442 ICT01, an anti-BTN3A mAb that activates Vg9Vd2 T cells, plus interleukin-2: a potent and promising combination for cancer immunotherapy

• Published in: Journal for immunotherapy of cancer 2020-11, Vol.8 (Suppl 3), p.A468-A468
• Main Authors: Gassart, Aude de, Brune, Patrick, Suong, LE, Agaugué, Sophie, Valentin, Emmanuel, Sims, Jennifer, Olive, Daniel, Frohna, Paul, Hoet, Rene
• Format: Article
• Language: English
• Subjects: Cancer; Cytokines; Immunology; Immunotherapy; Lymphocytes
• ISSN: 2051-1426
• DOI: 10.1136/jitc-2020-SITC2020.0442

Background gdT-cells are attractive targets for cancer immunotherapy given their strong cytolytic and pro-inflammatory cytokine secretion activities, and the association between tumor infiltration and positive prognosis.1 2 ImCheck Therapeutics is developing ICT01, an anti-human butyrophilin-3A (BTN3A/CD277) mAb specifically activating g9d2 T-cells in a phosphoantigen (pAg)-independent manner. ICT01 is currently in a Phase 1/2a study in solid and hematologic tumors (NCT04243499).IL-2 has been shown to expand g9d2 T-cells in vitro and in non-human primates in presence of pAgs.3 4 5 We wanted to characterize the proliferative effects of combining ICT01 with IL-2 on γ9δ2 T-cells as an approach to potentiate g9d2 T-cell mediated cancer immunotherapy.Methods g9d2 T-cell activation and expansion was assessed in vitro in human PBMCs treated with ICT01±IL-2, and in vivo, in the blood of immunocompromised NCG mice engrafted with 20 × 106 human PBMCs and treated with ICT01 (single IV dose, 5 mg/kg on Day 1) ±IL-2 (0.3MIU/kg IP on Day 1–4). A dose-ranging ICT01 (single IV dose, 1 or 5 mg/kg on Day 1)+IL-2 combination (1 MIU SC QD on Days 1–5) study was conducted in cynomolgus monkeys.ResultsIn PBMCs cultures in vitro, ICT01 selectively activated g9d2 T-cells and IL-2 significantly enhanced ICT01-mediated g9d2 T-cell proliferation, this compartment reaching >50% of T-cells after 8 days of treatment versus ~10% with ICT01 alone. This was confirmed in vivo in mice models. Flow cytometry analysis of mice blood revealed a 5.5-fold increase in human g9d2 T-cell number in the combination groups compared to ICT01 or IL-2 alone treated animals, with g9d2 T-cell frequency reaching ~35% of the CD3+ T-cell compartment. In Cynomolgus, a specific expansion and activation of peripheral g9d2 T-cells from ~1–2% at baseline to up to 30% of T cells 7 days post ICT01 administration was observed. No ICT01 effect was observed on other immune cells. Histopathological examinations revealed a trend towards higher numbers of g9d2 T-cells in several organs in ICT01+IL-2 treated monkeys. There was no evidence for a systemic cytokine release syndrome at any time point. Adverse effects with variable severity were observed, most of them being reversible and commonly associated with IL-2 alone, and not reported in the IND-enabling GLP toxicity study with ICT01 monotherapy at doses up to 100 mg/kg.ConclusionsThese results demonstrate the ability of ICT01+IL-2 combination to trigger profound γ9δ2 T-c