OBX-115

P1, N=21, Active, not recruiting, M.D. Anderson Cancer Center | N=30 --> 21 | Recruiting --> Active, not recruiting

P1/2, N=52, Recruiting, Obsidian Therapeutics, Inc. | N=32 --> 52

P1/2, N=32, Recruiting, Obsidian Therapeutics, Inc. | Active, not recruiting --> Recruiting

P1/2, N=32, Active, not recruiting, Obsidian Therapeutics, Inc.

We previously showed that melanoma TILs engineered to express membrane-bound IL15 (mbIL15) under the control of the ligand acetazolamide (ACZ) can achieve IL2-independent expansion during manufacturing, antigen-independent persistence in vitro and anti-tumor efficacy in vivo. Unlike unengineered TILs, cytoTIL15 cells + ACZ persisted in an antigen-free setting without IL2, were cytotoxic to autologous PDc and released IFNγ in response to autologous PDx tumor digest. Taken together, these data show that IL2-independent, fully functional cytoTIL15 cells can successfully be generated from tumors such as NSCLC, HNSCC & TNBC, which afflict large numbers of patients.

Methods cytoTIL15® therapy contains TILs engineered with mbIL15 under the control of a carbonic-anhydrase-2 drug responsive domain, regulated by the ligand acetazolamide (ACZ). Interestingly, the subpopulation of cytoTIL15® cells reactive to tumor-associated antigen MART-1 displayed increased expression of TCF-1, which in melanoma patients has been associated with responses to immune checkpoint blockade, in addition to progression-free and overall survival. Ethics Approval All animal studies were IACUC approved.

Cytokines modified with our carbonic anhydrase 2 (CA2)-based cytoDRiVE® drug responsive domain (DRD) were evaluated for control of protein levels with the CA2 ligand, acetazolamide (ACZ). Conclusions While IL-15 drives expansion and persistence of cytoTIL15 TM cells without IL-2, adding pleotropic and highly immune-stimulatory members of the IFN, IL-1 or TNF families may provide enhanced efficacy for patients with solid tumors marked by an immunosuppressive TME. Ethics Approval All animal studies were IACUC approved

To this end, we genetically engineered TIL to express membrane-bound IL-15 (mbIL15) under the control of Obsidian’s cytoDRIVE® technology (cytoTIL15TM), which allows regulation of protein expression via a drug-responsive domain upon acetazolamide (ACZ) administration. Moreover, enhanced cytoTIL15 cell infiltration and anti-tumor activity was associated with increases in pro-inflammatory cytokines (e.g., IFNγ). Taken together, these data clearly demonstrate the superiority of cytoTIL15 cells over uTIL for controlling or eradicating melanoma tumor outgrowth and the utility of an allogeneic PDX model for comparative evaluation of tumor-antigen specific TIL reactivity.

cytoTIL15 contains TILs engineered with mbIL15 under the control of a carbonic-anhydrase-2 DRD, controlled by the ligand acetazolamide (ACZ). Importantly, cytoTIL15 achieved significant tumor control in a human PDX model (figure 1D), which correlated with increased TIL accumulation in secondary lymphoid organs. Conclusions Taken together, the superior persistence and potency of cytoTIL15 in the complete absence of IL-2 highlights the clinical potential of cytoTIL15 as a novel TIL product with enhanced safety and efficacy for patients with melanomas, and other solid tumors.

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. 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. 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.