Breaking News
September 18, 2018 - Established Alzheimer’s Risk Gene Has a New Role
September 18, 2018 - Hospitalization after antibiotic initiation found to be higher for people with Alzheimer’s disease
September 18, 2018 - Many children with special healthcare needs do not have access to ‘PCMH-concordant’ care
September 18, 2018 - Investigational nasal influenza vaccine tested in children and teens
September 18, 2018 - Lymphatic vessels surrounding the brain play crucial role in multiple sclerosis, research suggests
September 18, 2018 - New fiber laser-based ultrasound sensor may have potential applications in medical diagnostics
September 18, 2018 - Protect your heart and health during ‘dog days’ of summer
September 18, 2018 - Faculty receive awards for promise in biomedical research, clinical care | News Center
September 18, 2018 - Digital games for CVD-related self-management improve exercise capacity and energy expenditure
September 18, 2018 - Adding PET scans to CT imaging can change treatment for women with cervical cancer
September 18, 2018 - Human brains may be wired to prefer lying on the couch, suggests research
September 18, 2018 - Zika virus vaccine shows promise for treatment of fatal glioblastoma
September 18, 2018 - Theravance Biopharma and Mylan to Report New Data from Phase 3 Studies of Yupelri (revefenacin) in Oral Presentation at European Respiratory Society International Congress 2018
September 18, 2018 - INSiGHT identifies unique retinal regulatory genes
September 18, 2018 - Diversity, science leadership grants awarded to student-faculty pairs | News Center
September 18, 2018 - Many parents blame electronics for sleep problems among teens
September 18, 2018 - Researchers study neuronal activity in brain that prevents individuals from doing physical activity
September 18, 2018 - Purifying Proteins from Mammalian Cell Culture
September 18, 2018 - Researchers map 3D structure of toxic proteins used by Pseudomonas aeruginosa to trigger infection
September 18, 2018 - Outcome of ACL reconstruction related to the way you move post-surgery
September 18, 2018 - Study aims to investigate risk factors for PPCs in surgical patients with gastric cancer
September 18, 2018 - Ardelyx Submits New Drug Application for Tenapanor for IBS-C
September 18, 2018 - Sociodemographic disparities in eyeglass use among elderly
September 18, 2018 - New Drug Shows Promise for Progressive Form of MS
September 18, 2018 - Babies exposed to higher levels of organochlorine compounds in womb may have worse lung function
September 18, 2018 - Women exposed to trauma in their lives gave birth to underweight male infants
September 18, 2018 - Probiotic supplementation may reduce use of antibiotics, scientific analysis shows
September 18, 2018 - Resveratrol decreases pain severity and levels of inflammatory biomarkers in osteoarthritis patients
September 18, 2018 - Research shows pollution is reaching the placenta
September 18, 2018 - KAIST researchers develop heart-targeting drug delivery technology using tannin acid
September 18, 2018 - Muscle relaxants used during general anesthesia can increase risk of pulmonary complications
September 18, 2018 - Silicone breast implants may increase risk of rare adverse outcomes in women
September 18, 2018 - Pediatricians Have a Role in Encouraging Play Among Children
September 18, 2018 - California’s Medicaid program hits ‘print’ when the feds need info
September 18, 2018 - Genes, environment and schizophrenia—new study finds the placenta is the missing link
September 18, 2018 - Boehringer Ingelheim announces study results of COPD patients treated with Spiolto Respimat
September 18, 2018 - PAREXEL launches Patient Innovation Center to improve drug development process
September 18, 2018 - Children’s National and NIAID launch pediatric clinical research partnership
September 18, 2018 - Researchers may be overlooking complexities in social relations of primates
September 18, 2018 - Key signaling molecule that helps stem cells make healthy bone declines as we age
September 18, 2018 - More women veterans with chronic pain use CIH therapies than men
September 18, 2018 - As Earth Warms, Heat-Related Deaths Will Multiply
September 18, 2018 - Labetalol use up for patients with preeclampsia and asthma
September 18, 2018 - MoreGrasp project shows significant results in field of thought-controlled grasp neuroprosthetics
September 18, 2018 - Drumming can benefit school children with autism
September 18, 2018 - Busyness can help people to make virtuous choices, research shows
September 18, 2018 - Two-minute bursts of in-class exercise breaks do not disrupt learning and teaching
September 18, 2018 - New online tools aid surgeons and specialists who care for older people
September 18, 2018 - Researchers use CRISPR to identify gene that helps cells resist flavivirus infection
September 18, 2018 - Brain’s support cells may play a central role in repetitive behaviors related to OCD
September 18, 2018 - Scientists discover novel mechanism by which synthesized proteins reach target compartment in cell
September 18, 2018 - Easy and rapid test for viral infections can cut antibiotic use, hospitalizations
September 18, 2018 - Gunshot victims more likely to require blood transfusions and die than other trauma patients
September 18, 2018 - Cyclacel Pharmaceuticals Announces Initiation of Phase 1b/2 Clinical Trial of Sapacitabine With Olaparib in BRCA Mutant Breast Cancer
September 18, 2018 - Older adults fitted with cochlear implants exhibit poor brain function
September 18, 2018 - Inexpensive testing spurs cancer patients’ relatives to assess own disease risk | News Center
September 18, 2018 - Aging may have originated at the very beginning of life, says study
September 18, 2018 - New research on sperm quality updates advice for couples trying to conceive
September 18, 2018 - Paracetamol use in infancy may increase risk of developing asthma by the age of 18
September 18, 2018 - Promising gene therapy for ‘day blind’ sheep now safe for clinical trials in human patients
September 18, 2018 - New research shows evidence of soot from polluted air in placentas
September 17, 2018 - Expanding primary care buprenorphine treatment could curb opioid overdose crisis
September 17, 2018 - A look inside the child detention centers near the U.S. border
September 17, 2018 - New issue considers role of coronary angiography after cardiac arrest
September 17, 2018 - Scientists explore whether seafood could be the source of next anti-cancer drug
September 17, 2018 - Epidural stimulation aids in recovery of individuals with spinal cord injury
September 17, 2018 - ATS publishes new guideline on role of weight management in sleep apnea treatment
September 17, 2018 - Study reveals long-term safety, efficacy of Ofev in patients with idiopathic pulmonary fibrosis
September 17, 2018 - Risks Posed by Spreading Oil and Gas Wastewater on Roads
September 17, 2018 - How to choose a nursing home: MedlinePlus Medical Encyclopedia
September 17, 2018 - Death from touching fentanyl? A myth, says Trump administration training video
September 17, 2018 - Physician or physician-scientist — a new curriculum at the School of Medicine trains both
September 17, 2018 - Why Genetic Mutations Cause Disease in Some People but Not Others
September 17, 2018 - EU-funded project makes recommendations to protect rights of intersex people
September 17, 2018 - Discovery of unusual biosynthetic pathways could aid in the search for new natural products
September 17, 2018 - FDA approves Teva’s AJOVY injection for preventive treatment of migraine in adults
September 17, 2018 - People battling substance use disorders may benefit from meth-relapse prevention compound
September 17, 2018 - Inhaled steroid use linked to greater risk of NTM lung infections
September 17, 2018 - KKH develops new test to enable faster diagnosis of critically ill children with rare diseases
September 17, 2018 - How to Reassure Kids When Florence Strikes
Researchers describe promising strategy to remove melanoma’s most powerful defenses

Researchers describe promising strategy to remove melanoma’s most powerful defenses

image_pdfDownload PDFimage_print

Immunotherapies use the immune system to fight cancer. But cancers like melanoma have found ways to turn off the immune system, allowing them to resist treatments and often leading to recurrence. Now University of Colorado Cancer Center clinical trial results published today in the journal International Immunopharmacology describe a promising strategy to remove one of melanoma’s most powerful defenses: By adding retinoic acid to standard-of-care treatment, researchers were able to turn off myeloid-derived suppressor cells (MDSCs) that turn off the immune system, leading to more immune system activity directed at melanoma.

“The immune response and MDSCs are like yin and yang, balancing each other. For example, you want the immune system to fight an infection and then you want MDSCs to shut down the immune system when the infection is gone,” says Martin McCarter, MD, investigator at the CU Cancer Center and surgical oncologist at the UCHealth University of Colorado Hospital.

“We started studying our melanoma patients and found a ton of these MDSCs in the circulation and in the tumor itself,” he says. “Melanoma induces these cells to be around the tumor microenvironment. After identifying that, yes, there are a lot of these cells around, we wanted to find ways to target those MDSCs. If we could render them dysfunctional then in theory a better immune response could go forward.”

Working in the McCarter lab with initial funding from a grateful patient, then-postdoctoral researcher Kim Jordan, PhD, studied ways to alter MDSC function and “identified a promising drug called all-trans retinoic acid or ATRA,” McCarter says.

Understanding how retinoic acid defuses MDSCs requires a little knowledge about each.

MDSCs are immature, undifferentiated cells that are produced in the bone marrow. When healthy, MDSCs quickly mature into cell types that aid immune function. But cancers like melanoma encourage MDSCs to remain immature, and this population of immature MDSCs turns off the immune system.

Retinoic acid is a well-known compound derived from the breakdown of Vitamin A. It encourages cells to differentiate, transitioning from stem-like cells into the mature cells the body needs for structure and function. Retinoic acid is a common ingredient in topical acne treatments and is also used to treat acute promyelocytic cancer. Work in the McCarter lab and elsewhere showed that the form of retinoic acid known as ATRA could force MDSCs to mature, switching their function from immune suppression to immune support.

“ATRA was available off the shelf. There was a lot of history and lot of knowledge about the drug itself,” McCarter says.

Based on promising laboratory work, Dr. Jordan wrote a proposal for an R21 grant, also known as an Exploratory/Development Grant, which is a program by the National Institutes of Health meant to encourage researcher-initiated trials.

“We wanted to take standard-of-care treatment and add ATRA,” McCarter says.

At the time, standard-of-care treatment included the drug ipilimumab, which is a checkpoint inhibitor targeting a protein called CTLA-4, which helps release the brakes on the immune system so that it can target cancer. The study enrolled 10 patients, with half receiving ipilimumab alone and half receiving ipilimumab plus ATRA.

“We were able to show several things,” McCarter says. “First is that we could reduce the number of circulating MDSCs in patients that got ATRA. We also showed that immunosuppressive MDSC genes were reduced in these patients. And we showed there was more activation of CD8 T cells. Basically, not only did immunosuppressive stuff go down, but the immune response went up. The other take-home is this was a safe combination – adding ATRA didn’t increase toxic side-effects.”

Then, partway through the trial, ipilimumab stopped being the standard of care. Instead of using ipilimumab to help the immune system target CTLA-4, doctors started using drugs like pembrolizumab and nivolumab to target PD-1.

“We didn’t have enough patients on the trial to show survival benefit but we were able to demonstrate the proof of principal to target MDSCs in humans,” McCarter says.

Meanwhile, McCarter’s postdoctoral researcher, Kim Jordan, took a position as an associate research professor in the CU School of Medicine Department of Immunology. Luckily, she was replaced by another postdoctoral researcher, Richard Tobin, PhD, who was able to shepherd the group’s promising preclinical work with ATRA and MDSCs from ipilimumab to pembrolizumab. A new trial of pembrolizumab with and without ATRA offered at the UCHealth University of Colorado Hospital to adult patients with stage III or IV melanoma has started enrollment and is recruiting patients (ClinicalTrials.gov #NCT03200847).

“This is a homegrown project, from the basic laboratory work, through the translational science, and now into investigator-initiated clinical trials,” McCarter says. “I couldn’t be more proud of Kim, Richard and the rest of my team. And we see the real potential that this strategy could be a useful and non-toxic addition to immunotherapies for patients with melanoma.”

The group expects results of the current trial of pembrolizumab plus ATRA in late 2019.

Source:

Clinical trial shows targeting suppressor cells with retinoic acid may improve immune response against melanoma

Tagged with:

About author

Related Articles