Category Archives: Cell Medicine

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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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...

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

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.

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

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:

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16. Farrell JJ, Al-Haddad MA, Jackson SA, Gonda TA. Incremental value of DNA analysis in pancreatic cysts stratified by clinical risk factors. Gastrointest Endosc. 2019;89(4):832-841 e2. doi:10.1016/j.gie.2018.10.049

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18. Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387(10018):545-557. doi:10.1016/S0140-6736(15)00986-1

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20. Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreatic cancer. N Engl J Med. 2018;379(25):2395-2406. doi:10.1056/NEJMoa1809775

21. Motoi F, Kosuge T, Ueno H, et al. Randomized phase II/III trial of neoadjuvant chemotherapy with gemcitabine and S-1 versus upfront surgery for resectable pancreatic cancer (Prep-02/JSAP05). Jpn J Clin Oncol. 2019;49(2):190-194. doi:10.1093/jjco/hyy190

22. Jang JY, Han Y, Lee H, et al. Oncological Benefits of neoadjuvant chemoradiation with gemcitabine versus upfront surgery in patients with borderline resectable pancreatic cancer: a prospective, randomized, open-label, multicenter phase 2/3 trial. Ann Surg. 2018;268(2):215-222. doi:10.1097/SLA.0000000000002705

23. Versteijne E, Suker M, Groothuis K, et al. Preoperative chemoradiotherapy versus immediate surgery for resectable and borderline resectable pancreatic cancer: results of the dutch randomized phase III PREOPANC trial. J Clin Oncol. 2020;38(16):1763-1773. doi:10.1200/JCO.19.02274

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25. Tempero M, Oh DY, Tabernero J, et al. Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: phase III RESOLVE study. Ann Oncol. 2021;doi:10.1016/j.annonc.2021.01.070

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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

Human interneuron progenitors derived from induced pluripotent stem cells (iPSCs) can be successfully transplanted and integrate into mouse brains, mature, and reverse signs of hippocampal network dysfunction associated with Alzheimer's disease, GABAeron scientists reported at ISSCR/JSRM.

Published: Oct. 27, 2021 at 7:00 AM CDT|Updated: 18 hours ago

SAN FRANCISCO, Oct. 27, 2021 /PRNewswire/ -- GABAeron, Inc. today presented promising preclinical data on their first-in-class, iPSC-based cell therapy product for Alzheimer's disease at the International Society for Stem Cell Research (ISSCR) and Japanese Society for Regenerative Medicine (JSRM) international meeting "Stem Cells: From Basic Science to Clinical Translation". The data, the first to be publicly shared since the company was founded in 2017, highlight the potential of transplanted, human iPSC-derived interneuron progenitors in treating Alzheimer's disease as well as other neurological disorders with interneuron deficit or loss.

GABAeron scientists successfully differentiated GABAergic interneuron progenitors from human iPSCs, and showed that when transplanted into the brains of an Alzheimer's disease mouse model carrying the major genetic risk factor apolipoprotein E4 (APOE4) the cells could mature, integrate into the hippocampus, and reverse signs of the hippocampal network dysfunction associated with Alzheimer's disease.

"We are incredibly excited by these data, which show the safety and efficacy of our novel iPSC-based approach in an Alzheimer's disease mouse model," said Robert W. Mahley, MD, PhD, chief executive officer and chief scientific officer of GABAeron. "Based on these results, we plan to continue our work to develop a cell replacement therapy to treat patients with APOE4-positive Alzheimer's disease."

Over the course of his career, Mahley president emeritus of the Gladstone Institutes and professor of pathology and medicine at the University of California, San Francisco has illuminated the importance and molecular details of the protein APOE. The gene for APOE comes in several versions and we now know that people with the APOE4 version of the gene have an increased risk of Alzheimer's disease and an earlier age of disease onset compared to people with the more common APOE3 version. Strikingly, APOE4 is associated with 6075% of all Alzheimer's disease cases.

GABAeron scientific co-founder Yadong Huang, MD, PhD, director of the Center for Translational Advancement at the Gladstone Institutes, San Francisco, discovered one important reason for the association between APOE4 and Alzheimer's disease. APOE4, his lab demonstrated, leads to the impairment and loss of hippocampal GABAergic interneurons cells critical for maintaining normal hippocampal activity, required for normal learning and memory, and damaged or lost in Alzheimer's disease brains.

"GABAeron was founded on the premise that if we can replace those interneurons via cell-based therapy, we can restore normal hippocampal activity and thus slow or reverse many of the memory and cognitive impairments associated with Alzheimer's disease," said Huang. "If this approach works, it will be a single treatment with long-lasting impact for Alzheimer'spatients."

In the new study, researchers led by Wen-Chin (Danny) Huang, PhD, and Iris Avellano, developed a novel effective method of coaxing human iPSCs carrying the APOE3 gene to differentiate into GABAergic interneuron progenitors. The resulting cells showed high viability, purity, and robust functionality with more than 90% committed to the correct developmental lineage.

A team led by Wan-Ying Hsieh, PhD, transplanted these interneuron progenitors into the hippocampus of 10-month-old mice carrying the human APOE4 gene; the interneuron progenitors showed robust survival and matured into functional GABAergic interneurons. At 7 months post-transplantation, more than half of the surviving cells had migrated out of the local area, populated the hippocampal subregions, and established connections with other existing neurons throughout the hippocampus.

"These exciting data reveal the high quality of human iPSC-derived interneuron progenitors generated at GABAeron and highlight the feasibility of their long-term survival and integration into mouse brains," said Hsieh. "Importantly, there was no tumor formation from the transplanted cells in over a hundred mice."

They next carried out electrophysiological recordings to study hippocampal network activity in the mice. As expected, the APOE4 mice had deficits in hippocampal activity that can underlie the memory impairments associated with Alzheimer's disease. Specifically, the mice had fewer sharp-wave ripples and their associated slow gamma power in the hippocampus both of which are critical for memory formation and retrieval. When each mouse was transplanted with approximately 120,000 iPSC-derived human interneuron progenitors carrying APOE3, these measurements of hippocampal activity both improved to the levels seen in healthy mice 7 months later.

"These results as a whole represent a critical step toward a potential interneuron-based therapy for APOE4-related Alzheimer's disease," said Qin Xu, PhD, senior director at GABAeron. "This builds up a solid foundation for our further work with clinical-grade human iPSCs."

GABAeron scientists are now adapting their culture techniques for the mass production of clinical-grade human iPSC-derived GABAergic interneuron progenitors. They are also working to identify the molecular characteristics of the mature GABAergic interneurons, which become successfully integrated into the hippocampus in the Alzheimer's disease mouse model.

"With this critical milestone reached, GABAeron will move forward, with great confidence, toward IND-enabling studies and future trials with clinical-grade human iPSC-derived interneuron progenitors for treating APOE4-related Alzheimer's disease," said Sheng Ding, PhD, scientific co-founder of GABAeron and a serial entrepreneur who co-founded two leading public companies, Fate Therapeutics (FATE) and Tenaya Therapeutics (TNYA). "We also plan to explore the usefulness of such a cell-based therapy for other neurological diseases with interneuron deficits or loss."

The ISSCR/JSRM international meeting "Stem Cells: From Basic Science to Clinical Translation" runs from October 2729, 2021 and is being held virtually this year.

About GABAeron

GABAeron, Inc. is a biopharmaceutical company founded in 2017, based on pioneer work initiated at the Gladstone Institutes, to build on the promise of combining precision medicine, regenerative medicine, and pharmaceutical intervention. The company is exploring a new first-in-class IND candidate to replace or restore neurons injured or lost in the brains of patients suffering from neurodegenerative and neurodevelopmental disorders.

For more information about GABAeron, please visit http://www.GABAeron.com.

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GABAeron Presents Promising Preclinical Data on Stem Cell-Based Therapy for Alzheimer's Disease - WJHG-TV

Researchers around the world have tried many ways, and for many years, to generate neurons in the lab so they could study them better. Neurons-on-demand might also provide a therapeutic option for replacing neurons lost in neurodegenerative conditions, such as Parkinsons disease. In June 2020, University of California San Diego School of Medicine researchers announced a major step toward that goal: With one dose of a new proto-drug, they were able to turn other cell types directly into neurons, a feat that alleviated all Parkinsons disease symptoms in a mouse model.

Now, the UC San Diego-led team will receive a $9 million grant from the Aligning Science Across Parkinsons (ASAP) initiative to help advance this research and position it for the next phases of drug development. ASAP is a coordinated research initiative to advance targeted basic research for Parkinsons disease. Its mission is to accelerate the pace of discovery and inform the path to a cure through collaboration, research-enabling resources and data-sharing. The Michael J. Fox Foundation for Parkinsons Research is the implementation partner for ASAP and issuer of the grant, which contributes to the Campaign for UC San Diego.

Top: Mouse brain before treatment, with dopamine-producing neurons shown in green. Bottom: Mouse brain after PTB antisense oligonucleotide treatment, which converts brain support cells into dopamine-producing neurons (green).

Xiang-Dong Fu, PhD, Distinguished Professor of Cellular and Molecular Medicine is the lead investigator for the project, along with William C. Mobley, MD, PhD, Distinguished Professor of Neurosciences; and Bing Ren, PhD, and Steve Dowdy, PhD, both professors of cellular and molecular medicine at UC San Diego School of Medicine. The team also includes researchers from the Chinese Academy of Sciences.

This grant is supporting some of the most incredible progress being made in the Parkinsons sphere. Its a game-changing strategy that we hope will improve how Parkinsons is treated, said David Brenner, MD, vice chancellor of Health Sciences. We are grateful to ASAP for making these advancements possible.

The teams work centers on a protein called PTB, which is known for binding RNA and influencing which genes are turned on or off in a cell. Their previous studies showed that inhibiting the gene that encodes PTB transforms several types of mouse cells directly into new neurons in laboratory dishes.

To inhibit PTB in living organisms, the researchers developed a virus that carries an antisense oligonucleotide sequence an artificial piece of DNA designed to specifically bind the RNA coding for PTB, thus preventing it from being translated into a functional protein and instead stimulating neuron development. The virus infects brain cells, but cannot be transmitted from the injected mice to others.

The researchers have demonstrated that just a single treatment to inhibit PTB in mice converts native astrocytes, star-shaped support cells of the brain, into neurons that produce the neurotransmitter dopamine. Treatment restores normal dopamine levels in mice engineered to mimic Parkinsons disease. Physically, the mice recover motor function within three months after a single treatment, and remain free from Parkinsons disease symptoms for the rest of their lives.

Of course, mice arent people, and the animal model the team used doesnt perfectly recapitulate all essential features of Parkinsons disease. But the study provides an exciting proof of concept, they said.

With ASAPs support, the researchers will now be able to optimize their methods and test the methodology in other pre-clinical models. They have also patented the PTB antisense oligonucleotide treatment in order to move forward toward testing in clinical trials.

Parkinson's disease is a brain disorder that progressively worsens, leading to shaking, difficulty with coordination and struggles with walking and talking. The condition occurs when neurons in an area of the brain that controls movement slowly cease to function properly and die. Normally, these neurons produce a brain chemical called dopamine. When neurons become impaired, they produce less dopamine, which causes the movement problems indicative of the disease.

Although there is no current cure for Parkinson's disease, there are some medicines and surgical treatments that can relieve some symptoms, such as medications that increase dopamine levels or therapeutically affect other brain chemicals.

Private support, like the grant from ASAP, contributes to the Campaign for UC San Diego a university-wide comprehensive fundraising effort concluding in 2022. Alongside UC San Diegos philanthropic partners, the university is continuing its nontraditional path toward revolutionary ideas, unexpected answers, lifesaving discoveries and planet-changing impact. Learn more at Campaign for UC San Diego.

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UC San Diego-Led Team Receives $9M to Advance Parkinson's Disease Treatments - UC San Diego Health

Collapsed femoral heads caused by osteonecrosisotherwise known as avascular necrosis unfortunately represent the root cause for approximately 10% of all hip replacements nationwide. Daniel Wiznia, MD, is utilizing a stem cell treatment at Yale School of Medicine and integrating new techniques along with 3D imaging technology as part of a joint-preservation procedure.

Occurring in more than 20,000 Americans each year, osteonecrosis of the femoral head is commonly diagnosed in patients in their 30s and 40s. The disease is caused by injury of the blood supply to the head of the femur, which is the ball portion of the hips ball and socket joint.

If unaddressed, this disease may ultimately lead to the collapse of the femoral head, requiring the patient to undergo a hip replacement. For patients in this age group, a total hip replacement is not ideal as it likely will wear out and the patient will require more surgery.

The goal for each case is clear: prevent the femoral head from collapsing and the need for a hip replacement. As part of a surgical procedure, Wiznia harvests bone marrow from the patients pelvis. The individuals own stem cells are then isolated from the marrow, concentrated, and injected into lesions within the avascular portion of the femura treatment that is only taking place at some of the nations largest medical centers.

The key in these instances is to discover the avascular necrosis before the head collapses, Wiznia said. Because the vascular injury is usually a painless event, patients are generally unaware of the specific point in time when the vascular injury occurred, which is why cases are rarely discovered in time. However, we do know that 80% of patients who have avascular necrosis on one side of the hip have it on the opposite side. We usually are able to catch that second asymptomatic side in those situations and conduct the core decompression with stem cell treatment before it collapses.

According to Wiznia, this treatment reduces the risk of the head of the femur from collapsing, and the stem cell therapy has shown promising results. Soon after the procedure, many patients with avascular necrosis experience rejuvenated blood supply to the area and the bone is repopulated with new cells. This can additionally alleviate the short-term need for a hip replacement.

This novel stem cell therapy has demonstrated improved pain and function, and the stem cells decrease the risk of the femoral head from collapsing, Wiznia said. This translates into fewer young patients requiring hip replacements, and subsequent surgeries in their later years.

As an engineer himself, Wiznia works closely with the Yale School of Engineering & Applied Sciences and the Integrated 3D Surgical Team to better tailor this treatment to each specific patient.

One of the challenges of orthopaedic surgery in the human body is that surgeons are operating in a three-dimensional space and are often reliant on two-dimensional imagery such as X-rays, Wiznia added. Through the use of computer modeling, we are able to customize those images and create models that are specific to each patient, which, in turn, enhances outcomes and overall post-operative success rates.

Enhanced models and 3D imaging enable surgeons like Wiznia to better locate and target both the lesions and necrotized bone in these instances. Effectively doing so regenerates the femoral head and stimulates new osteoblast growth, which will heal the region, maintain the integrity of the joint, and decrease the chance of femoral head collapse and need for a hip replacement.

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Stem Cells Used to Treat Avascular Necrosis of the Femoral Head - Yale School of Medicine