Regulatable membrane-bound IL-15 engineered TIL cell therapy for immune checkpoint inhibitor-resistant advanced melanoma: pooled analysis of phase 1 and 1/2 trials.

November 3, 2026| Source: Nature medicine

Amsokigene autoleucel (amsoki-cel, OBX-115) is a tumor-infiltrating lymphocyte (TIL) cell therapy engineered to express acetazolamide (ACZ)-regulatable membrane-bound interleukin-15, abrogating the need for interleukin-2. In two single-arm trials (completed phase 1 single-center first-in-human (FIH) and ongoing phase 1/2 multicenter Agni-01), patients with immune checkpoint inhibitor (ICI)-resistant advanced melanoma received lymphodepletion and varying doses and schedules of amsoki-cel and ACZ. The primary objective of FIH and Agni-01 phase 1 was safety, tolerability and recommended phase 2 dose (RP2D); the primary objective of Agni-01 phase 2 was objective response rate (ORR) at the RP2D. The first patient treated experienced rapid lymphocyte expansion and vasogenic edema of a previously irradiated brain metastasis, prompting protocol modifications and dose deescalation in FIH, including 80% reduction in maximum amsoki-cel dose and 75% reduction in ACZ dose. After preliminary demonstration of safety at the lower dose, doses were increased in FIH, and reescalation was initiated in Agni-01. Across studies, 37 patients were treated (FIH, n = 17; Agni-01, n = 20). Post hoc pooled analysis demonstrated no dose-limiting toxicities, ICU care or treatment-related mortality. Most common grade 3 or higher treatment-emergent adverse events (TEAEs) included neutropenia (64.9% (24/37)), leukopenia/lymphopenia (56.8% (21/37) each) and anemia/thrombocytopenia (37.8% (14/37) each). Serious TEAEs were reported for 10 patients, including eight patients with grade 3 or higher events (non-hematologic, 13.5% (5/37); hematologic, 13.5% (5/37)). RP2D was selected based on overall safety and tolerability as well as preliminary anti-tumor activity in Agni-01 phase 1. The phase 2 preliminary ORR was 66.7% (6/9). In total, 15 patients were treated at RP2D and comprise the Key Efficacy Set (Agni-01: phase 1, n = 6; phase 2, n = 9), of which 10 patients (66.7%; 95% confidence interval 38-88%) achieved objective responses (including two complete responses). Amsoki-cel demonstrated favorable safety and promising early clinical activity in patients with ICI-resistant melanoma. A separate phase 2 pivotal Agni-01 cohort is ongoing. ClinicalTrials.gov identifiers: NCT05470283 and NCT06060613 .

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