Clinical Success of Adoptive Cell Transfer Therapy Using Tumor Infiltrating Lymphocytes

Abstract

One of the hallmarks of cancer is the infiltration of all tumors (both primary and metastatic sites) with immune cells composed of lymphocytes and myeloid cells to various extents. This is indicative of the intrinsic inflammatory nature of all tumors as “invaders” in resident normal tissues causing local immune activation and immune cell recruitment. In most cases, a cascade of events sets in motion immune responses that drive innate immunity at the tumor site which then drives adaptive responses mediated by antigen-specific T cells. Tumors are infiltrated to various degrees with previously activated CD8⁺ and CD4⁺ T cells that are products of this immune response. These cells, also called “tumor-infiltrating lymphocytes” (TIL) have emerged as critical factors controlling cancer growth at localized tumor sites by recognizing not only over-expressed self-antigens, but also mutated neo-antigens specific for each patient for which immune tolerance does not exist. These are emerging to be the most powerful tumor antigens recognized by TIL. Many studies have now shown that increased T-cell infiltration into tumors at different disease stages is correlated with increased survival for many different type of cancers. Harnessing the intrinsic effector properties and antigen specificity of these TIL has emerged over a number of decades of dedicated pre-clinical and clinical research as a powerful approach to cancer immunotherapy through the adoptive transfer of TIL expanded ex vivo followed by re-infusion into the patient. This form of adoptive cell therapy has been highly developed to treat metastatic melanoma with consistent response rates ranging from 45 to 50 % and complete durable response rates as high as 20 %. These results, together with advances in methods to expand TIL ex vivo to therapeutic numbers, has set the stage now for further developing TIL adoptive cell therapy as a standard-of-care for melanoma through practical commercial manufacturing systems. In this chapter, we introduce T-cell therapy and comprehensively describe TIL therapy for metastatic melanoma, including a discussion of how TIL are expanded for therapy, outstanding technical and biological questions relating to T-cell differentiation being addressed in the field, and the growing area of predictive biomarker research that is revealing new mechanistic insights into how TIL work and opening up the possibility to select patients for T-cell therapy by interrogating factors within the tumor microenvironment. Overall, TIL therapy for melanoma has proven to be an effective regimen to treat melanoma in multiple clinical centers now across the world, especially in a salvage setting when other front-line therapies have failed, including T-cell checkpoint blockade, such as anti-CTLA-4, anti-PD-1, and anti-PD-L1. A number of cytokine signaling mechanisms and genes regulating the differentiation of TIL in culture towards end-stage, senescent cells, especially CD8⁺ T cells, have been elucidated allowing us to manipulate these pathways during ex vivo cell expansion to keep the cells “younger” and less differentiated when infused to ensure improved persistence in vivo. A number of promising biomarkers are being discovered in the original tumors used to expand TIL for therapy. These markers, together with other patient-specific biomarkers can be incorporated into biomarker signatures allowing for accurate selection of patients most likely to respond to therapy. All these developments, together with newer ways to selectively expand more tumor-specific TIL, will push this cell therapy more and more into the mainstream cancer care as part of growing “immunological toolbox” for cancer.