Tumor Infiltrating Lymphocyte (TIL) Therapy for Solid Tumor Treatment: Progressions and Challenges

Abstract

Over the past decade, immunotherapy, especially cell-based immunotherapy, has provided new strategies for cancer therapy. Recent clinical studies demonstrated that adopting cell transfer of tumor-infiltrating lymphocytes (TILs) for advanced solid tumors showed good efficacy. TIL therapy is a type of cell-based immunotherapy using the patient's own immune cells from the microenvironment of the solid tumor to kill tumor cells. In this review, we provide a comprehensive summary of the current strategies and challenges in TIL isolation and generation. Moreover, the current clinical experience of TIL therapy is summarized and discussed, with an emphasis on lymphodepletion regimen, the use of interleukin-2, and related toxicity. Furthermore, we highlight the clinical trials where TIL therapy is used independently and in combination with other types of therapy for solid cancers. Finally, the limitations, future potential, and directions of TIL therapy for solid tumor treatment are also discussed.

Keywords: immunotherapy; solid tumor; tumor infiltrating lymphocytes (TIL).

Figure 1

General scheme of the preparation of TILs. After excision, the tumor tissue is fragmented or digested into a single-cell suspension and then cultured in cell culture plates with IL-2. Using the selected TIL method, the detection of tumor reactivity is based on the production of IFN-γ by co-culturing with autologous tumor cells. In the “young” TIL method, the assays for specific tumor recognition are omitted. TILs could be enriched by FACS or MACS. TIL cultures are then expanded to treatment levels by REP. These TILs are then infused back into the lymphodepleted patient. On the other side, the tumor cells and normal cells undergo WES and RNA-seq to identify mutations. Based on this information, TMG or peptides are synthesized. These TMG or peptides are then processed by autologous APC and presented to T cells which are co-cultured with APCs. The recognition of neoantigen-specific T cells depends on IFN-γ ELISPOT assays, and these identified T cells with activated surface markers (such as CD137) can be purified by FACS.

Figure 2

The combination of TIL therapy and other therapies. The following four methods of combined therapy are described in the form of figures: (A) a BRAF inhibitor can reduce immunosuppressive signals and facilitate tumor infiltration of lymphocytes; (B) DCs are stimulated by signals and loaded with tumor-specific antigens on MHC to activate the antigen-specific T-cells; (C) PD-L1 or PD-1 blockers may prevent the interaction of PD-1 and PDL-1 between TILs and tumor cells; and (D) blocking CTLA-4, which competes with CD28 to bind the B7 molecule, allows T cell killing of tumor cell.