Phase I study of sustained and local delivery of intraperitoneal IL-2 using encapsulated cells in patients with platinum-resistant high-grade serous carcinoma.

5562 Background: Platinum-resistant high-grade serous carcinoma's (HGSC) propensity to metastasize throughout the peritoneal cavity has generated interest in the development of high-intensity locoregional treatment administered intraperitoneally. Prior efforts have been limited by administration difficulties and potential for local toxicity. We describe a phase I trial using AVB-001, a novel intraperitoneally administered, alginate-encapsulated, allogeneic cell line modified for constitutive expression of human interleukin-2 (hIL-2). Preclinically, this new platform allows self-limited anti-tumor immune-activation without the toxicities associated with systemic administration or prior intraperitoneal formulations. The primary objectives of this study were to investigate the feasibility, safety, and tolerability of treatment with AVB-001. Secondary objectives included evaluation of clinical efficacy and translational correlates. Methods: This was an open-label, multicenter, phase I dose escalation study. A single dose of AVB-001 was administered via laparoscopy at 1 of 4 dose levels ranging from 0.6 to 3.6 μg hIL-2/kg/day. Escalation to a higher dose was based upon Bayesian optimal interval 3+3 design. Toxicity was evaluated via NCI CTCAE v5.0 and response was assessed via RECIST v1.1. Translational analyses were performed to evaluate serum hIL-2 concentration and immunological changes in peripheral blood. Results: The trial enrolled 14 patients. Eleven patients had ovarian cancer, two had fallopian tube cancer, and one had peritoneal cancer. Median age was 68 (range 47-75). In terms of safety, 4 of 14 patients (28.6%) experienced a grade 3 treatment-related adverse event (TRAE). There were no grade 4 or 5 TRAEs. One patient exhibited an unconfirmed partial response lasting 29 days (ORR 1/14, 7.1%). Stable disease was observed in 7 patients with a median duration of clinical stability lasting 2.57 months (range 2.03-4.23). On translational analyses, dose-dependent immunologic changes were noted in the peripheral blood. CTLA-4 receptor expression was upregulated with increasing dose levels in both CD8+ and CD4+ T cells, however significant upregulation was not observed for either PD-1 or TIM-3. The study was terminated early due to funding limitations. Conclusions: The administration of AVB-001 is safe, feasible, and shows potential for meaningful clinical activity. A dose-dependent upregulation of the CTLA-4 checkpoint on CD8+ and CD4+ T cells was noted after administration, suggesting a rationale for combination therapies involving cytokines as “priming agents” to engage checkpoint inhibition. Finally, we demonstrate feasibility of this approach for delivery of hIL-2 and other future biologics via our ability to reproducibly manufacture multiple clinical batches of AVB-001 and deliver at point of patient care. Clinical trial information: NCT05538624 .