Retinoic acid may improve immune response against melanoma

August 16, 2018, CU Anschutz Medical Campus

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, Ph.D., studied ways to alter MDSC function and "identified a promising drug called all-trans 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 . 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 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, Ph.D., 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.

Explore further: Novel compound restores immune response in patients with melanoma

More information: Richard P. Tobin et al, Targeting myeloid-derived suppressor cells using all-trans retinoic acid in melanoma patients treated with Ipilimumab, International Immunopharmacology (2018). DOI: 10.1016/j.intimp.2018.08.007

Related Stories

Novel compound restores immune response in patients with melanoma

December 8, 2017
A novel compound may restore immune response in patients with melanoma, according to a study presented at the ESMO Immuno Oncology Congress 2017.

Nixing the cells that nix immune response against cancer

February 2, 2017
Some cells excite the immune system. Others soothe it. Myeloid-derived suppressor cells (MDSCs) are one type of soothing cell, and previous work shows that cancer may specifically boost production of MDSCs as a way to tamp ...

Soluble antibodies play immune suppressive role in tumor progression

April 12, 2018
Wistar researchers have found that soluble antibodies promote tumor progression by inducing accumulation of myeloid-derived suppressor cells (MDSCs) in pre-clinical cancer models. Results were published online in Cancer Immunology ...

Can myeloid derived suppressor cells subdue viral infections?

January 26, 2017
Myeloid derived suppressor cells (MDSCs), produced in the bone marrow as part of the human immune response to a tumor, may have a potent immunoregulatory role following viral infection. The similarities and differences between ...

Scientists identify marker for myeloid-derived suppressor cells

August 5, 2016
Myeloid-derived suppressor cells (MDSCs) are a population of immune cells that have been implicated in tumor resistance to various types of cancer treatment, including targeted therapies, chemotherapy and immunotherapy. Polymorphonuclear ...

New immunotherapy approach boosts body's ability to destroy cancer cells

January 12, 2018
Few cancer treatments are generating more excitement these days than immunotherapy—drugs based on the principle that the immune system can be harnessed to detect and kill cancer cells, much in the same way that it goes ...

Recommended for you

Obesity both feeds tumors and helps immunotherapy kill cancer

November 12, 2018
A groundbreaking new study by UC Davis researchers has uncovered why obesity both fuels cancer growth and allows blockbuster new immunotherapies to work better against those same tumors.

Cancer stem cells get energy from protein, and it's proving to be their Achilles' heel

November 12, 2018
Think of energy metabolism like a party popper: Ripping something apart releases a bang. Most of your cells rip apart sugar to release the "bang" of energy. Sometimes they rip apart fats, and in a pinch, cells can even metabolize ...

Spread of deadly eye cancer halted in cells and animals

November 12, 2018
By comparing genetic sequences in the eye tumors of children whose cancers spread with tumors that didn't spread, Johns Hopkins Medicine researchers report new evidence that a domino effect in cells is responsible for the ...

Scientists shine new light on link between obesity and cancer

November 12, 2018
Scientists have made a major discovery that shines a new, explanatory light on the link between obesity and cancer. Their research confirms why the body's immune surveillance systems—led by cancer-fighting Natural Killer ...

Two-pronged device enables maverick immune cells to identify and kill cancers

November 12, 2018
Immune cells called Gamma Delta T cells can act independently to identify and kill cancer cells, defying the conventional view of the immune system, reveals new research from the Francis Crick Institute and King's College ...

Research brings personalized medicine to treat leukemia one step closer

November 12, 2018
Scientists at the University of Birmingham have revealed the roles that different types of gene mutations play in causing blood cancers in a study that was the culmination of a decade's research.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.