BCMA targeting CAR T cells using a novel D-domain binder for multiple myeloma: clinical development update

Abstract

Relapsed and refractory multiple myeloma patients have poor prognoses and limited treatment options even with the recent FDA approval of idecabtagene vicleucel. Idecabtagene vicleucel joins four other US FDA approved chimeric antigen receptor T cell therapies each with promising efficacy and response rates across various hematological malignancies. Notwithstanding the early success of chimeric antigen receptor T therapies, there remain many challenges that warrant further development of chimeric antigen receptor T structure and function as they relate to durability of response, T cell exhaustion due to tonic signaling, immunogenicity, manufacturing-related limitations, and incidence of serious adverse events including cytokine release syndrome and immune effector cell associated neurotoxicity syndrome. D-domain based chimeric antigen receptor T cells are a new class of structurally and functionally distinct cell therapies that represent an alternative to conventional single-chain variable fragment based chimeric antigen receptor T cells. Preclinical studies of a D-domain based targeting B cell maturation antigen (CART-ddBCMA) have demonstrated effective anti-tumor response in both&nbsp;<em>in vitro</em>&nbsp;and tumor models. These studies currently support a first-in-human clinical study of CART-ddBCMA in multiple myeloma patients. Interim Phase 1 data presented at American Society of Hematology 2021 Annual Meeting further demonstrates the promising potential of CART-ddBCMA cells in the treatment of multiple myeloma. Herein, we present an overview of chimeric antigen receptor T cell therapies including challenges in chimeric antigen receptor T therapies, advances in CAR design, structural and functional properties of novel D domain-based chimeric antigen receptor T cells, and an update on the development of CART-ddBCMA in multiple myeloma patients.