SPOTLIGHT Researchers are continually working to develop a much deeper understanding of additional immune checkpoint proteins and how they may be targeted alone or in combinations for cancer treatment. Progress in this area is reflected by the 2022 FDA approval of an ICI targeting a new immune checkpoint protein, called LAG-3 (1). Researchers are investigating the therapeutic potential of targeting other immune checkpoint proteins, such as B and T lymphocyte attenuator (BTLA) (524), T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3) (525), V-domain Ig suppressor of T-cell activation (VISTA) (526), and T-cell immunoreceptor with Ig and ITIM domains (TIGIT) (527), to unleash the immune system against tumors. Of these ICIs, researchers have identified TIGIT as one of the most promising new targets for cancer immunotherapy. TIGIT is present on T cells and NK cells (see Sidebar 38, p. 100), and functions as a brake on the immune system. As one example, initial findings from an ongoing phase II clinical trial evaluating the potential of one such TIGIT inhibitor, tiragolumab, showed promising results in treating patients with lung cancer (528). In another phase II clinical trial, treatment of patients with stage IV lung cancer with a different TIGIT inhibitor, domvanalimab, showed improvement in progression-free survival (see Sidebar 32, p. 80) (529). It is important to note that these are still preliminary data and larger, randomized phase III studies are needed to establish whether TIGIT inhibitors will improve health outcomes for patients with cancer. There are currently 85 ongoing clinical studies evaluating more than 15 inhibitors of TIGIT at various phases of clinical development (530). Findings from these and future studies will provide further insight into the effectiveness of TIGIT inhibitors in cancer immunotherapy. Researchers are also evaluating ICIs that can release the brakes on other types of immune cells beyond T cells and unleash them against cancer. As one example, research has shown that macrophages (see Sidebar 38, p. 100) have a protein, called signal regulatory protein α (SIRPα), on their surface. SIRPα functions as a brake on macrophages and stops them from killing microorganisms, removing dead cells, or activating other immune cells. Interestingly, many tumor cells have high amounts of a protein, called CD47, on their surface, which binds to SIRPα, and sends the “do not eat me” signal to macrophages (531). Ongoing research is focused on developing drugs that can release the interaction between the two proteins and activate macrophages against different types of cancer (532,533). A New Wave of Adoptive Cell Therapeutics While all of the ACTs currently approved by FDA are based on CAR T cells (see Sidebar 40, p. 117), extensive ongoing research is exploring the utility of other ways to modify T cells (534), as well as of other types of immune cells as anticancer agents. One group of immune cells with therapeutic potential against cancer are called natural killer (NK) cells. NK cells act rapidly and directly to kill infected, damaged, or cancer cells by releasing toxic compounds. This efficiency and speed of killing unwanted cells make NK cells an ideal candidate for developing effective immunotherapeutics. Compared to the currently approved CAR T-cell therapies, immunotherapeutics based on NK cells have several advantages including relatively better availability (NK cell-based treatments do not necessarily rely on cells isolated from patients; cells could potentially be isolated from healthy individuals), comparatively shorter time to be available for therapy (NK cells can be prepared and stored for later use), and potentially fewer side effects (536). Similar to the T-cell based immunotherapies, therapies based on NK cells are developed against proteins present on the surface of cancer cells which helps NK cells recognize cancer cells and kill them. However, NK cells lack many of the advantages of T cells, GLOBAL LANDSCAPE OF ADOPTIVE CELL THERAPIES IN CLINICAL DEVELOPMENT IN 2022 As of April 5, 2022, there are 2,756 active cell therapy agents in clinical development globally. Developed from (535). 200 300 0 100 400 500 600 CAR T-cell therapy CAR NK-cell therapy TCR T-cell therapy TIL therapy Other T cell-based therapies NUMBER OF CLINICAL TRIALS 568 73 67 37 70 0 Blood Cancers Solid Tumors CD19 BCMA CD22 TAA HER2 MSLN NUMBER OF DRUGS AGAINST THE INDICATED TARGETS 100 150 50 200 250 300 260 92 53 157 41 34 Immunotherapy: Pushing the Frontier of Cancer Medicine AACR Cancer Progress Report 2023 129
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