First-in-human study of ICT01, an anti-BTN3A activating monoclonal antibody in combination with low dose IL-2 in patients with advanced solid tumors (EVICTION-2 study)

Abstract Background: ICT01, an anti-BTN3A mAb, selectively activates γ9δ2 T cells resulting in remodeling of the tumor microenvironment by activated γ9δ2 T, CD8 T, and NK cells (EVICTION- NCT04243499; AACR 2022 CT188). Response to ICT01 depends on the baseline number of γ9δ2 T cells with many cancer patients having inadequate numbers due to prior chemotherapy and/or the underlying malignancy. ICT01 plus IL-2 induces selective expansion of γ9δ2 T cells with minimal Treg expansion in NHPs and is currently being tested in the EVICTION-2 Trial, a phase I/IIa, open-label study to characterize the safety, tolerability, pharmacodynamics, and antitumor activity of ICT01 in combination with low dose subcutaneous (LDSC) IL-2 in patients with advanced-stage solid tumors (NCT04243499). Methods: ICT01 (1, 5, 20 or 75 mg, IV Q3W) is given in combination with LDSC IL-2 (Proleukin®, 1 or 2 MIU/m2) on days 1-5 of the first 3 cycles and will be continued alone thereafter. Per dose combination two patients are enrolled for dose escalation based on the BOIN simulations to identify a safe and pharmacodynamically active dose combination(s) for Phase IIa expansion. Results: To date, 9 patients with colorectal (n=6), ovarian (n=2) or pancreatic cancer (n=1) with a mean/median of 6 prior lines of therapy have received at least their first cycle of ICT01 1, 5, 20 or 75 mg + IL-2 1MIU/m2 or ICT01 1mg + IL-2 2MIU/m2. Treatment-related adverse events (TRAE) were mainly infusion related reactions comprising fever and chills grade 1 and 2 in 8/9 patients, not different in severity from ICT01 or IL-2 monotherapy. No dose limiting toxicities were reported. By RECIST, Stable Disease was observed in 2/6 patients with a Week 8 assessment. In all patients, a 2-to-9-fold increase in γ9δ2 T cells was observed for each of the 3 combination cycles, which is accompanied by peripheral activation, mobilization, and proliferation of CD8 T cells, NKs and granulocytes, which is consistent with the expected contribution of IL-2. Increased IFNγ and IL-8 levels (2.4-to-140 fold and 2-to-94 fold respectively) were observed within 24h after each dose of ICT01/IL-2. Flow cytometry of Tregs in frozen PBMCs and IHC of tumor biopsies collected at baseline and on Day 28 are being analyzed to quantify tumor infiltration. Conclusions ICT01 plus LDSC IL-2 safely induced robust γ9δ2 T cell expansion leading to a broad immune response involving CD8 T cells, NKs, and granulocytes at lower doses than observed with ICT01 monotherapy. More patient data are needed to confirm that IL-2 potentiates the antitumor effects of ICT01 and that this leads to better clinical outcomes. Citation Format: Johann de Bono, Stéphane Champiat, Francois-Xavier Danlos, Martin Wermke, Volker Kunzmann, Aude De Gassart, Emmanuel Valentin, Marina Iche, Maelle Mairesse, Patrick Brune, Katrien Lemmens, Aurélien Marabelle, Daniel Olive, Paul Frohna. First-in-human study of ICT01, an anti-BTN3A activating monoclonal antibody in combination with low dose IL-2 in patients with advanced solid tumors (EVICTION-2 study) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT179.