Tumor Infiltrating Lymphocytes (TIL): From Bench to Bedside

While the number of therapeutic options for patients with cancer have grown exponentially as the collective knowledge of cancer biology and genomics has improved, the fact remains that the majority of those with metastatic solid tumors will never be cured of their disease. With the development of targeted therapies that disrupt aberrant signaling pathways in cancer cells caused by distinct genetic alterations, the paradigm of “personalized therapy” has developed, with the goal of individualizing a patient’s treatment to their own tumor’s distinct mutational make-up. However, a truly personalized approach that takes advantage of the ability of the immune system to not only recognize and destroy tumor cells, but also to prevent recurrence through immune memory, has been successfully applied to patients with metastatic disease for more than 3 decades. Preclinical observations by many groups using mouse models beginning in the first half of the twentieth century led to pioneering work carried out by the group led by Steven A. Rosenberg at the Surgery Branch of the National Cancer Institute (NCI) that developed adoptive cellular therapy (ACT) with tumor infiltrating lymphocytes (TIL). Numerous clinical trials have now demonstrated the feasibility of generating large numbers of TIL from surgical biopsies which can be safely administered to patients to effectively treat multiple solid tumor histologies. The availability of TIL products has proven instrumental for the demonstration that tumor-specific T-cell populations are capable of inducing complete therapeutic responses lasting for decades. As our understanding of how the immune system recognizes pathogens and is regulated to prevent autoimmunity has grown, pharmacologic approaches utilizing antibody-mediated blockade of immunologic “checkpoint” molecules now provide additional treatment options for patients. This has led to the opening of a substantial gap in the treatment landscape of many solid tumors of patients that do not derive long-term benefit from currently available immunotherapies, and much ongoing work is directed at filling this gap with novel TIL approaches in the coming years. Here, we review the preclinical studies that served as the basis for human translation of TIL therapies, clinical trial data for TIL across tumor types, and discuss future developments in TIL therapy that seek to refine personalized treatments for patients directed at tumor-specific mutations.KeywordsTumor infiltrating lymphocytes (TIL)Adoptive cellular therapy (ACT)Lymphokine-activated killer (LAK) cellsIL-2MelanomaRenal cell carcinomaNon-small cell lung cancerMalignant gliomasGastrointestinal cancersGynecologic malignanciesLifileucelCD28CD27Tumor-associated antigens (TAA)Cancer-germline/cancer testis antigens (CTA)Tumor-specific antigensNeoantigens