New Research Suggests Why PD-1 Blockers Don't Work for All Melanoma Patients

Immunotherapy using anti-PD-1 antibodies has been a game change for metastatic melanoma patients, but 60 to 70 percent of patients’ melanoma tumors are resistant to the anti-PD-1 antibodies.

Now new research out of UCLA suggests that patterns of gene mutations and expression in a melanoma tumor before starting anti-PD-1 immunotherapy may forecast whether the treatment will work.

The study is published online in the journal Cell.

Dermatologist Roger Lo, MD,  the study’s lead author and a UCLA Jonsson Comprehensive Cancer Center member, analyzed melanoma tumors from patients before anti-PD-1 therapy. The samples were subsequently divided into two groups, based on whether those patients responded or failed to respond to treatment. They then sought to assess the “on” or “off” status of a tumor cell’s genes by detecting their mutational rates and/or gene expression levels.

The degree to which genes and groups of genes are turned on or off has a major influence on whether a tumor will respond to or resist a drug, says Dr. Lo, an associate professor in the departments of medicine (dermatology), and molecular and medical pharmacology at UCLA.

“Once we observed how groups of genes were expressed at different levels between the responding versus non-responding tumors, we could compute the biological processes these genes likely participate in to promote resistance,” Lo explains. “This anti-PD-1 resistance-associated gene expression pattern defined a signature which was also detected across other common cancers of the lung, colon, kidney and pancreas.”

From other computational experiments, the investigators also found that tumors with more mutations were associated with longer patient survival after anti-PD-1 therapy. And in a surprise discovery, the team found that another common therapy for advanced melanoma that utilizes small molecules to turn off a specific pathway activated by the BRAF mutation can induce processes inside a tumor similar to those associated with anti-PD-1 resistance.

Despite the potential of BRAF and PD-1 targeted combination therapies to deliver further improvements in patient survival, future development of this approach should consider the altered immune microenvironment brought on by BRAF targeted therapy, the researchers note.

The research was supported by National Institutes of Health (NIH), Cancer Research Institute, The Ressler Family Foundation, The Steven C. Gordon Family Foundation and the Ian Copeland Melanoma Fund established by The Friedman Foundation.