Abstract IA15: CARs and armored CARs: Improving CAR T-cell therapy for cancer

Abstract

Abstract Significant progress has been made in the field of cancer cell therapy over the last 2 decades. Specifically, a patient's own T cells may be genetically engineered to express an artificial T-cell receptor, termed a chimeric antigen receptor (CAR), which, when expressed in a T cell, can alter the specificity of the T cell. A CAR consists of a binding domain, typically derived from a monoclonal antibody, fused to T-cell signaling domains including a co-stimulatory domain, CD28 or 4-1BB, fused to a distal CD3 zeta chain cytoplasmic signaling domain. CAR T cells targeted to the CD19 antigen, expressed on most B-cell malignancies, have demonstrated the greatest clinical efficacy, and commercial CAR T-cell products have recently been FDA approved in the treatment of relapsed and refractory B-cell lymphomas as well as B-cell acute lymphoblastic leukemias. Similarly, CAR T cells targeting the BCMA antigen, expressed on most multiple myeloma tumor cells, have demonstrated impressive antitumor responses in relapsed and refractory disease in both early-phase clinical trials as well as ongoing registration trials. While response rates in the context of CAR T cells targeted to CD19 and BCMA have been impressive, unfortunately the durability of response in some patients is limited and others fail to respond to treatment entirely. The complete list of etiologies responsible for treatment failures remains to be fully defined. Likely causes for treatment failures include the loss of target antigen expression by the tumor, limited persistence of CAR T cells in vivo, and suppression of CAR T cells in the context of an immune-suppressive tumor microenvironment. While this list is likely incomplete, investigators in the CAR T cell field are working on designing next-generation CAR T cells that could address these current limitations. Armored CAR T cells are CAR T cells further modified to enhance persistence and cytotoxicity. Specifically, CAR T cells may be modified to express or secrete biologically active cytokines or ligands designed to modulate the tumor microenvironment and recruit endogenous antitumor immune effectors to enhance the antitumor immune response. Examples of armored CAR T cells include cytokine-secreting CAR T cells (IL-12, IL-18), co-stimulatory ligand-expressing CAR T cells (4-1BBL, CD40L), CAR T cells that secrete single-fragment-length antibodies (scFvs) targeted to immune checkpoint receptors (PD-1), and CAR T cells that express dominant negative chimeric receptors (Fas, TGF-B). Preclinical studies in the context of these armored CAR T cells have demonstrated markedly enhanced antitumor activity in mice when compared to T cells modified to express the CAR alone. Outcomes of planned and ongoing early-stage clinical trials are pending but may markedly change the field in the foreseeable future. Citation Format: Renier J. Brentjens. CARs and armored CARs: Improving CAR T-cell therapy for cancer [abstract]. In: Proceedings of the AACR Virtual Meeting: Advances in Malignant Lymphoma; 2020 Aug 17-19. Philadelphia (PA): AACR; Blood Cancer Discov 2020;1(3_Suppl):Abstract nr IA15.