Synthetic TILs: Engineered Tumor-Infiltrating Lymphocytes With Improved Therapeutic Potential

Abstract

Immunotherapy has emerged as an effective and life-changing approach for several types of cancers, both liquid and solid tumors. In combination with traditional treatments such as radiotherapy and/or chemotherapy, immune checkpoints inhibitors have improved prognosis and overall survival of patients with advanced melanoma and many other cancers. Among adoptive cell therapies (ACT), while chimeric antigen receptor T cell therapies have demonstrated remarkable efficacy in some hematologic malignancies, such as B cell leukemias, their success in solid tumors remains scarce due to the characteristics of the tumor microenvironment. On the other hand, ACT using tumor-infiltrating lymphocytes (TILs) is arguably the most effective treatment for metastatic melanoma patients, but even if their isolation has been achieved in epithelial tumors, their success beyond melanoma remains limited. Here, we review several aspects impacting TIL- and gene-modified "synthetic" TIL-based therapies and discuss future challenges that must be addressed with these approaches.

Keywords: adoptive cell therapy; cancer immunotherapy; genetically engineered TILs; synthetic TILs; tumor-infiltrating lymphocytes.

Figure 1

Synthetic TILs manufacturing. After initial TILs isolation from fresh tumor fragments, retroviral or lentiviral vectors are used to genetically modified TILs in order to improve cytotoxicity, enhance tumor homing or reduce T cell exhaustion. Then, synthetic TILs are ex vivo expanded for 14 days in the presence of allogeneic irradiated peripheral blood mononuclear cells, soluble anti-CD3 antibodies and IL-2. Prior to synthetic TIL infusion, the patients receive lymphodepleting chemotherapy to ensure TIL persistence and expansion. CRC, Colorectal Cancer. LC, Lung Cancer. MM, Metastatic Melanoma..