How do CARs work?: Early insights from recent clinical studies targeting CD19

Abstract

Second-generation chimeric antigen receptors (CARs) are powerful tools to redirect antigen-specific T cells independently of HLA-restriction. Recent clinical studies evaluating CD19-targeted T cells in patients with B-cell malignancies demonstrate the potency of CAR-engineered T cells. With results from 28 subjects enrolled by five centers conducting studies in patients with chronic lymphocytic leukemia (CLL) or lymphoma, some insights into the parameters that determine T-cell function and clinical outcome of CAR-based approaches are emerging. These parameters involve CAR design, T-cell production methods, conditioning chemotherapy as well as patient selection. Here, we discuss the potential relevance of these findings and in particular the interplay between the adoptive transfer of T cells and pre-transfer patient conditioning.

Figure 1. The mechanics of chimeric antigen receptor (CAR)-based trials. Inner circle (purple): key steps in patient preparation and T-cell manufacture. Outer circle (orange): key differences between studies targeting CD19⁺ malignancies with CARs. BENDA, bendamustine; CTX, cyclophosphamide; FLU, fludarabine. PENT, pentostatin.

Figure 2. Schematic diagram of chimeric antigen receptor (CARs) used to treat chronic lymphocytic leukemia (CLL) patients at MSKCC, NCI and UPenn. (A) 19–28ζ (MSKCC). (B) FMC63–28ζ (NCI). (C) 19-BB-ζ (UPenn). Groups at MSKCC and NCI utilized the CD28/ζ design described by Maher, et al. The UPenn group used the 4–1BBζ design described by Imai, et al. The MSKCC group used the SJ single-chain variable fragment (scFv) while researchers at NCI and UPenn used the FMC63 scFv. TM, transmembrane.