P02.13 Combination of adoptive cell therapy with ANV419, a selective IL-2Rβ/γ agonist, in patients with advanced melanoma

Background Adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) has demonstrated substantial clinical benefits for patients with treatment-resistant metastatic melanoma. Standard TIL-ACT involves the administration of high-dose interleukin-2 (HD IL-2) to support the expansion, persistence and function of the transferred TILs. However, this regimen is associated with considerable systemic toxicity, which limits patient eligibility and often requires intensive care unit monitoring and interventions. Furthermore, HD IL-2 can expand regulatory T cells (Tregs) by signaling through the high-affinity IL-2 receptor α chain, potentially constraining antitumor immunity.Methods BaseTIL-03M ( NCT05869539) is a phase I clinical trial evaluating the safety and preliminary efficacy of TIL-ACT in combination with ANV419, an IL-2Rβ/γ-selective IL-2 variant with an extended half-life and preferential stimulation of effector lymphocytes. Ten patients with metastatic cutaneous melanoma refractory to standard therapies were enrolled and received TIL-ACT followed by two intravenous doses of ANV419 (243 mcg/kg), administered on the day of TIL transfer and again on day 14. Assessment of clinical safety and efficacy was complemented by comprehensive translational analyses, including evaluation of systemic immune activation by multiplex serum cytokine profiling seven days after TIL transfer. These data were compared with TIL-ACT cohorts from other clinical trials receiving low-dose (LD) IL-2 (125’000 IU/kg once daily for 10 days) or HD IL-2 (600’000 IU/kg every 8 hours for up to 8 doses).Results As reported previously at the ESMO Immuno-Oncology Congress 2025, TIL-ACT in combination with ANV419 was well tolerated, with no dose-limiting toxicities and a 30-day mortality rate of 0%. Multiplex serum profiling revealed a distinct immune activation signature following TIL transfer with ANV419, characterized by increased levels of granzyme A, granzyme B, TNF-α, and soluble CD137. This cytokine profile differed from that observed in TIL-ACT cohorts receiving LD or HD IL-2, suggesting qualitatively distinct immune modulation by β/γ-selective IL-2 signaling. Comprehensive analyses of intratumoral immune composition by multiplex spatial proteomics, together with assessments of T cell differentiation states and clonal dynamics by flow cytometry and TCR sequencing, are ongoing.Conclusion While clinical data indicate that combining TIL-ACT with ANV419 is feasible and potentially better tolerated than conventional HD IL-2, translational data provide evidence for distinct immunological effects of ANV419 compared with LD or HD IL-2 regimens. Together, these findings support the further investigation of IL-2Rβ/γ-selective IL-2 variants as a strategy to enhance the therapeutic index of TIL therapy.