Abstract
Chimeric antigen receptor T cells (CAR-T) targeting CD19 or B cell maturation antigen (BCMA) are highly effective against B cell malignancies. However, application of CAR-T to less differentially expressed targets remains a challenge due to lack of tumor-specific antigens and CAR-T controllability. CD123, a highly promising leukemia target, is expressed not only by leukemic and leukemia-initiating cells, but also by myeloid, hematopoietic progenitor, and certain endothelial cells. Thus, CAR-T lacking fine-tuned control mechanisms pose a high toxicity risk. To extend the CAR-T target landscape and widen the therapeutic window, we adapted our rapidly switchable universal CAR-T platform (UniCAR) to target CD123. UniCAR-T efficiently eradicated CD123+ leukemia in vitro and in vivo. Activation, cytolytic response, and cytokine release were strictly dependent on the presence of the CD123-specific targeting module (TM123) with comparable efficacy to CD123-specific CAR-T in vitro. We further demonstrated a pre-clinical proof of concept for the safety-switch mechanism using a hematotoxicity mouse model wherein TM123-redirected UniCAR-T showed reversible toxicity toward hematopoietic cells compared to CD123 CAR-T. In conclusion, UniCAR-T maintain full anti-leukemic efficacy, while ensuring rapid controllability to improve safety and versatility of CD123-directed immunotherapy. The safety and efficacy of UniCAR-T in combination with TM123 will now be assessed in a phase I clinical trial (ClinicalTrials.gov: NCT04230265).
Highlights
Despite constant emergence of new treatment options, relapsed or refractory (r/r) malignancies of the hematopoietic system are still associated with poor prognosis
T cells are engineered to express a universal CAR (UniCAR-T) that recognizes a small linear peptide derived from the nuclear human La/SS-B protein (UniCAR epitope [UCE]), which is not presented on the cell surface
Upon completion of a screen of 34 cytokines, we found interferon g (IFN-g), interleukin 2 (IL-2), granulocyte-macrophage colony-stimulating factor (GMCSF), macrophage-inflammatory protein 1a/b (MIP-1a/b), and IL-1 receptor antagonist (IL-1RA) as the dominant cytokines released by
Summary
Despite constant emergence of new treatment options, relapsed or refractory (r/r) malignancies of the hematopoietic system are still associated with poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative treatment option for r/r acute myeloid leukemia (AML). Allo-HSCT is associated with significant treatment-related mortality and morbidity.[1,2] innovative new immunotherapeutic concepts have been developed in recent years. The application of monoclonal antibodies (mAbs),[3,4] redirection of autologous T cells with. Our group developed a rapidly switchable universal CAR-T platform (UniCAR) to allow for a highly controlled and dose-dependent activation of CAR-T.30. Our group developed a rapidly switchable universal CAR-T platform (UniCAR) to allow for a highly controlled and dose-dependent activation of CAR-T.30 The platform approach was successfully
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