cytoTIL15 genetically engineered tumor-infiltrating lymphocytes, armored with regulatable membrane-bound IL15, demonstrate IL2-independent expansion, persistence, and anti-tumor activity in preclinical melanoma models.

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 (IL2) co- administration during TIL cell therapy limits patient eligibility and restricts it to dedicated units due to the risk of severe side effects. Instead, engineering TIL with membrane-bound (mb) interleukin 15 (cytoTIL15TM) has the potential to promote expansion, anti-tumor activity, and persistence of CD8+ T-cells, without the use of IL2. cytoTIL15 cells express regulatable mbIL15 fused to a drug-responsive domain, regulated by the small molecule acetazolamide (ACZ) and are propagated without IL2 in the presence of engineered K562 feeder cells expressing 4-1BBL and IL21. cytoTIL15 cells exhibit potent ACZ dose- dependent tumor-killing activity and persistence in vitro and in vivo, without IL2. Spatiotemporal profiling of cytoTIL15 cells in PDX tumors revealed infiltrating TIL to be highly cytotoxic and less exhausted than unengineered TIL plus IL2. This novel platform creates a powerful, IL2-free TIL cell therapy that could enable treatment of previously ineligible patients, while allowing pharmacologic control of the TIL product.