State of the art in CAR T cell therapy for CD19+ B cell malignancies

Abstract

Cellular therapy for hematologic malignancies is a rapidly evolving field, with new iterations of novel constructs being developed at a rapid pace. Since the initial reports of chimeric antigen receptor T cell (CAR T cell)success in CD19+ B cell malignancies, multiple clinical trials of CAR T cell therapy directed to CD19 have led to the approval of this therapy by the FDA and the European Medicines Agency for specific indications. Despite strikingly similar efficacy, investigators at multiple centers participating in these studies have observed the nuances of each CAR T cell product, including variability in manufacturing, availability, and toxicity profiles. Here we review state-of-the-art clinical data on CD19-directed CAR T cell therapies in B cell hematologic malignancies, advances made in understanding and modeling associated toxicities, and several exciting advances and creative solutions for overcoming challenges with this therapeutic modality.

Figure 1. Summary of mechanisms discovered in two animal models designed to recapitulate cytokine release syndrome.

Figure 2. Examples of mechanisms underlying CD19^– loss in B cell malignancies.

(A) Wild-type CD19 and observed frameshift mutations that result in lack of surface expression of the CD19 molecule in B cell leukemia. (B) CAR-transduced B cells with self-binding (“masking”) of CD19 by the CAR expressed on the cell surface of leukemic B cells. (C) Trogocytosis, in which CAR T cells “rip off” the CD19 molecules from the leukemic blasts by membrane transfer, resulting in lowered expression of CD19 by the leukemic blasts. In (i), CAR T encounters B-ALL cell; in (ii), CAR T has trogocytosed bits of membrane-bound CD19 from the B-ALL cell onto the CAR T cell, and some of the CD19 on the CAR T cell is masked; in (iii), the CAR T cell with membrane-bound CD19 may become susceptible to lysis by another CAR T cell.

Figure 3. Summary of strategies for targeting multiple antigens with CAR T cells.

(A) Pooled CAR populations: Two cell populations are transduced with two different CARs, each with a single specificity (red and blue); these two cell products are then pooled or coinfused into the patient. (B) Double transduction: One cell population is cotransduced with two CARs, each with a single specificity (red and blue). (C) Tandem CARs: Two different binding specificities (red and blue) are molecularly linked in tandem and fused to a single transmembrane/signaling domain. The specificities can be combined in different formats to achieve productive binding of each. (D) Polyspecific binders: A cross-reactive CAR (purple) binds with two different specificities. These can be linked together in tandem to form multimeric binding domains. (E) Secreting CARs: The CAR has one specificity (blue) and a second binder is secreted from the CAR (red). This can also take the form of a T cell engager (yellow) if the secreted form has a bispecific format.