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442 ICT01, an anti-BTN3A mAb that activates Vg9Vd2 T cells, plus interleukin-2: a potent and promising combination for cancer immunotherapy
  1. Aude de Gassart1,
  2. Patrick Brune1,
  3. LE Suong1,
  4. Sophie Agaugué1,
  5. Emmanuel Valentin1,
  6. Jennifer Sims2,
  7. Daniel Olive3,
  8. Paul Frohna1 and
  9. Rene Hoet1
  1. 1Imcheck Therapeutics, Marseille, France
  2. 2Integrated Biologix GmbH, Basel, Switzerland
  3. 3CRCM, Marseille, France


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.

Results In 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.

Conclusions These results demonstrate the ability of ICT01+IL-2 combination to trigger profound γ9δ2 T-cell activation and expansion, suggesting that the clinical combination of ICT01 with a lymphoproliferative cytokine (e.g., IL-2) may be a novel therapeutic approach for cancer patients.

Ethics Approval Pseudonymized samples isolated from healthy volunteers: whole blood by ImCheck Therapeutics under the agreement n° 7173 between ImCheck Therapeutic SAS and EFS PACA (Etablissement Français du Sang Provence-Alpes-cote d’Azur)


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  5. Ali Z, Shao L, Halliday L, et al. Prolonged (E)-4-Hydroxy-3-Methyl-But-2-Enyl pyrophosphate-driven antimicrobial and cytotoxic responses of pulmonary and systemic Vγ2Vδ2 T cells in macaques. The Journal of Immunology 2007;179(12):8287–8296.

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