Thanks to Immunotherapy, Melanoma Deaths are Declining
Elizabeth Reap

Thanks to Immunotherapy, Melanoma Deaths are Declining

But the percentage of patients who have durable responses is still too low. New areas of research could help change those odds.

Several weeks ago, the US National Cancer Institute released some very encouraging data indicating an increase in survival rates for patients with melanoma. Annual mortality rates from melanoma declined 8.5 percent among men from 2014 to 2016, and 6.3 percent among women from 2013 to 2016. The improvements were even greater among African Americans, who develop melanoma less often but of more severe varieties.

The dramatic decline correlates with the rise of powerful immune checkpoint inhibitors (ICIs), a revolutionary milestone in the field of cancer immunotherapy. Melanoma, which arises when pigment-producing cells—known as melanocytes—mutate and become cancerous, was one of the earliest targets of ICIs. In the 10 years since the first checkpoint inhibitors hit the market, survival rates for melanoma have been on the upswing.

Ironically, it wasn’t too long ago that scientists took a dim view of cancer immunotherapies, reasoning that if the immune system had anything to do with cancer, we would all be capable of clearing cancer from our body. There were a few mavericks. In the 1950s and 1960s, Lewis Thomas and Nobel laureate Frank Macfarlane Burnet suggested that T-cells were the pivotal sentinel in the immune system’s response to cancer, but the idea was highly controversial. Most researchers didn’t think there was any meaningful crosstalk between the immune system and cancer and viewed cancer cells as simply normal cells that had gone rogue.

It was James Allison, an immunologist at the University of Texas MD Anderson Center, who helped to change the conversation about how we viewed this relationship. Allison’s crucial insight was to block a protein on T-cells that acts as a brake on their activation, freeing the T-cells to attack cancer. He developed an antibody to block the checkpoint protein CTLA-4 and demonstrated the success of the approach in experimental models. His work led to development of the first immune checkpoint inhibitor antibody, ipilimumab, approved for late-stage melanoma by the U.S. Food and Drug Administration in 2011. Last year, Allison received the Nobel Prize in Physiology or Medicine for his pioneering work in cancer immunotherapy. Allison’s co-recipient was Tasuku Honjo of Kyoto University, who discovered the T-cell protein PD-1, which when blocked also puts the brakes on the immune system.

Today, there are seven approved ICI antibodies in the US that block three different proteins on T-cells. The immunotherapy drugs target melanoma, lung cancer, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancers, Hodgkin lymphoma, Merkel cell skin cancer, and other cancers. The number of experimental immunotherapy targets is growing exponentially, and there are currently around 3,300 agents under clinical or pre-clinical investigation.

Due to the exciting discovery by the two laureates, a paradigm shift in how to treat cancer has occurred. In recent years, research on antibodies that inhibit CTLA-4 and PD-1 has progressed at a rapid pace in both the clinical and pre-clinical arenas. Treatments that block PD-1 have been shown to be effective in lung and renal cancers, lymphomas, and melanoma.

Recent clinical work that combined therapies targeting CTLA-4 and PD-1 in patients with melanoma showed that this approach can be even more effective than anti-CTLA-4 alone. Numerous pre-clinical studies are now underway to evaluate the efficacy of checkpoint therapy against most types of cancer, and scientists are testing numerous other checkpoint proteins to see if they could act as targets.

Clearly, immunotherapy is changing the lives of people with cancer and allowing them to have a shot at longer survival. But the story is far from over. Cancer still kills millions of people every year—20 Americans die every day of melanoma—and significant challenges impede immunotherapy’s full potential. A recent study published in the Journal of the American Medical Association found that while the percentage of people eligible for ICI drugs increased from 1.5% in 2011 to around 44% in 2018, checkpoint inhibitors may at best lead to responses in fewer than 13% of patients with cancer in the US. So while the responses tend to be very durable over time, the percentage of people who do respond is too low.

Scientists are exploring different ways to improve the odds of success. One active area of research is pairing immune checkpoint drugs with a targeted therapy, which takes aim at a cancer's specific genes, proteins, or the tissue environment that contributes to cancer growth and survival.

Another area of exploration is the hunt for newly formed antigens that arise as tumors mutate. One possible reason why ICI showed efficacy in melanoma and lung cancer is that these tumors have a lot of genetic mutations. Tumor cells share a majority of their DNA with healthy cells, but if you look deeper, it is clear there are areas where tumor DNA is distinct. It’s these differences which manifest as so-called neoantigens that offer a ‘seek-and-destroy’ signal for our immune systems to home in on.

Using neoantigens to elicit an immune response helped researchers predict responses to ICI. They are now becoming an important focus in the development of personalized cancer vaccines. Therapeutic vaccines involve sequencing a patient’s tumor and writing sophisticated algorithms to analyze and decode the genetic information. If the information reveals unique targets that provoke the immune system to attack, a vaccine might then be custom-built to induce a similar response to the “neoantigens.”

These are indeed exciting times. As we head into summer—the most dangerous season for skin cancer—it’s important to remember how far we’ve come in fighting this awful disease and how far we need to go toward winning this battle.

Elizabeth Reap's article will also be appearing in the upcoming addition of Oncology Fast Five, produced by Charles River.