OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy with regulatable membrane-bound IL15 (mbIL15) in patients (pts) with immune checkpoint inhibitor (ICI)–resistant advanced melanoma: Phase 1 results of the Agni-01 multicenter study.

Abstract

9517 Background: OBX-115 TIL are engineered to express mbIL15 regulated by the FDA-approved small-molecule drug acetazolamide (ACZ), abrogating the need for toxic high-dose IL2 after TIL infusion. Single-center phase 1 data (NCT05470283) demonstrated differentiated early safety (Amaria ASCO 2024). We report the first data evaluating OBX-115 in pts with advanced melanoma in the multicenter phase 1/2 Agni-01 study (NCT06060613). Methods: This single-arm, open-label study assesses safety, tolerability, and efficacy of the OBX-115 TIL cell therapy regimen in pts with advanced melanoma and NSCLC (Shoushtari AACR 2025). Phase 1 characterizes safety (treatment-emergent adverse events [TEAEs]: AEs ≤30 d after OBX-115 infusion) and tolerability in escalating dose levels of OBX-115 and ACZ to establish a recommended phase 2 dose (RP2D). Phase 2 evaluates efficacy of the regimen at RP2D (RECIST v1.1 per investigator). OBX-115 is manufactured from pt tumor tissue (core needle biopsy or surgical excision) and infused after standard- or low-dose (Cy 750 mg/m 2 /d × 3; Flu 30 mg/m 2 /d × 4) lymphodepletion (LD). No IL2 is administered. Oral ACZ starts day of OBX-115 infusion (QD up to 14 d), and is redosed (QD up to 7 d) every 6 wks after recovery from LD. Results: In phase 1,as of 01 Jan 2025, OBX-115 was successfully manufactured and infused for 11 pts with ICI-resistant advanced melanoma (median study follow-up, 22.3 wks [range, 13.3–52.1]) including 6 treated at RP2D (OBX-115 1–100×10 9 cells, ACZ 500 mg/d). Majority (n = 10) received low-dose LD, including 1 in the outpatient setting. There was no dose-limiting toxicity (DLT), treatment-emergent ICU transfer, or treatment-related mortality (TRM). Eight pts had G≥3 nonhematologic TEAEs (events in > 1 pt: hyponatremia, hypokalemia [n = 2 each]). One pt reported 2 OBX-115–related serious AEs, including 1 CRS event (G2) without IL6 elevation (IL6 < 100 pg/mL). Across dose levels (n = 11), confirmed ORR was 36% (4 PR, 5 SD; DCR 82%). For 6 pts receiving RP2D, ORR was 67% (4 PR, 2 SD; DCR 100%). Conclusions: Early data support clinical benefit (RP2D ORR 67%, DCR 100%) of OBX-115regulatableengineeredTIL cell therapy in the absence of IL2, including with outpatient low-dose LD. The safety profile is highly differentiated, without TRM, ICU transfer, or high-grade CRS. ACZ redosing is well-tolerated and offers an opportunity to deepen responses by inducing re-expression of mbIL15 on engrafted OBX-115 TIL, a unique capability among adoptive cell therapies. These attributes may comprehensively address the unmet need in post-ICI advanced melanoma and other cancers, and data support continued investigation of OBX-115 in the ongoing phase 2 portion of the Agni-01 study. Clinical trial information: NCT06060613 .