Adoptive transfer of tumor-infiltrating lymphocytes in melanoma: a viable treatment option

Abstract

The treatment of metastatic melanoma patients with autologous tumor-infiltrating lymphocytes (TIL) shows robust, reproducible, clinical responses in clinical trials executed in several specialized centers over the world. Even in the era of targeted therapy and immune checkpoint inhibition, TIL therapy can be an additional and clinically relevant treatment line. This review provides an overview of the clinical experiences with TIL therapy thus far, including lymphodepleting regimens, the use of interleukin-2 (IL-2) and the associated toxicity. Characteristics of the TIL products and the antigen recognition pattern will be discussed, as well as the current and upcoming production strategies, including the selective expansion of specific fractions from the cell product. In addition, the future potential of TIL therapy in melanoma and other tumor types will be covered.

Keywords: Adoptive cell therapy; Antigen recognition; Combination therapy; Immunotherapy; Interleukin-2; Lymphodepletion; Melanoma; Tumor-infiltrating lymphocytes.

Fig. 1

Schematic Overview of the Current TIL Production Protocol and Potential Improvements. Currently, surgically removed melanoma metastases are processed into single cell digest or smaller tumor pieces. At this point in production, direct selection of tumor reactive cells based on activation markers such as PD-1 or CD137, or CD8⁺ T cells or multimers can be applied. TIL outgrowth currently occurs in HD IL-2. Outgrowth of TIL could be improved in the presence of alternative cytokines such as IL-7, IL-15 or IL-21 or agonistic co-stimulatory antibodies such as CD137. In addition, a variation of gene modifications of homing or co-stimulatory factors can be applied. The current REP protocol consists of addition of activating soluble anti-CD3, HD IL-2 and irradiated feeders, but may be improved by addition of alternative cytokines such as IL-7, IL-15 and IL-21 and artificial feeders may be used. Also, the current REP time may be shortened. After REP, gene modification can also be applied. The infusion procedure of TIL to the patient currently consists of a conditioning lymphodepleting regimen, usually cyclophosphamide and fludarabine and administration of HD IL-2 following TIL infusion. However, multiple studies are being conducted with adjusted doses and treatment schedules of the lymphodepleting regimen and IL-2, as are studies being conducted with TIL as combination therapy to further potentiate the anti-tumor effect of TIL