Regular readers of this column will recall previous articles about immunotherapy and its great promise as a form of cancer treatment. Indeed, it has been hailed as a major medical breakthrough, and is credited with achieving remission and extending the lives of countless cancer patients, many whom were considered terminal prior to treatment. This year, the Nobel Prize committee agreed, and awarded two physicians/researchers with the Nobel Prize in Physiology or Medicine for the groundbreaking work they’ve accomplished in this area over the course of nearly thirty years.
Back in the 1990s Dr. James Allison, Chairman of Immunology at the University of Texas M.D. Anderson Cancer Center and Dr. Tasuko Honjo, Professor of Immunology and Genomic Medicine at Kyoto, Japan discovered (independently of each other) that certain proteins on T-cells (an integral part of the immune system) function as “brakes” which hamper their ability to attack malignant cells. The scientists surmised that if these proteins could be suppressed, perhaps it could transform the body’s ability to fight cancer.
Traditionally the trifecta of cancer treatment has been surgery, radiation and chemotherapy, with each addressing the cancer cells directly. Immune checkpoint therapy aims to unleash the body’s own immune system to attack the cancer and treat it as it would any other invader. This is tricky because cancer cells are normal cells made by our own bodies, which have acquired mutations that cause them to divide abnormally. Because the immune system recognizes the mutant cells as “family members” it is reluctant to attack and kill them.
T-cells are white blood cells that have special molecules on their surfaces called receptors (aka proteins), which allow them to recognize bacterial and viral organisms. This ability to identify and kill infected or damaged cells is the hallmark of an effective immune system. Unfortunately, because they are a product of our own body’s making, cancer cells carry receptors that the T-cells recognize as “friendly” and so they are often spared destruction. Nobel laureates Allison and Honjo each discovered checkpoints on T-cells, that when disabled, allow them to recognize the cancer cells as intruders and launch an attack. The drugs that have been developed as a result of this science are called immune checkpoint inhibitors. Essentially, they uncloak the cancer cell, thereby inhibiting its ability to appear friendly or familiar. Without its “disguise” T-cells are more able to recognize and attack the cancer.
The first checkpoint inhibitor to be approved by the FDA was Yervoy (ipilimumab). It was approved in 2011 for the treatment of melanoma. Keytruda (pembrolizumab) has received a lot of press because it has been extremely effective in the treatment of several cancers. Notably, former President Jimmy Carter is free of the melanoma that had metastasized to his brain and liver after being treated with Keytruda. Currently, only between fifteen and twenty percent of people respond to these treatments, but that response can be dramatic, sometimes even offering remission for patients who were considered terminal.
The research is ongoing and presents several avenues to explore. For starters, targeting more than one checkpoint often increases the treatment’s overall effectiveness. Because Dr. Allison and Dr. Honjo each discovered different checkpoints that can be attenuated by different mechanisms, the cancer can be attacked simultaneously by more than one immunotherapy. This leads experts to foresee (for example) a future scenario where more than half of melanoma patients treated with a combination of ipilimubab (Yervoy) and nivolumab (Opdivo) achieve long-term responses that last a decade or more.
In awarding Dr. Allison and Dr. Honjo with the Nobel Peace Prize, the committee recognized that their work was akin to creating “a new pillar in cancer therapy.”
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Related articles: Cancer Tricks the Immune System and Developments in Cancer Treatment and Immunotherapy.