There can be little doubt that immunotherapy has been one of the great advances in cancer treatment of the past 25 years. And while there are various ways in which to utilize or activate the immune system to fight against cancer, the approach that has yielded the most meaningful results, at least up until now, has been with a class of pharmacologic agents known as checkpoint blockade inhibitors.
T cells are a type of lymphocyte, perhaps the most important cells involved in the immunological defenses of the body, which recognize cells as self or “other.” It is obviously important to make this distinction—you would not want a policeman to arrest or destroy a citizen as opposed to a non-citizen. There are proteins on the surfaces of normal cells that shut off the immune cells so that they do not react to the normal cells and harm them. While malignant cells should not have such safeguards and should be rejected by the immune system and destroyed, it was discovered that most cancer cells do express these checkpoint inhibitor proteins and thereby protect themselves against the destructive effects of the T cells—think of it as having a fake ID card. Examples of such proteins are PD-L1 and PD-L2 (programmed death-ligand 1 and 2) on the surface of the tumor cells and CTLA4 and PD-1 (programmed cell death protein 1) on the T cell surface to which these proteins bind and inactivate the T cell. The binding of these proteins on the surface of the T cells causes the T cell to shut off its immune response to the cancer cell. The elucidation of this mechanism led to the awarding of the 2018 Nobel Prize in Medicine to James Allison of the MD Anderson Cancer Center in Houston and to Tasuku Honjo of the University of Kyoto in Japan.
The first clinically effective checkpoint inhibitor was ipilimumab (Yervoy), which was a human monoclonal antibody to block CTLA-4. It proved promising against metastatic melanoma in early clinical trials and ultimately was tested in a phase III randomized clinical trial. In this study, published in the New England Journal of Medicine in 2010, ipilimumab as a single agent for advanced melanoma was compared to gp100 (a melanoma-specific vaccine) or to a third arm with the two together (ipilimumab and gp100). The study found an overall survival of 10.1 months for ipilimumab alone versus 10.0 months for the two drugs together versus 6.4 months for gp100; on the basis of this trial, ipilimumab was approved by the FDA for advanced melanoma. The drug also proved to be efficacious in the adjuvant treatment of patients with resected stage III melanoma for which the five-year overall survival was 65.4% for the group treated with ipilimumab versus 54.4% for the placebo group.
Another approach to checkpoint blockade is through the PD-1 antigen on the T cell. The two drugs that have been most prominent through this mechanism are pembrolizumab (Keytruda) and nivolumab (Opdivo). Thus, a prior study, also published in the New England Journal of Medicine in 2015, compared the use of combined ipilimumab and nivolumab versus either drug alone for advanced melanoma. The progression-free survival was 11.5 months for the two drugs together, 2.9 months for ipilimumab alone, and 6.9 months for nivolumab alone. Several subsequent randomized trials confirmed that combination therapy was superior to a single agent.
The Checkmate 067 Trial randomized 945 patients with advanced melanoma between July 2013 and March 2014 to ipilimumab alone, nivolumab alone, or the combination. Interim results after 6.5 years of follow-up were published in 2022 and showed a dramatic improvement in survival for the combination arm versus either drug separately. Just recently, in January of 2025, the final 10-year outcomes of this important trial were published in the New England Journal of Medicine. They found a median overall survival of 71.9 months for the ipilimumab-nivolumab combination versus 36.9 months for nivolumab alone versus 19.9 months for ipilimumab alone. The median melanoma-specific survival was more than 120 months for the combination, with 37% of the patients in that arm still alive.
It is important to consider these extraordinary survival outcomes in light of the prognosis that metastatic melanoma had prior to this class of drugs. In effect, the disease was untreatable with a survival measured in months, e.g., six to nine months. This is one of the more remarkable therapeutic successes for systemic therapy in oncology.
Alfred I. Neugut, MD, PhD, is a medical oncologist and cancer epidemiologist at Columbia University Irving Medical Center/New York Presbyterian and Mailman School of Public Health in New York. Email: [email protected].
This article is for educational purposes only and is not intended to be a substitute for professional medical advice, diagnosis, or treatment, and does not constitute medical or other professional advice. Always seek the advice of your qualified health provider with any questions you may have regarding a medical condition or treatment.
