Do we need pigment to develop melanoma?

New insights into the pigment pathway are improving the understanding of how immunotherapy works in melanoma, David E. Fisher M.D., Ph.D., said in a plenary presentation at 26th European Academy of Dermatology and Venereology (EADV) Congress in Geneva.

The findings may help improve the efficacy of these novel agents beyond the minority of patients who currently benefit from immunotherapy, says Dr. Fisher who is director of the Melanoma Program at Massachusetts General Hospital Cancer Center in Boston.

“We believe that for this new generation of drugs - known as checkpoint inhibitors - there is an important role for melanocyte-specific pigment genes as targets of the immune response,” Dr. Fisher said in an interview with Dermatology Times.

Improving immunotherapy

Although checkpoint inhibitors (eg, ipilimumab, pembrolizumab and nivolumab) have demonstrated considerable efficacy, only about one-third of metastatic melanoma patients have a profound benefit, he said. However, recent investigations suggest that insights into the pigment pathway may lead to new strategies that potentiate the efficacy of checkpoint inhibitors in melanoma.

“There is a phenomenon we do not entirely understand in mice and even in humans that after the [checkpoint] drug is given, there is essentially an autoimmunity against melanocyte proteins capable of participating in the destruction of a melanoma,” Dr. Fisher said.

See related article:  Checkpoint inhibitors flourish

Initial evidence has suggested that patients who respond best to checkpoint inhibitors may be the ones who have many mutations in the genomes of their tumors. With that premise in mind, Dr. Fisher and colleagues conducted mouse model experiments using melanoma cells engineered to have a high number of UV-induced mutations. They found that checkpoint inhibitor therapy does in fact trigger a better response in those melanomas vs melanomas with low numbers of UV-induced mutations. Notably, however, once that immune response is activated, the effect did not appear to be restricted to UV-mutated proteins.

In fact, in mice with UV-mutated melanoma that were treated, cured, and then re-challenged several months later with non-UV-mutated melanoma, 75% of the mice rejected the non-UV-mutated melanoma. That suggested that the initial immune response, even though definitely an amplified response due to the UV mutations, then spread beyond UV mutations and was and able to recognize normal melanocyte proteins.

“We call this epitope spreading,” Dr. Fisher said. “The T-cells now are able to recognize normal melanocyte proteins. We can see this is being induced by these drugs, and we can quantify that in the tumors of mice who have UV-mutated melanoma.”

Potential clinical implications

These findings have potentially important clinical implications for the many melanoma patients who do not respond adequately to checkpoint inhibitors, possibly due to low numbers of mutations. “We think mutations are important, but only for triggering the initial inflammatory response. After that, the response snowballs, and it really doesn’t need those mutations anymore,” he said.

Dr. Fisher and colleagues are now leveraging these insights to experiment with ways of “tricking” the immune system into mounting a snowball reaction. In a mouse model experiment, researchers evaluated an intraperitoneal injection of an anti-PD1 checkpoint inhibitor combined with topical imquimod and fractional laser treatment. Results of the study have not yet been published, but Dr. Fisher says the results were “successful” and a report is under review.

“It actually evolves an attack against non-mutated proteins,” Dr. Fisher said. “The results of our studies imply that there may be opportunities to exploit the recognition by the immune system of non-mutated protein epitopes against melanocytes as a way of successfully targeting melanoma cells.”

See related article:  Immune checkpoint inhibitors advance melanoma treatment

Summary

New insights into the pigment pathway are improving the understanding of how immunotherapy works in melanoma, and may one day improve the efficacy of these novel agents beyond the minority of patients who currently benefit from immunotherapy.

Checkpoint inhibitor therapy appears to trigger a better response in melanomas with a higher number of UV-induced mutations, but that once activated, the effect does not appear to be restricted to UV-mutated proteins.

Further, yet unpublished investigations suggest there may be opportunities to exploit the recognition by the immune system of non-mutated protein epitopes against melanocytes as a way of successfully targeting melanoma cells.