Abstract LB-A010: Translational data validate OBX-115 mechanism of action: Impact of dosing on clinical outcome in advanced (adv) melanoma

Abstract Background: Non-engineered, conventional TIL cell therapy requires administration of interleukin 2 (IL2), which is associated with toxicity (Chesney J Immunother Cancer 2022) and limits patient (pt) eligibility. OBX-115 TIL express membrane-bound IL15 (mbIL15) regulated by the FDA-approved small-molecule drug acetazolamide (ACZ), abrogating the need for IL2 and resulting in differentiated clinical safety and promising efficacy (Amaria ASCO 2024, Chesney ASCO 2025). We report translational data from pts with adv melanoma treated with escalating dose levels (DL) of cryopreserved OBX-115 and ACZ in the Agni-01 study to further validate OBX-115 mechanism of action. Methods: This multicenter, single-arm, open-label ph 1/2 study (NCT06060613) assesses the OBX-115 regimen in pts with adv melanoma and NSCLC. After lymphodepletion (LD), OBX-115 is infused at doses of ≤30 ×109 (DL1) or ≤100 ×109 (DL2, DL3) cells. Oral ACZ is administered daily (≤14 d) after OBX-115 infusion (Day 0 [D0]) at 250 (DL1, DL2) or 500 (DL3; D0–6, D14–20) mg and can be redosed as an outpatient. OBX-115 infusion product and Baseline (BL) and post-infusion PBMC and tumor were analyzed. Exploratory ctDNA analysis was performed in a subset of pts with evaluable tumor samples and sufficient somatic mutations to establish an informative tumor-derived mutation panel. Results: Among the first 11 pts with melanoma, 10 (91%) received low-dose LD (Cy 750 mg/m2/d ×3, Flu 30 mg/m2/d ×4). ORR was 67% (4/6, 1 CR) at DL3 (RP2D); 3 responses were ongoing past Wk 24. Pts receiving DL3/RP2D received a higher mean cumulative initial ACZ dose compared with DL1+DL2 (6125 mg vs 2400 mg) and demonstrated greater initial OBX-115 expansion (median peak 506.1 vs 175.4 cells/µL). PBMC TCR seq showed dose-dependent persistence and repertoire remodeling by OBX-115–derived clonotypes (D42 OBX-115 clonotypes in PBMC: DL3/RP2D 33.1% vs DL1+DL2 10.9%). TCR seq showed dose-dependent tumor clonotype remodeling (D42 OBX-115 clonotypes in tumor: DL3/RP2D 82.2% vs DL1+DL2 21.9%); RNA FISH confirmed OBX-115 TIL infiltration and persistence (not shown). Spectral flow cytometry demonstrated comparable peripheral expansion of infused CD8+ cells (DL3/RP2D 76.6% vs DL1+DL2 77.7%) and surge of endogenous NK (27.1% vs 26.3%) and NK-like T cells (2.2% vs 4.9%) during lymphocyte recovery from LD regardless of dose group. ctDNA analysis demonstrated reduction post-infusion in all pts, and clearance in 2 pts receiving DL3/RP2D; median ctDNA fold-decrease was higher in DL3/RP2D than DL1+DL2 (134.1 vs 6.4). Conclusions: Cytokine signal provided by ACZ dose-dependent mbIL15 expression supports expansion, persistence, and infiltration of OBX-115 into tumors, remodeling of PBMC and tumor TCR repertoire, and cis- and trans-immune cell activation. ctDNA profile suggests antitumor activity regardless of dose and eventual RECIST response. This regulatable cytokine delivery mechanism for TIL cell therapy enables a low-dose LD and IL2-sparing regimen, which may improve safety and expand pt eligibility. Ph 2 enrollment is ongoing. Citation Format: Gino K. In, Alexander N. Shoushtari, Rodabe N. Amaria, Allison S. Betof, Tirrell T. Johnson, Justin T. Moyers, Giridharan Ramsingh, Bulent Arman Aksoy, Rachel Burga, Prakash Prabhakar, Lauren Mclaughlin, Mercay Reuter, Jason A. Chesney. Translational data validate OBX-115 mechanism of action: Impact of dosing on clinical outcome in advanced (adv) melanoma [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr LB-A010.