Chimeric antigen receptors for the adoptive T cell therapy of hematologic malignancies

Abstract

The genetic modification of autologous T cells with chimeric antigen receptors (CARs) represents a breakthrough for gene engineering as a cancer therapy for hematologic malignancies. By targeting the CD19 antigen, we have demonstrated robust and rapid anti-leukemia activity in patients with heavily pre-treated and chemotherapy-refractory B cell acute lymphoblastic leukemia (B-ALL). We demonstrated rapid induction of deep molecular remissions in adults, which has been recently confirmed in a case report involving a child with B-ALL. In contrast to the results when treating B-ALL, outcomes have been more modest in patients with chronic lymphocytic leukemia (CLL) or other non-hodgkin's lymphoma (NHL). We review the clinical trial experience targeting B-ALL and CLL and speculate on the possible reasons for the different outcomes and propose potential optimization to CAR T cell therapy when targeting CLL or other indolent NHL. Lastly, we discuss the pre-clinical development and potential for clinical translation for using CAR T cells against multiple myeloma and acute myeloid leukemia. We highlight the potential risks and benefits by targeting these poor outcome hematologic malignancies.

Fig. 1

CAR T cell activation and killing of tumor targets. Tumor cell recognition occurs when a CAR on a T cell ligates its antigen on the tumor. Signaling and activation is mediated by the intra-cytoplasmic signaling domains within the CAR. Activation can lead to direct cytotoxicity of tumor target by CAR T cell mediated release of granzyme and perforin. Tumor killing can also be mediated by activation of other components of the immune system through release of cytokines by CD4⁺ T cells. Long-term eradication and prevention against tumor relapse may be provided by long-term memory CAR T cells that form after the initial activation

Fig. 2

Production of CAR T cells in a GMP facility. Production begins with (1) leukapheresis of the patient and is then followed by selection of T cells (2), and their activation, from the leukapheresis product by positive selection with a CD3 antibody ± a CD28 antibody. After a few days the activated T cells are incubated with retroviral supernatant to transfer the CAR gene (3). Expansion, washing, and formulation result in infusion back into the patient (4–6). In general, at our center this process takes about 2 weeks