IL-2-independent expansion, persistence, and antitumor activity in TIL expressing regulatable membrane-bound IL-15

Abstract

Adoptive cell therapy using tumor-infiltrating lymphocytes (TIL) has demonstrated great potential for patients with treatment-refractory metastatic melanoma. However, the need for interleukin-2 (IL-2) co-administration during TIL cell therapy limits patient eligibility and restricts treatment to intensive care units due to the risk of severe side effects. Instead, engineering TIL with membrane-bound interleukin-15 (mbIL15) has the potential to promote TIL expansion, antitumor activity, and persistence of CD8+ T cells, without the use of IL-2. cytoTIL15 cells express mbIL15 fused to a drug-responsive domain (DRD) that is regulated by the Food and Drug Administration-approved small-molecule drug acetazolamide (ACZ). As such, cytoTIL15 cells are manufactured with ACZ instead of IL-2, in the presence of engineered feeder cells. The cytoTIL15 cell product exhibits ACZ dose-dependent expansion and persistence in vitro and in vivo and potent tumor-killing activity in human melanoma models in the absence of IL-2. In patient-derived xenograft (PDX) tumors, spatial profiling revealed infiltrating cytoTIL15 cells to be highly cytotoxic and less exhausted than non-engineered TIL. This novel platform creates a powerful, IL-2-free TIL cell therapy with a potentially improved tolerability and safety profile, while allowing individualized pharmacologic regulation of the TIL product.

Keywords: TIL; adoptive cell therapy; degron; drug-responsive domain; membrane-bound interleukin-15; regulation; synthetic biology; tumor-infiltrating lymphocytes.