Wednesday, April 24, 2019
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Nobel Prize in Medicine: Coronation of the Cancer Immunotherapy Revolution

In recent years, first in metastasized melanoma, then progressively in other solid tumors, immunotherapy has revolutionized the treatment of cancer and has saved patients who have hitherto been incurable. The Nobel Prize for Medicine, which was awarded on Monday to 2 researchers, crowns their efforts on 2 essential aspects of modern immunotherapy.
Classically, when we talked about immunotherapy, we were referring to the development of vaccines used to stimulate the immune system. But the responses to vaccination, highly dependent on the antigen and the immune system of the patient, are often very variable, to the point of being sometimes dangerous. Modern immunotherapy is at once more targeted, more effective and better controlled.
New vision of immunotherapy
The work of these two researchers focused on deciphering the activation system of immune cells that control the immune response, and to remove the "brakes" put in place by cancer to prevent the immune system from defending the body. against him.
The 2 researchers made it possible to better understand the role of 2 proteins on the surface of immune cells, CD4 T cells. Their work now makes it possible to strengthen the immune defenses of cancer patients (who are still reduced) and to attack cancer cells in different types of solid tumors, the first being melanoma whose prognosis has been transformed into advanced or metastatic stages. .
A life dedicated to cancer
James P. Allison, current Chair of the Department of Immunology at the MD Anderson Cancer Center, initially did his work at UC Berkeley in the 1990s and then at Memorial Sloan Kettering Cancer in New York. He first worked on a protein on the surface of lymphocytes called PD-1 / PD-L1, or checkpoint inhibitor. It is a protein that was initially identified as a brake on the immune system, and is actually a protein used by the cancer cell to camouflage itself.
By working on the understanding of how T cells work, Allison found that by blocking this PD-1 / PD-L1 protein, cancer cells were "unmasked" by the T cells and an immune response became possible again. against this cancer.
Originally tested in advanced melanoma, PD-1 / PD-L1 inhibitors are revolutionizing the treatment of cancer by attacking lung cancer, bladder cancer, mesothelioma … in the advanced stage as, now , in the earliest stages.
Another way to strengthen the defenses
Tasuku Honjo is working at Kyoto University in Japan, where he first studied another protein on the surface of T cells known as CTLA-4. It has been identified as one of the cofactors involved in the activation / braking of T-CD4 lymphocytes, and more specifically as a brake on these cells. CD4 T lymphocytes play a major role in the activation of the immune system.
Honjo then developed an antibody capable of neutralizing this protein and achieved dramatic results in stimulating CD4 T-cell activity and in cancer studies in mice. Her work was relayed by Allison and her colleagues who demonstrated that mice with cancer could be cured by this antibody. Research continued until this drug, called "ipilimumab", was adapted for humans and approved by the US Food and Drug Administration (FDA) in 2011 for patients with advanced melanoma .
Two sides of immunotherapy
Meanwhile, the development of anti-PD-1 has continued and other molecules have been approved successively. As monotherapy, anti-PD-1 treatments appear to be more effective than anti-CTLA-4 treatments, but the combination of the two is remarkably more effective, particularly in melanoma. When combining these two types of immunotherapy, CTLA-4 which stimulates immunity, and PD-1 / PD-L1, which prevents the camouflage of cancer, the anti-cancer responses are better. In addition, when patients suffering from melanoma are in prolonged response under treatment, it becomes possible to envisage an interruption of double immunotherapy without immediate relapse, which is not as possible in the case of treatment with a PD inhibitor. -1 as monotherapy.
All is not rosy
The combination of immunotherapies, however, increases the side effects, which become more important and must be managed. Despite the wave of hope aroused by these new treatments, all patients can not yet benefit: some cancers do not respond to these treatments, especially those that are not inflammatory and where there are few immune cells in cancer . In addition, these treatments are very expensive and jeopardize the financial balance of health insurance in the different countries.
There is still a lot of work to be done so that these new treatments can help more patients. Over the past 40 years, oncologists have perfected the use of standard cancer treatments such as surgery, chemotherapy and radiation therapy. Immunotherapy will not make them disappear and it is, on the contrary, necessary to develop future good combinations of different treatments to the best of the needs of each patient. The inclusion of immunotherapy when it is most useful will open a whole new field of possibilities.
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