SPOTLIGHT The story of ICIs began in 1987, when researchers discovered a gene that they called CTLA-4 (see Figure 18, p. 102) (424). However, it took nearly eight years before the immune checkpoint function of CTLA-4 was discovered, and another 16 years of basic and clinical research before this knowledge was translated into a clinically effective therapy, a therapeutic antibody that targets CTLA-4, ipilimumab (Yervoy). Upon attaching to CTLA-4 on the surface of patients’ T cells, ipilimumab releases a set of brakes on T cells, spurring them into action. Ipilimumab was the first treatment in history to improve survival for patients with metastatic melanoma and was approved by FDA for this use in March 2011. Decades of Research Breakthroughs Along the Way to Developing Immune Checkpoint Inhibitors Immune checkpoint inhibitors (ICIs) are cancer immunotherapeutics that work by releasing certain “brakes” called immune checkpoint proteins on the surface of cancer-fighting immune cells. The first ICI to be approved by the U.S. Food and Drug Administration (FDA) was ipilimumab, in March 2011. Ipilimumab targets an immune checkpoint protein on T cells called CTLA-4. Tremelimumab—the only other ICI that works similarly—was approved in October 2022. Several other ICIs target a second immune checkpoint protein called PD-1 and its binding partner, a protein called PD-L1. The first of these immunotherapeutics to be approved by FDA was pembrolizumab, in September 2014, and retifanlimab-dlwr—the newest member of this class of immunotherapeutics—was approved in March 2023. Yet another checkpoint protein, called LAG-3, is the target of relatlimab-rmbw, an ICI that was approved by FDA in March 2022. Decades of basic, translational, and clinical research underpinned the development of ipilimumab, pembrolizumab, and relatlimab-rmbw, starting with the discoveries of the CTLA-4, LAG-3, and PD-1 genes in 1987, 1990, and 1992, respectively. Other milestones along the way to the FDA approvals include the identification of the brake function of CTLA-4, LAG-3, and PD-1, the identification of binding partners that attach to and trigger the brake function, and the demonstration that ICIs targeting these brakes can prevent them from being triggered. While all the ICIs currently approved by FDA work on brakes located on T cells, ongoing research is evaluating the clinical utility of targeting brakes on additional immune cell types. Adapted from (163). FIGURE 18 2014 First PD-1–targeted checkpoint inhibitor pembrolizumab for advanced melanoma 2022 First LAG3-targeted checkpoint inhibitor relatlimab-rmbw for advanced melanoma 1995 CTLA-4 discovered to function as a T-cell brake 1999 PD-1 discovered to function as a T-cell brake 2001 The CTLA-4–targeted checkpoint inhibitor ipilimumab enters phase I/II clinical trials for melanoma in the U.S. 1991 B7-1, the first protein that attaches to CTLA-4, discovered 1987 Gene encoding CTLA-4 discovered 1990 Gene encoding LAG-3 is discovered 1992 Gene encoding PD-1 discovered 1996 Targeting CTLA-4 shown to cause tumor elimination in mice 2002 Targeting PD-1/PD-L1 shown to have anticancer eects in mice 2005 LAG-3 discovered to function as a T-cell brake in vivo 2013 Anti-LAG-3 antibody enters phase I/II clinical trial to treat solid tumors July 2023 Eleven immune checkpoint inhibitors approved by FDA to treat multiple cancer types 2018 James P. Allison, PhD, and Tasuku Honjo, MD, PhD, recognized with Nobel Prize in Physiology or Medicine for their discovery of checkpoint inhibition 2000 First protein that attaches to PD-1 discovered, PD-L1 2011 Ipilimumab for advanced melanoma 2006 First PD-1–targeted checkpoint inhibitor enters phase I/II clinical trials for advanced solid tumors 1974 Major histocompatibility complex is identified AACR Cancer Progress Report 2023 Immunotherapy: Pushing the Frontier of Cancer Medicine 102
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