Next-Generation CAR T-cell Therapies

Abstract

CD19- and B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T cells have enabled unprecedented responses in a subset of refractory patients with B-cell and plasma cell malignancies, leading to their approval by the FDA for the treatment of leukemia, lymphoma, and myeloma. These "living drugs" can become part of a synthetic immune system, persisting at least a decade in some patients. However, despite this tremendous impact, significant unmet treatment needs remain for patients with hematologic malignancies and solid cancers. In this perspective, we highlight recent innovations that advance the field toward production of a more potent and universal cellular immunotherapy of the future. Next-generation CAR T cells will incorporate advances in gene engineering and synthetic biology to enhance functionality and persistence, and reduce treatment-associated toxicities. The combination of autologous CAR T cells with various allogeneic cell treatment strategies designed to target the immunosuppressive tumor microenvironment will broaden the impact of future CAR T-cell therapies.

Fig. 1:. Overview of next-generation CAR T cell approaches.

a) To reduce the risk of tumor relapse due to antigen-escape (e.g., loss or downregulation of CD19 or CD22), two CAR T cell products specific for different target antigens can be co-administered. The same T cell can also be transduced with two viral CAR vectors encoding for different constructs, or with one CAR construct with two single chain variable fragments (Dual or Tandem-CAR). b) CAR constructs with advanced functionalities include T cells redirected for antigen-unrestricted cytokine-initiated killing (TRUCK), which secrete cytokines upon activation (e.g., IL-18 or IL-12). In addition, CAR T cell function can be further enhanced by using switch-receptors (e.g., TGFβ), or through addition of orthogonal cytokine receptor system that act specifically on CAR-transduced cells (e.g., orthogonal IL2 receptor, oIL2R). TF= transcription factor. c) To overcome on-target / off-tumor toxicities in hematological malignancies, CAR T cells can be combined with hematopoietic stem cell transplantation (HSCT) that has been engineered to lack the CAR T cell target antigen (e.g., CD33 knock-out hematopoietic stem cells, CD33 KO HSC). For solid tumors, AND and NOT logic-gated CAR T cells have been developed that recognize combinatorial antigen expression to trigger or inhibit CAR T cell effector function. d) The additional administration of engineered viruses can effectively modulate the tumor microenvironment and engage innate / adaptive immunity. Also, CAR-macrophages can phagocytose tumor cells and induce anti-tumor bystander immune cells.

Fig. 2:. Broadening product availability.

The use of gene-edited allogeneic (‘off-the-shelf’) TCR/CAR T cells could provide immediate availability of cryopreserved cells, increase product quality, and decrease costs by using an industrial process. Beyond T cells, natural killer (NK) cells could be used as an allogeneic cellular immunotherapy.