Leveraging the immune system to fight melanoma has been a logical and promising concept for many years. Long ago, scientists clinically observed the spontaneous regression of some primary cutaneous melanomas, leading them to hypothesize that the immune system could indeed somehow be harnessed to treat melanoma. Numerous attempts to stimulate the immune system by exposing it to melanoma antigens and immune stimulatory cytokines, while occasionally successful to a point, usually proved futile. These failures, however, led to insights, the most important being immune tolerance. The understanding that exposing the immune system to melanoma can sometimes, instead of stimulating the immune system, shut it down was a watershed moment for melanoma therapy in particular and for cancer therapy in general.
This understanding led to the discovery of immune checkpoints, most prominently CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and PD-1 (programmed death-1), which signal to turn off the immune response to prevent persistent inflammation in the absence of foreign invaders. Unfortunately, some metastatic melanoma cells co-opt these checkpoints to protect themselves from immune attack.
On the heels of this discovery, investigators developed revolutionary checkpoint-blocking agents, including the now FDA-approved anti-CTLA-4 monoclonal antibody ipilimumab (YervoyR) and the anti-PD-1 monoclonal antibodies pembrolizumab (KeytrudaR) and nivolumab (OpdivoR). By blocking the activity of their respective checkpoints, these medicines can release the power of the immune system to effect life-prolonging responses in patients with stage IV or unresectable stage III melanoma. Five-year survival rates have jumped from 3-5 percent to 20 percent with single agent therapy, and now, with the advent of combination blockers, to as high as 40 percent, with many of these patients basically cured (a term we are still careful not to use in clinical practice).
In this issue of The Melanoma Letter, Drs. Jedd Wolchok and James Larkin report on the exciting synergistic benefits of nivolumab-ipilimumab, the only FDA-approved combination checkpoint blockade therapy to date. While this drug combination has produced spectacular results, the authors also point out the serious side effects that can come with it, rarely life-threatening but sometimes requiring lifelong management. They also acknowledge that 30 or 40 percent survival is still far from ideal, and that concerted research must continue to find alternate and complementary ways to harness the immune system more perfectly, as well as markers that can tell us more precisely which individual and combination therapies will work best for which patients.
We have come so far, yet so much work remains to be done to fulfill the now very real vision of a future where no one has to die from this still devastating disease.
Allan C. Halpern, MD . Editor-in-Chief
Ashfaq A. Marghoob, MD . Associate Editor