Breaking News
May 3, 2019 - Vaping and Smoking May Signal Greater Motivation to Quit
May 3, 2019 - Dementia looks different in brains of Hispanics
May 3, 2019 - Short-Staffed Nursing Homes See Drop In Medicare Ratings
May 3, 2019 - Study of teens with eating disorders explores how substance users differ from non-substance users
May 3, 2019 - Scientists develop new video game that may help in the study of Alzheimer’s
May 3, 2019 - Arc Bio introduces Galileo Pathogen Solution product line at ASM Clinical Virology Symposium
May 3, 2019 - Cornell University study uncovers relationship between starch digestion gene and gut bacteria
May 3, 2019 - How to Safely Use Glucose Meters and Test Strips for Diabetes
May 3, 2019 - Anti-inflammatory drugs ineffective for prevention of Alzheimer’s disease
May 3, 2019 - Study tracks Pennsylvania’s oil and gas waste-disposal practices
May 3, 2019 - Creating a better radiation diagnostic test for astronauts
May 3, 2019 - Vegans are often deficient in these four nutrients
May 3, 2019 - PPDC announces seed grants to develop medical devices for children
May 3, 2019 - Study maps out the frequency and impact of water polo head injuries
May 3, 2019 - Research on Reddit identifies risks associated with unproven treatments for opioid addiction
May 3, 2019 - Good smells may help ease tobacco cravings
May 3, 2019 - Medical financial hardship found to be very common among people in the United States
May 3, 2019 - Researchers develop multimodal system for personalized post-stroke rehabilitation
May 3, 2019 - Study shows significant mortality benefit with CABG over percutaneous coronary intervention
May 3, 2019 - Will gene-editing of human embryos ever be justifiable?
May 3, 2019 - FDA Approves Dengvaxia (dengue vaccine) for the Prevention of Dengue Disease in Endemic Regions
May 3, 2019 - Why Tonsillitis Keeps Coming Back
May 3, 2019 - Fighting the opioid epidemic with data
May 3, 2019 - Maggot sausages may soon be a reality
May 3, 2019 - Deletion of ATDC gene prevents development of pancreatic cancer in mice
May 2, 2019 - Targeted Therapy Promising for Rare Hematologic Cancer
May 2, 2019 - Alzheimer’s disease is a ‘double-prion disorder,’ study shows
May 2, 2019 - Reservoir bugs: How one bacterial menace makes its home in the human stomach
May 2, 2019 - Clinical, Admin Staff From Cardiology Get Sneak Peek at Epic
May 2, 2019 - Depression increases hospital use and mortality in children
May 2, 2019 - Vicon and NOC support CURE International to create first gait lab in Ethiopia
May 2, 2019 - Researchers use 3D printer to make paper organs
May 2, 2019 - Viral infection in utero associated with behavioral abnormalities in offspring
May 2, 2019 - U.S. Teen Opioid Deaths Soaring
May 2, 2019 - Opioid distribution data should be public
May 2, 2019 - In the Spotlight: “I’m learning every single day”
May 2, 2019 - 2019 Schaefer Scholars Announced
May 2, 2019 - Podcast: KHN’s ‘What The Health?’ Bye-Bye, ACA, And Hello ‘Medicare-For-All’?
May 2, 2019 - Study describes new viral molecular evasion mechanism used by cytomegalovirus
May 2, 2019 - SLU study suggests a more equitable way for Medicare reimbursement
May 2, 2019 - Scientists discover first gene involved in lower urinary tract obstruction
May 2, 2019 - Researchers identify 34 genes associated with increased risk of ovarian cancer
May 2, 2019 - Many low-income infants receive formula in the first few days of life, finds study
May 2, 2019 - Global study finds high success rate for hip and knee replacements
May 2, 2019 - Taking depression seriously: What is it?
May 2, 2019 - With Head Injuries Mounting, Will Cities Put Their Feet Down On E-Scooters?
May 2, 2019 - Scientists develop small fluorophores for tracking metabolites in living cells
May 2, 2019 - Study casts new light into how mothers’ and babies’ genes influence birth weight
May 2, 2019 - Researchers uncover new brain mechanisms regulating body weight
May 2, 2019 - Organ-on-chip systems offered to Asia-Pacific regions by Sydney’s AXT
May 2, 2019 - Adoption of new rules drops readmission penalties against safety net hospitals
May 2, 2019 - Kids and teens who consume zero-calorie sweetened beverages do not save calories
May 2, 2019 - Improved procedure for cancer-related erectile dysfunction
May 2, 2019 - Hormone may improve social behavior in autism
May 2, 2019 - Alzheimer’s disease may be caused by infectious proteins called prions
May 2, 2019 - Even Doctors Can’t Navigate Our ‘Broken Health Care System’
May 2, 2019 - Study looks at the impact on criminal persistence of head injuries
May 2, 2019 - Honey ‘as high in sugars as table sugar’
May 2, 2019 - Innovations to U.S. food system could help consumers in choosing healthy foods
May 2, 2019 - FDA Approves Mavyret (glecaprevir and pibrentasvir) as First Treatment for All Genotypes of Hepatitis C in Pediatric Patients
May 2, 2019 - Women underreport prevalence and intensity of their own snoring
May 2, 2019 - Concussion summit focuses on science behind brain injury
May 2, 2019 - Booker’s Argument For Environmental Justice Stays Within The Lines
May 2, 2019 - Cornell research explains increased metastatic cancer risk in diabetics
May 2, 2019 - Mount Sinai study provides fresh insights into cellular pathways that cause cancer
May 2, 2019 - Researchers to study link between prenatal pesticide exposures and childhood ADHD
May 2, 2019 - CoGEN Congress 2019: Speakers’ overviews
May 2, 2019 - A new strategy for managing diabetic macular edema in people with good vision
May 2, 2019 - Sagent Pharmaceuticals Issues Voluntary Nationwide Recall of Ketorolac Tromethamine Injection, USP, 60mg/2mL (30mg per mL) Due to Lack of Sterility Assurance
May 2, 2019 - Screen time associated with behavioral problems in preschoolers
May 2, 2019 - Hormone reduces social impairment in kids with autism | News Center
May 2, 2019 - Researchers synthesize peroxidase-mimicking nanozyme with low cost and superior catalytic activity
May 2, 2019 - Study results of a potential drug to treat Type 2 diabetes in children announced
May 2, 2019 - Multigene test helps doctors to make effective treatment decisions for breast cancer patients
May 2, 2019 - UNC School of Medicine initiative providing unique care to dementia patients
May 2, 2019 - Nestlé Health Science and VHP join forces to launch innovative COPES program for cancer patients
May 2, 2019 - Study examines how our brain generates consciousness and loses it during anesthesia
May 2, 2019 - Transition Support Program May Aid Young Adults With Type 1 Diabetes
May 2, 2019 - Study shows how neutrophils exacerbate atherosclerosis by inducing smooth muscle-cell death
May 2, 2019 - Research reveals complexity of how we make decisions
Neoadjuvant clinical trial of immune checkpoint blockade for melanoma patients yields high response rate

Neoadjuvant clinical trial of immune checkpoint blockade for melanoma patients yields high response rate

Combination checkpoint blockade before surgery (neoadjuvant therapy) produced a high response rate among patients with high-risk stage 3 melanoma, with nearly half having no sign of disease at surgery, but a high incidence of side effects caused the trial to be closed early.

The phase II study was led by researchers at The University of Texas MD Anderson Cancer Center. Results of the study, the first randomized neoadjuvant clinical trial of immune checkpoint blockade for melanoma patients, are reported in Nature Medicine.

Patients received either the PD-1 inhibitor nivolumab or the combination of nivolumab and the CTLA-4 checkpoint inhibitor ipilimumab. Each drug blocks a separate off-switch on T cells, freeing the immune system to attack cancer. All patients received nivolumab after surgery.

On the combination arm, 8 of 11 (73 percent) patients had their tumors shrink, 5 (45 percent) had no evidence of disease at surgery (pathological complete response), and 73 percent had grade 3 side effects, causing dose delays in 64 percent and delaying surgery for some. There were no grade 4 side effects.

In the nivolumab arm, 3 of 12 (25 percent) had their tumors shrink and had pathological complete response, only 8 percent had grade 3 side effects. Two patients progressed to stage 4 metastatic disease before they could get to surgery.

“In this trial, treatment with single-agent anti-PD-1 was associated with modest response rates, and we were concerned that two patients on that arm progressed and could not go to surgery,” said co-first author Rodabe Amaria, M.D., assistant professor of Melanoma Medical Oncology. “Treatment with combined checkpoint blockade was much more effective, but at the expense of significant toxicity. It is clear from this trial that we need to further optimize this treatment approach.”

All of those who achieved pathological complete response in either arm remain without evidence of disease recurrence. Overall survival was 100 percent at 24 months in the combination arm and 75 percent in the nivolumab arm.

“The advantage of a neoadjuvant approach in this setting is that it enables an interval evaluation of the tumor cells after therapy to determine the extent to which those tumor cells responded to the therapy in real time and predict which patients are likely to experience durable responses going forward. It also provides us the tissue resources to determine why tumors may not respond to therapy and thus tailor therapies going forward as we learn more about resistance,” said co-senior author on the study, Michael Tetzlaff, M.D. Ph.D., associate professor of Pathology and Translational and Molecular Pathology.

Checkpoint blockade has been effective against metastatic melanoma and in reducing the risk of relapse after surgery for high-risk stage 3 disease. However, there is evidence in preclinical models that treatment before surgery may be superior to giving these agents in the adjuvant setting (after surgery).

Amaria and senior author Jennifer Wargo, M.D., associate professor of Surgical Oncology and Genomic Medicine, launched the investigator-initiated trial through MD Anderson’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.

Due to the results of this study, the team re-designed the study to explore the safety and efficacy of nivolumab plus relatlimab, an inhibitor of the LAG3 immune checkpoint, a combination that Amaria notes thinks may be more effective than nivolumab alone with a better side effect profile than treatment with combined CTLA-4 and PD-1 blockade.

Identifying biomarkers of response and resistance

“This presurgical platform provides an ideal setting to study biomarkers of response, mechanisms of resistance, and differential effects of these two commonly used treatment regimens,” said co-first author Sangeetha Reddy, M.D., instructor in Cancer Medicine. “In this study we confirmed known biomarkers of response and observed novel biomarkers of therapeutic response that we are now studying further”.

Analysis of biopsies and blood samples taken at multiple time points during the trial revealed:

  • Baseline infiltration of tumors by lymphoid cells and total mutational burden were associated with response to therapy.
  • Early on-treatment biopsies were better predictive of who would respond to both therapies compared to baseline biopsies.
  • Molecular analyses using a novel spatial profiling technology identified differential abundance of multiple immune markers that correlated with response and/or resistance to neoadjuvant immune checkpoint blockade.
  • T cell receptor sequencing identified differential patterns in responders versus non-responders to anti-PD-1 therapy versus combined CTLA-4 and PD-1 blockade. Responders to PD-1 monotherapy showed evidence of a pre-existing but inhibited T cell repertoire that further expanded during treatment, while treatment with combination therapy was associated with more variable changes in the T cell repertoire.

This trial was performed in parallel to a trial co-led by Christian Blank, M.D., Ph.D., and Ton Schumacher, Ph.D. of the Netherlands Cancer Institute – who tested the use of neoadjuvant versus adjuvant (post-surgical) treatment with combined CTLA-4 and PD-1 blockade in a similar patient population.

“The findings in their trial are provocative, demonstrating that a higher number of tumor-resident TCRs expanded in the peripheral blood of patients receiving neoadjuvant as opposed to adjuvant checkpoint blockade – supportive of what was seen in preclinical models – and suggests that the neoadjuvant approach may be superior.” Wargo said.

This MD Anderson-led team is now working with others worldwide in an international neoadjuvant melanoma consortium to harmonize these efforts.

Source:

https://www.mdanderson.org/newsroom/2018/10/neoadjuvant-combination-checkpoint-blockade-trial-yields-high-response-rates-for-melanoma-patients.html

Tagged with:

About author

Related Articles