OBX-115 engineered tumor-infiltrating lymphocytes (TIL) with regulatable membrane-bound IL15 (mbIL15): Translational data from a single-center phase 1 trial in patients (pts) with immune checkpoint inhibitor (ICI)–resistant advanced melanoma.

9519 Background: Non-engineered TIL cell therapy is approved for ICI-resistant advanced melanoma, but requires co-administration of toxic high-dose IL2. OBX-115 engineered TIL express mbIL15 under pharmacologic regulation using the FDA-approved small-molecule drug acetazolamide (ACZ), abrogating the need for IL2. We present data supporting OBX-115 mechanism of action. Methods: Trial design and clinical results were previously reported (Amaria ASCO 2024; NCT05470283); briefly, pts received lymphodepletion (Day [D] -7 to -1) followed by OBX-115 infusion (D0) and ≤7 days of orally administered ACZ (D2–9). Peripheral blood (PB) and tumor tissue samples were collected for longitudinal ddPCR analysis and immune profiling. Results: Eight pts received OBX-115 (fresh) and are included in this analysis. PB samples demonstrated ACZ-driven OBX-115 TIL expansion, reaching a median of 1697 cells/µL at D14 (approximate day of OBX-115 expansion peak); in 3 pts with ≥6 mo follow-up, OBX‐115 remained detectable through 6 mo and ongoing up to 15 mo. In the immediate post-infusion phase (up to D14), PB flow cytometry indicated expansion of product-derived CD3+CD8+ cells expressing Ki67 (during ACZ exposure) and endogenous NK cells (CD3-CD56+), while CD4+ cell levels decreased (Table). Post-infusion tumor tissue demonstrated presence of IL15-expressing T cells (of CD3+: D21, 68.6%; D42, 88.4%). Importantly, median post-infusion serum levels of IL15 and IL7 were not significantly elevated above Baseline through D42 (paired one-tailed t-test adjusted for multiple comparisons; Table); IL6 was below limit of detection at all timepoints, even in pts with fevers. T-cell receptor (TCR) clonotypes present in the OBX-115 infusion product were enriched in post-infusion PB and tumor (Table). Conclusions: These data support the proposed OBX-115 mechanism of action, demonstrating ACZ-driven OBX-115 TIL expansion, engraftment, and persistence; endogenous NK cell expansion, presumably driven by transactivation via mbIL15 on OBX-115, without systemic cytokine elevation; and TCR repertoire remodeling with tumor-derived, antigen-specific T cells. Investigation of OBX-115 TIL cell therapy in pts with advanced solid tumors (NCT06060613) is ongoing. Clinical trial information: NCT05470283 . Pre- and post-infusion immune profile. Characteristic, median (N=8) Baseline* D14 D28 D42 CD3-CD56+ (of live, PB), † % 14.7 27.0 35.5 56.7 CD3+ (of live, PB), † % 50.7 69.9 49.5 54.2 CD8+ (of CD3+, PB), † % 27.9 75.2 85.6 87.6 CD4+ (of CD3+, PB), † % 59.7 5.7 10.6 9.3 Ki67+ (of CD8+, PB), † % 1.5 11.1 3.7 3.2 IL15, serum, pg/mL 8.5 9.5 10.0 10.8 IL7, serum, pg/mL 2.4 3.3 3.3 2.8 OBX-115 TCR clonotypes in PB, % 14.5 80.9 69.3 59.6 OBX-115 TCR clonotypes in tumor, % 28.2 Not available 86.2 ‡ 70.4 *Pre-lymphodepletion. † n<8. ‡ D21.