Gruber Lecture: Immunotherapy advances and blocking BRAF improve melanoma treatments

Antoni Ribas, MD, PhD: 'As a field, the treatment of advanced melanoma has seen as many remarkable changes as any field of medicine has ever seen in a short span of three to four years.'

Antoni Ribas, MD, PhD: ‘As a field, the treatment of advanced melanoma has seen as many remarkable changes as any field of medicine has ever seen in a short span of three to four years.’

greater understanding of how the immune system deals with melanoma is key in developing therapies that lead to long-lasting responses in melanoma, and blocking the BRAF oncogene that drives the growth of about half of melanomas results in high-frequency antitumor responses.

Listen to Dr. Ribas’ podcast at aad-365.aadmeetingnews.org

A leading international cancer researcher, Antoni Ribas, MD, PhD, discussed these advances in melanoma therapy Sunday during the Lila and Murray Gruber Memorial Cancer Research Award and Lectureship, “Blocking BRAF and PD-1 to Treat Melanoma,” and in a separate interview about his work.

“Melanoma tries to hide from the immune system by turning off the immune response to the cancer. But inhibitors like CTLA-4 and PD-1 can unleash the immune system to fight the cancer. Our field has been studying how we can use this to combat melanoma, and it has led to the development of new active agents that in the last few years have become the new drugs for metastatic melanoma that are making a difference,” Dr. Ribas said.

Dr. Ribas, a professor of medicine, surgery, and molecular and medical pharmacology at the University of California, Los Angeles, focuses his research on developing new treatments for melanoma. He also is the director of the Tumor Immunology Program at UCLA’s Jonsson Comprehensive Cancer Center and chair of the melanoma committee of the National Cancer Institute-sponsored Southwest Oncology Group.

“We now have a good understanding of the mechanisms that lead to resistance to BRAF inhibitors,” he said. “The majority of patients with BRAF-mutated melanoma will respond to the BRAF inhibitors, but within months the tumor will become resistant to them in most, but not all, cases. There are several molecular mechanisms that will lead to that, and by studying those we are now developing a new generation of combinations of signaling inhibitors that can increase the activity of BRAF inhibitors.”

That research in understanding immune responses to melanoma has led to the development of PD-1 antibodies that allow the immune system to respond more strongly to the cancer, but only one-third of patients with advanced melanoma will respond to the treatment. Dr. Ribas said researchers are “interested in why it works in one-third — and not two-thirds — of the patients.”

“From the interaction between the immune system and the cancer, we realized that the patients who responded had an immune system that was ready to fight the cancer but was turned off by PD-1, and it was only in these people where the therapy would work,” he said. “Knowing this lets us think about the combinations that we should be testing, and are already testing in the clinic, for patients who do not have features that would lead to a tumor response.”

Moving forward, a new wave of clinical trials will study combinations of two-part treatments using BRAF inhibitors and PD-1 antibodies, Dr. Ribas said.

“We need to know they are safe in combination and then design the studies to demonstrate their superior effects, but that takes bigger and longer studies. I assume that in the next two years we will continue to see big advances in the treatment of metastatic melanoma,” he said. “As a field, the treatment of advanced melanoma has seen as many remarkable changes as any field of medicine has ever seen in a short span of three to four years.”

These advances reaffirm Dr. Ribas’ leap of faith — made more than 18 years ago — to move from his native Spain to UCLA to study tumor immunology.

“I was a medical oncologist treating many people with chemotherapy,” he said. “Many were saying targeted therapy may be the wave of the future, and I wanted to learn something new, so I sent four or five letters telling investigators that I would like to come to their lab to do some research, and I would find a way to support myself with a grant or something.

“When I left, colleagues I was training with and my supervisors were saying, ‘Why are you going to the U.S. to study tumor immunology that just doesn’t work?’ Now, tumor immunology is the hottest area of research in cancer. I go around giving talks about it and people are interested in learning how the immune system works with cancer. Things worked out for me.”

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