Biology and clinical application of CAR T cells for B cell malignancies

Abstract

Chimeric antigen receptor (CAR)-modified T cells have generated broad interest in oncology following a series of dramatic clinical successes in patients with chemorefractory B cell malignancies. CAR therapy now appears to be on the cusp of regulatory approval as a cell-based immunotherapy. We review here the T cell biology and cell engineering research that led to the development of second generation CARs, the selection of CD19 as a CAR target, and the preclinical studies in animal models that laid the foundation for clinical trials targeting CD19+ malignancies. We further summarize the status of CD19 CAR clinical therapy for non-Hodgkin lymphoma and B cell acute lymphoblastic leukemia, including their efficacy, toxicities (cytokine release syndrome, neurotoxicity and B cell aplasia) and current management in humans. We conclude with an overview of recent pre-clinical advances in CAR design that argues favorably for the advancement of CAR therapy to tackle other hematological malignancies as well as solid tumors.

Keywords: Adoptive T cell therapy; CD19; Chimeric antigen receptor; Immunotherapy; T cell engineering.

Figure 1. Second generation CAR structure

A common CAR design, depicted here, comprises a signal peptide (SP) followed by the scFv, which is composed of IgH and IgL rearrangements separated by a linker such as the glycine-serine (G/S) linker. A linker domain of variable length, followed by a transmembrane region is followed by costimulatory and activation domains. The synthetic CAR cDNA is encoded by a vector used to transduce patient T cells. The resulting CAR T cells are thus targeted to the tumor and functionally enhanced.

Figure 2. Main CAR T cell functions

1) A CAR T cell encounters the CD19 antigen on B cell blasts and initiates tumor killing. Engagement of CD19 by CAR T cells also leads to 2) massive cytokine production and 3) cell proliferation, which results in cytokine release syndrome toxicities and leukemia eradication. Some CAR T cells are able to access the CNS by 4) potentially crossing the blood brain barrier (BBB) from capillaries and presumably mediate neurotoxicities, directly or indirectly, with or without crossing the BBB. In addition to killing malignant B cells, CD19-targeted CAR T cells will 5) engage and kill normal B cells resulting in B cell aplasia that lasts for as long as the CAR T cells persist and remain functional.