Adoptive immunotherapy for B-cell malignancies with autologous chimeric antigen receptor modified tumor targeted T cells

Abstract

Chemotherapy-resistant B-cell hematologic malignancies may be cured with allogeneic hematopoietic stem cell transplantation (HSCT), demonstrating the potential susceptibility of these tumors to donor T-cell mediated immune responses. However, high rates of transplant-related morbidity and mortality limit this approach. For this reason, there is an urgent need for less-toxic forms of immune-based cellular therapy to treat these malignancies. Adoptive transfer of autologous T cells genetically modified to express chimeric antigen receptors (CARs) targeted to specific tumor-associated antigens represents an attractive means of overcoming the limitations of conventional HSCT. To this end, investigators have generated CARs targeted to various antigens expressed by B-cell malignancies, optimized the design of these CARs to enhance receptor mediated T cell signaling, and demonstrated significant anti-tumor efficacy of the resulting CAR modified T cells both in vitro and in vivo mouse tumor models. These encouraging preclinical data have justified the translation of this approach to the clinical setting with currently 12 open clinical trials and one completed clinical trial treating various B-cell malignancies utilizing CAR modified T cells targeted to either the CD19 or CD20 B-cell specific antigens.

Figure 1

Structure of chimeric antigen receptors (CARs). First-generation CARs are typically composed of a single fragment length antibody (scFv) containing the heavy (V_H) and light chain (V_L) variable regions specific to a TAA, fused to an inert TM domain of the CD8, fused to a cytoplasmic signaling domain of the T cell receptor (TCR) (most commonly the TCR ζ chain). Second-generation CARs include a co-stimulatory signaling domain (CD28, 4-1BB, or OX40), while third-generation CARs contain tandem cytoplasmic signaling domains from 2 co-stimulatory receptors (i.e., CD28-4-1BB and CD28-OX40).