A lymphodepleted non-human primate model for the assessment of acute on-target and off-tumor toxicity of human chimeric antigen receptor-T cells.

Clinical & Translational Immunology
Shigeki YagyuYozo Nakazawa

Abstract

Chimeric antigen receptor (CAR)-T cell therapy possesses the potential to cause unexpected on-target toxicities that may be life-threatening. Non-human primates (NHPs) share considerable structural homology and expression profiles of most proteins with humans and are therefore utilised as an animal model for non-clinical safety studies. We have developed a lymphodepleted NHP model by conditioning the animals with immunosuppressive chemotherapy designed to simulate clinical practice conditions, to induce transient mixed chimerism before the administration of human CAR-T cells redirected to target Ephrin type-B receptor 4 (EPHB4-CAR-T cells) to evaluate the toxicity of these cells. We administered 60 mg m-2 day-1 of fludarabine for 4 days and 30 mg kg-1 day-1 of cyclophosphamide for 2 days intravenously to cynomolgus macaques for lymphodepletion; then, 3.3 × 106 kg-1 of non-transduced or EPHB4-CAR-T cells was infused into the macaques, respectively. All macaques were closely monitored and evaluated for potential toxicity for 7 days. Lymphodepletion was successfully achieved on day -1 before T-cell infusion and persisted over 7 days without severe organ toxicities. A single administration of human EPHB4-CAR-T cells did not induce ...Continue Reading

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