SPOTLIGHT data and evidence of clinical efficacy for ICI in the neoadjuvant setting (442,443). These critical data set the stage for additional neoadjuvant clinical trials with ICI. Based on such studies FDA has approved the ICIs pembrolizumab and nivolumab as neoadjuvant treatments for patients with triple-negative breast cancer and lung cancer, respectively, that are diagnosed at an early stage. The immense benefit of ICIs as neoadjuvant therapy was highlighted in two recent clinical trials conducted in patients with early-stage colorectal cancer that has specific genetic characteristics. Neoadjuvant treatment with either of the ICIs pembrolizumab or dostarlimab yielded remarkable responses, with some patients not even needing surgery and showing no evidence of cancer for years following the ICI therapy (444,445). A similar benefit of neoadjuvant ICI therapy has been noted in patients with melanoma, and those with cutaneous squamous cell carcinoma—the second most common type of skin cancer diagnosed in the United States— among other diseases (446,447). Collectively, these results highlight a paradigm shift in the treatment of early-stage cancers, with researchers hypothesizing that ICI therapy alone may eliminate cancers for certain patients without the need for any further treatments. While these data bring new hope to the cancer community, before such approaches to ICI use can become standard of care, it is important that they are shown in rigorous, well-designed, large clinical trials to prevent/delay cancer recurrence and improve how long patients live. Ongoing research and future efforts will identify optimal biomarkers for determining patients who would most benefit from such novel ICI regimens. Boosting the Cancer-killing Power of Immune Cells Research has shown that immune cells, such as T cells, are naturally capable of destroying cancer cells. It has also shown that in patients with cancer, there are often insufficient numbers of cancer-killing T cells, and that the cancer-killing T cells that are present are unable to find or destroy the cancer cells for one of several reasons. This knowledge has led researchers to identify several ways to boost the ability of T cells to eliminate cancer cells. Adoptive Cell Therapy Adoptive cell therapy (ACT), also called cellular immunotherapy, is designed to dramatically increase the number of cancerkilling immune cells a patient has, thereby boosting the immune system’s ability to seek and destroy cancer cells (448). While many of the adoptive cell therapies currently in late-stage clinical development and all that are approved by FDA utilize patientderived T cells (see Sidebar 39, p. 116), ongoing research is looking to harness the cancer killing power of other immune cell types including natural killer (NK) cells and macrophages, among others (see A New Wave of Adoptive Cell Therapeutics, p. 129). Chimeric antigen receptor (CAR) T-cell therapy is one type of ACT that has generated enormous excitement in cancer medicine in recent years. This is because treatment with CAR T cells has demonstrated unprecedented efficacy in certain patients with very advanced leukemia or lymphoma. Like ICIs, CAR T-cell therapy is the culmination of decades of basic, translational, and clinical research utilizing knowledge of the cellular and molecular components of the immune system, genetic engineering, and the biological underpinnings of blood cancers. The concept of a synthetic receptor was first reported in the late 1980s when researchers showed that the engineered proteins could be introduced into T cells and upon binding with appropriate partners could activate T cells, leading to killing of cancer cells (449). These discoveries, along with scientific breakthroughs in the 1990s on ways to expand T cells in large numbers in the laboratory and return them to the body where they could attack cancer cells, laid the foundation for the first clinical studies in the early 2010s that evaluated CAR T-cell therapy in patients with advanced leukemia (450-452). In 2017, tisagenlecleucel (Kymriah) became the first FDA approved CAR T-cell therapy when it was approved for the treatment of children and young adults with B-cell acute lymphoblastic leukemia that had not responded to standard treatments or had relapsed at least twice. The approval was based on results from a phase II clinical trial, showing that more than 80 percent of the children and young adults who were treated with tisagenlecleucel achieved a remission within three months of receiving the CAR T-cell therapy (453). This revolutionary immunotherapeutic has allowed some children with leukemia, like Cayden Addison, p. 114, to experience complete remission following treatment. In a recent study, long-term follow-up of patients treated with tisagenlecleucel showed that more than 60 percent were living three years or longer after their first infusion of CAR T cells, suggesting that CAR T cells can lead to durable cancer control (454). In 2022, 264 clinical trials were initiated, globally, investigating the use of CAR T-cell therapy in cancer treatment. The number of trials evaluating CAR T-cell therapy in solid tumors increased by 30 percent compared to 2021 (332). continued on page 116 Immunotherapy: Pushing the Frontier of Cancer Medicine AACR Cancer Progress Report 2023 109
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