CARs in chronic lymphocytic leukemia -- ready to drive

Abstract

Adoptive transfer of antigen-specific T cells has been adapted by investigators for treatment of chronic lymphocytic leukemia (CLL). To overcome issues of immune tolerance which limits the endogenous adaptive immune response to tumor-associated antigens (TAAs), robust systems for the genetic modification and characterization of T cells expressing chimeric antigen receptors (CARs) to redirect specificity have been produced. Refinements with regards to persistence and trafficking of the genetically modified T cells are underway to help improve potency. Clinical trials utilizing this technology demonstrate feasibility, and increasingly, these early-phase trials are demonstrating impressive anti-tumor effects, particularly for CLL patients, paving the way for multi-center trials to establish the efficacy of CAR(+) T cell therapy.

Fig. 1

CAR structures expressed by clinical-grade genetically modified T cells to target CD19. Most CARs combine an antibody binding domain (scFv) that recognizes a desired tumor associated antigen (TAA) with one or more T cell receptor signaling endodomains. Oligomerization of CAR on the T cell surface (such as by chimeric Fc regions derived from immunoglobulin) leads to activation of T cells through CD3ζ and other chimeric co-stimulatory domains (e.g., CD28 and CD137). Signaling through CAR in addition to CD3ζ appears to enhance the therapeutic potential of the genetically modified T cells. Thus, second-generation CARs are considered superior to a first-generation CAR design that activates T cells solely through CD3ζ. The final choice for design of second-generation CAR structure has not been determined and likely depends on tumor load, TAA density, and the sub-type of genetically modified lymphocytes to be infused. Based on available clinical data it appears that populations of CAR⁺ T cells that are activated through CD137/CD3ζ and CD28/CD3ζ can both target malignant cells (and normal B cells). However, a CAR that signals through CD137/CD3ζ has resulted in the most impressive anti-tumor effects to date and thus is currently considered by many to be the preferred second-generation design