IL-2-independent expansion, persistence, and antitumor activity in TIL expressing regulatable membrane-bound IL-15
Rachel A. Burga, Bülent Arman Aksoy, Zheng Ao, Jeremy H. Tchaicha, Dhruv K. Sethi, Alonso Villasmil Ocando, Gauri Suhas Kulkarni, Scott Lajoie, Kyle D. Pedro, Jack Ryan Tremblay, Meghan Langley, Benjamin Primack, Violet Young, Theresa Ross, Mithun Khattar, Dexue Sun, Dan Jun Li, Shyam Subramanian, Michelle Ols, Jan ter Meulen
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.