Abstract 1008P
Background
Tumor-infiltrating lymphocyte (TIL) therapy is at the cusp of approval for heavily pretreated patients with solid tumor malignancies. TIL therapy currently requires IL2 for in vivo maintenance of TILs, significantly limiting its application due to patient safety and eligibility hurdles. cytoTIL15 is a TIL product engineered with regulatable membrane bound IL15 (mbIL15) designed via our cytoDRiVE® platform. Armoring TILs with endogenous mbIL15 has several advantages over systemic IL2. Unlike IL2, IL15 does not increase immunosuppressive regulatory T-cells and drives T-cell differentiation towards a stem-cell memory phenotype associated with long-term persistence.
Methods
cytoTIL15 uses Obsidian’s cytoDRiVE® platform, which consists of a carbonic anhydrase 2 (CA2) derived drug responsive domain that enables regulated expression of mbIL15 under control of acetazolamide (ACZ), an FDA-approved orally bioavailable small molecule ligand. We use a proprietary process for high efficiency transduction of TILs with regulatable mbIL15 and expansion without IL2, after which TILs can be cryopreserved or used fresh in downstream in vitro and in vivo assays.
Results
Our process achieved robust expression of ACZ-regulatable mbIL15 on TILs that expand in the absence of IL2 to levels required for clinical manufacturing. Upon administration in NSG mice, cytoTIL15 exhibited significantly higher expansion and persistence compared to conventional TILs treated with clinically analogous IL2 dosing. cytoTIL15 have a CD8+ effector T-cell biased immunophenotypic profile distinct from conventional TILs, while maintaining a diverse TCR repertoire and tumor reactivity with robust IFNg production. In addition, cytoTIL15 demonstrated significantly higher tumor cytotoxicity in vitro in the absence of exogenous IL2 in comparison to conventional TILs, indicative of superior potency.
Conclusions
cytoTIL15 is a more potent and persistent TIL product that does not require infusion of IL2, thereby enhancing the safety and durable efficacy of TIL therapy for patients with metastatic melanoma and other solid tumor malignancies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Obsidian Therapeutics.
Funding
Obsidian Therapeutics.
Disclosure
M. Khattar: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. R. Burga: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. K. Pedro: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. C. Foley: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. S. Lajoie: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. A.V. Ocando: Financial Interests, Institutional, Stocks/Shares: Obsidian therapeutics. J. Tremblay: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. D. Thornton: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. S. Tam: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. F. Nabulsi: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. C. Vallaster: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. S. Saha: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. G. Wilmes: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. G. Helmlinger: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. J. Tchaicha: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. D. Sethi: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. M. Ols: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. G. Vanasse: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. S. Subramanian: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics. J. ter Meulen: Financial Interests, Institutional, Stocks/Shares: Obsidian Therapeutics.