Work

566 OBX-115 TIL cell therapy in ICI-resistant advanced melanoma: pooled safety and updated efficacy with minimally invasive tumor tissue procurement, low-dose lymphodepletion, and IL2-free regimen

Year: 2026

Type: conference-abstract

Abstract: Background OBX-115 tumor-infiltrating lymphocytes (TIL) are engineered to express acetazolamide (ACZ)-regulatable membrane-bound IL15 (mbIL15), abrogating the need for systemic IL2 and demonstrating a favorable safety profile with promising efficacy in immune checkpoint inhibitor (ICI)-resistant advanced melanoma. 1 2 We report outcomes across the phase 1 and phase 1/2 trial experience.Methods Two single-arm open-label trials (single-center, NCT05470283; multicenter, NCT06060613) explored dosing, safety, and efficacy of the investigational OBX-115 regimen in patients with ICI-resistant advanced melanoma. Patients underwent tumor tissue procurement (TTP) by core needle biopsy (CNB; 18-gauge needle, ≥ 4-cm cumulative length) or surgical excision, followed by low- or standard-dose lymphodepletion, OBX-115 infusion (per-protocol escalating maximum cell doses), and oral ACZ (per-protocol escalating doses/schedules). No IL2 was administered.Result As of 05 May 2026, 37 patients were treated across studies and dose levels. No TTP-related TEAEs were reported, including in 10 (27.0%) patients undergoing CNB. Twenty-six patients (70.3%, including all 15 receiving the recommended phase 2 dose [RP2D]) received low-dose lymphodepletion, with lower rates and severity of hematologic TEAEs than in those receiving standard-dose lymphodepletion (all-grade, 69.2% vs 100%, p = 0.038; Grade ≥ 3, 65.4% vs 100%, p = 0.025). Four patients received outpatient low-dose lymphodepletion. ACZ was well-tolerated overall, and 30 patients (81.1%) received ACZ redosing (all outpatient). ACZ-induced mbIL15 expression was not associated with ICANS, capillary leak, Grade 4 cytokine release syndrome or other Grade ≥3 immune-related TEAEs, or treatment-related mortality. No patient required ICU transfer.Among 15 patients treated at RP2D, confirmed ORR (RECIST v1.1) was 67% (10/15, 2 CR); 2 patients had CNB TTP, both with confirmed response. At median (range) study follow-up of 8.3 months (4.1–21.4), median (95% CI) PFS was 8.1 months (3.9-not estimable) after infusion; 6 of 10 responders, including both CRs, remained in response at last assessment (range, 2.8+ to 17.9+ months). CNS progression was observed in 1 patient, who had prior treated symptomatic CNS disease.Conclusions Investigational OBX-115 TIL cell therapy demonstrates meaningful patient-centric benefits, including CNB TTP, low-dose lymphodepletion, and replacement of IL2 with ACZ-regulatable mbIL15. Minimally invasive CNB TTP may enable broader patient eligibility and facilitate sampling from multiple lesions, while maintaining antitumor activity. Immune-related TEAEs were infrequent overall, and reduced rates and severity of hematologic TEAEs with low-dose lymphodepletion support continued evaluation of this regimen in ongoing and future studies. Together with promising response durability and favorable safety, these findings suggest that OBX-115 may address the unmet medical need in ICI-resistant advanced melanoma.Acknowledgements Editorial and writing assistance was provided by Amanda M Kelly (Obsidian Therapeutics, Inc.).Trial Registration Clinicaltrials.gov: NCT05470283, NCT06060613References Amaria RN, et al. OBX-115, an interleukin 2 (IL2)-sparing engineered tumor-infiltrating lymphocyte (TIL) cell therapy, in patients with immune checkpoint inhibitor (ICI)-resistant unresectable or metastatic melanoma. J Clin Oncol. 2024;42(Suppl 16):Abstract 9515.Betof A, et al. OBX-115 engineered tumor-infiltrating lymphocyte (TIL) cell therapy with regulatable membrane-bound IL15 (mbIL15) in patients with advanced melanoma that has progressed on/after immune checkpoint inhibitors (ICI): phase 2 results. J Clin Oncol. 2026;44(Suppl 16):Abstract 9507.Ethics Approval The first-in-human (Clinicaltrials.gov: NCT05470283) and Agni-01 (Clinicaltrials.gov: NCT06060613) studies were approved by local institutional or central review boards at 9 sites (FIH, 1 site) and conducted in accordance with the principles of the Declaration of Helsinki; independent safety review boards monitored overall safety and dose-optimization decisions. All patients provided written informed consent.

Source: Journal for ImmunoTherapy of Cancer

DOI: 10.1136/jitc-2026-sitc2026.0566