Novel cellular therapies for leukemia: CAR-modified T cells targeted to the CD19 antigen

Abstract

The ability of immune-competent donor T cells to mediate a beneficial graft-versus-leukemia (GVL) effect was first identified in the setting of allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematologic malignancies. Unfortunately, with the exception of chronic myelogenous leukemia and EBV-induced lymphoproliferative disease, allo-HSCT GVL lacks the potency to significantly affect disease progression or recurrence in most other hematologic malignancies. The inadequacy of a GVL effect using past approaches is particularly evident in patients with lymphoid malignancies. However, with the advent of improved gene transfer technology, genetically modified tumor-specific immune effectors have extended cellular immunotherapy to lymphoid malignancies. One promising strategy entails the introduction of genes encoding artificial receptors called chimeric antigen receptors (CARs), which redirect the specificity and function of immune effectors. CAR-modified T cells targeted to the B cell-specific CD19 antigen have demonstrated promising results in multiple early clinical trials, supporting further investigation in patients with B-cell cancers. However, disparities in clinical trial design and CAR structure have complicated the discovery of the optimal application of this technology. Recent preclinical studies support additional genetic modifications of CAR-modified T cells to achieve optimal clinical efficacy using this novel adoptive cellular therapy.

Figure 1. CAR technology evolution through the generation of more potent CARs

First-generation CARs classically contain only one signaling domain, typically the cytoplasmic signaling domain of the CD3 TCRζ chain. Second-generation CARs containing 2 signaling domains typically include the addition of the cytoplasmic signaling domains of the costimulatory receptors CD28, 4-1BB, or OX-40, among others. Third-generation CARs attempt to harness the signaling potential of 2 costimulatory domains: classically, the CD28 domain followed by either the 4-1BB or OX-40 signaling domains. CAR-modified T-cell potency may be further enhanced through the introduction of additional genes, including those encoding proproliferative cytokines (ie, IL-12) or costimulatory ligands (ie, 4-1BBL), thus producing “armored” fourth-generation CAR-modified T cells.

Figure 2. Variables in clinical trial design

Multiple, potentially clinically relevant variables exist between various published clinical trial outcomes treating patients with CD19-targeted, CAR-modified T cells. There are variables in the methodology of CAR gene transfer (1), the design of the CAR (2), the inclusion or exclusion of prior conditioning chemotherapy (3), whether conditioning chemotherapy may reduce tumor burden (4), and whether additional cytokine support with IL-2 is provided exogenously after modified T-cell infusion (5). Whether one or more of these variables are indeed relevant to ultimate clinical outcomes awaits additional multicenter trials resolving these variables by direct comparison to establish the optimal conditions in which these CAR-modified T cells may induce an optimal clinical response.