the complexity of the immunotherapeutic combinations increased from 2016 onwards. These trends are likely to indicate an acknowledgement of the need to address the immunological complexity of PDAC if we are to hope for a significant benefit for most patients with PDAC.

The Future of Pancreatic Cancer Management

As we contemplate the future, the trajectory for advances in pancreatic cancer management are encouraging. The 5-year survival rate more than doubled over the past 25 years, from 4.6% to 11.2%, whereas survival from all cancers combined exhibited a more modest increase from 62% to 69% (SEER-9, 1990-1992 vs 2011-2017).

Advances for pancreatic cancer are coming at both ends of the spectrum: the detection of earlier stage disease and the management of metastatic disease.The change in guidelines so patients with pancreatic cancer get tested for predisposition genes and inform family members should significantly increase the number of individuals aware of an elevated pancreatic cancer risk. Advances in blood-based biomarkers for early detection will be facilitated by studies collecting pre-diagnostic samples for validation studies, and artificial intelligence approaches to imaging are likely to improve the detection of pancreatic cancer at a much earlier, resectable stage. Improved survival following standard chemotherapies, the growing list of FDA-approved drugs for molecularly defined cancers, and the substantial efforts focused on converting the pancreatic cancer microenvironment into one that is responsive to immunotherapies suggests there will be many more tools in the medical oncologists toolkit soon.

The FDA has suggested that master protocol platform trials represent the future of cancer clinical research.42 The pancreatic cancer field has joined this movement, and the Pancreatic Cancer Action Networks Precision Promisesm, a phase 2/3 registration-ready platform trial for metastatic pancreatic cancer in the first and second line, joins platform trials in several other diseases as a way to streamline and accelerate development and FDA approval of new therapies. We look forward to the day when pancreatic cancer is no longer considered the poster child for a terminal disease.

References:

1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71(1):7-33. doi:10.3322/caac.21654

2. 2021 Snapshot: State of the Oncology Workforce in America. JCO Oncol Pract. 2021;17(5):249. doi:10.1200/OP.21.00166

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World Pancreatic Cancer Awareness Day: Advances in Pancreatic Cancer Detection and Treatment - Targeted Oncology

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A microscopy technique created at UT Southwestern and powered by machine learning can detect multiple biochemical reactions in single cells in real time. The study found levels of the Xbp1 protein (green) rise in response to repeated or prolonged stress. Each colored hexagon corresponds to a different biochemical reaction tracked in the cells displayed in the center hexagon.

DALLAS Oct. 26, 2021 UT Southwestern researchers have identified a new mechanism by which stress causes cells to stop dividing.

Using techniques created at UT Southwestern, the team identified a protein in yeast that plays a previously unrecognized role in halting the cell cycle, the process by which one cell reproduces itself by splitting into two. After accumulating in response to stressful events, the Xbp1 protein appears to suppress the cell cycle, the study suggests.

The findings, published in the Journal of Cell Biology, appear to solve one long-standing mystery of the cell cycle. If scientists can identify a protein in mammals with a similar function, the research might eventually lead to new ways to accelerate wound healing by encouraging cell division or improve cancer treatment by doing the opposite.

Scientists have been studying this fundamental process for nearly seven decades, said Orlando Argello-Miranda, Ph.D., an Instructor who co-led the study with Assistant Professor Jungsik Noh, Ph.D., both of UTSWs Lyda Hill Department of Bioinformatics. Weve essentially identified a protein that can stop the cell cycle in response to stressful conditions.

Scientists have long known that the cell cycle consists of several defined stages as a cell goes from a resting state to increasing in size as it copies its genetic material or DNA in a process known as DNA replication, condenses its DNA, and finally divides into two daughter cells.

It has long been known that a stressful event such as starvation can send a cell into a protective state known as quiescence. Typically, the cell cycle halts just before DNA replication takes place, Dr. Argello-Miranda explained. However, a minority of cells seem to become quiescent at other points in the process.

To understand why, Dr. Argello-Miranda, Dr. Noh, and their colleagues studied yeast cells challenged by nutritional stress. The researchers were able to study individual cells in that state by using a technique called microfluidics six-color imaging developed at UT Southwestern. That technique combines a technology for cell culture called microfluidics with a six-color fluorescent-microscopy approach pioneered at UTSW in 2018. In microfluidics six-color-imaging, investigators pass cells through a tiny, fluid-filled chamber monitored with a specialized microscope and camera array. The researchers also used machine learning to track and detect up to six biochemical reactions in single cells in real time.

In previous studies in the field, researchers cultured yeast cells in flasks and were unable to track single cells, Dr. Argello-Miranda said. In contrast, we have obtained movies that record how individual cells stop dividing and enter quiescence.

Although most of the starved cells entered quiescence at the expected stage, right before DNA replication, about 7% paused at another stage of the cell cycle, he said.

Using the new techniques to tag and follow specific proteins in individual cells over time, the researchers found that all the starved cells showed elevated levels of a suite of stress response proteins. However, cells that became quiescent at unexpected points in the cell cycle all had an abundance of Xbp1, which the study found is needed to stop the cell cycle after DNA replication.

Further experiments showed that this accumulation of Xbp1 caused the cell cycle to pause, even when the activity of another protein called Cdk1 that encourages cell proliferation is high. A closer look showed that Xbp1 levels werent static rather, they climbed higher after each stressful event an individual cell experienced or the longer a stressful event lasted.

This accumulation was so predictable we could tell how many stressful events a cell had been exposed to by how much Xbp1 was present in the cell nucleus, Dr. Argello-Miranda said. The findings suggest that Xbp1 has a newly discovered function in regulating the cell cycle, allowing yeast cells to remember exposure to stress and to protect themselves by entering quiescence, he added.

Although there is no direct homolog to Xbp1 in mammals, other proteins seem to show similar biochemical activity in mammalian cells. Those proteins will be the subject of future research, he said.

This work was supported by grants from the Cancer Prevention and Research Institute of Texas (RP150596 and RR150058), The Welch Foundation (I-1919-20170325), and the National Institute of General Medical Sciences of the National Institutes of Health (K99GM135487).

Other UTSW researchers who contributed to this study include Ashley J. Marchand, Taylor Kennedy, and Marielle AX Russo.

About UTSouthwestern Medical Center

UTSouthwestern, one of the nations premier academic medical centers, integrates pioneering biomedical research with exceptional clinical care and education. The institutions faculty has received six Nobel Prizes and includes 25 members of the National Academy of Sciences, 16 members of the National Academy of Medicine, and 14 Howard Hughes Medical Institute Investigators. The full-time faculty of more than 2,800 is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UTSouthwestern physicians provide care in about 80 specialties to more than 117,000 hospitalized patients, more than 360,000 emergency room cases, and oversee nearly 3 million outpatient visits a year.

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UTSW scientists identify protein that stops cell cycle in response to stress - UT Southwestern