SPOTLIGHT including the abilities to significantly expand upon recognizing their target and to form long-term memory, and don’t have the fine specificity of T cells. Currently, several NK cell-based immunotherapeutics to treat many types of cancer are at various stages of clinical development (537). Another group of immune cells with great potential as an immunotherapeutic are tumor-infiltrating lymphocytes (TILs). These cells are present inside the tumor microenvironment and can recognize and kill cancer cells (see Tumor Microenvironment, p. 35). In TIL therapy, researchers remove a portion of the tumor from a patient, isolate TILs from it, grow them in large numbers quickly, and infuse them back into the patient (see Sidebar 39, p. 116). In early clinical studies, TIL therapy has shown remarkable success in a number of cancer types, including melanoma and cancers of the cervix, colon and rectum, bladder, lung, and breast (539). As one example, cancer-free survival more than doubled in patients with advanced skin cancer who received TIL therapy, compared to those who received standard of care treatment (540). It is also noteworthy that, compared to the currently approved CAR-T cell-based ACT, both NK cell-based and TIL immunotherapeutics have shown greater success in treating solid tumors. An exciting new approach is to combine the power of ACTs with technological advances in genetic engineering to target specific mutations present in a patient’s tumor. There are several advantages to this approach, including personalizing the treatment to the patient’s tumor, increasing the time the engineered immune cells can stay in the body, and reducing their ability to fight a patient’s normal cells (541). Engineered T cells with T-cell receptors (TCRs) targeting tumors with mutations in cancer-driving genes, such as KRAS (542), have already shown efficacy in patients, and more trials using newly isolated TCRs specific for such targets are poised to begin in 2023 (543). With technological advances and increased knowledge of immunology, the field of ACT is on the verge of unleashing the potential of the immune system even further for the benefit of patients with cancer. A New Age of Therapeutic Combinations Precision medicine approaches including immunotherapy and molecularly targeted therapy have transformed the landscape of cancer care. However, only a fraction of patients responds to these treatments, and most tumors eventually develop resistance to current treatments (see Sidebar 35, p. 87) (545). To address these challenges, researchers are evaluating combinations of therapeutics within and between various treatment modalities, such as immunotherapy, molecularly targeted therapy, and radiotherapy, in many clinical trials against a wide array of cancers. There is already emerging evidence that combination therapy is an effective way to overcome or delay the development of resistance (546). Immunotherapeutics, especially ICIs, have shown remarkable success when used in combination with other methods of treating cancer. The success of using immunotherapeutics in combination is underscored by several FDA approvals of drug combinations to treat different types of cancer. Research has shown that the best outcomes are achieved when therapeutics are combined rationally based on their underlying mechanisms of action (547). Among the most promising of combinations are those that combine an immunotherapeutic with a molecularly targeted therapeutic or two different immunotherapeutics (549). Treatment with ICIs has also been effective when given before the surgery to remove the tumor (to shrink the tumor size and kill cancer cells that have spread in the body) (550), or after the tumor is surgically removed (to kill remaining Tumor cells T cells COLD TUMOR HOT TUMOR Immune-nonresponsive Immune-responsive Source: (538). Macrophages Tumor cells Researchers used precision genome editing to modify healthy T cells so that the cells were targeted against a patient’s cancer, and did not attack the body’s normal cells. Administration of the genetically modified T cells completely eliminated leukemia in a 13-year-old patient, who is one of the first 10 patients to receive this cutting-edge cancer treatment (544). AACR Cancer Progress Report 2023 Immunotherapy: Pushing the Frontier of Cancer Medicine 130
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