Expanding the Therapeutic Window for CAR T Cell Therapy in Solid Tumors: The Knowns and Unknowns of CAR T Cell Biology

Abstract

A major obstacle for chimeric antigen receptor (CAR) T cell therapy in solid tumors is the lack of truly tumor-specific target antigens, which translates to the targeting of tumor-associated antigens (TAAs) overexpressed on tumors but shared with normal organs, raising safety concerns. In addition, expression of TAAs in solid tumors is particularly heterogeneous. In this regard, it is critical to deeply understand the sensitivity of CAR T cells, especially against low-density targets and the possible therapeutic window of antigen density targeted by CAR T cells. In this review, we discuss the recent findings of mechanisms of antigen recognition through CAR, including immunological synapse formation, and the impact of target antigen density for induction of distinct T cell functions. We also discuss rational strategies to adjust and expand the therapeutic window for effective and safe targeting of solid tumors by CAR T cell platforms.

Keywords: T cell biology; cancer immunology; chimeric antigen receptors; immune synapse formation; immunotherapy.

Figure 1

Immunological synapse formation through TCRs and CARs. (A) TCR immune synapse shows a well-organized bull's eye structure including the central supramolecular activation complex (cSMAC) (pink), the peripheral SMAC (pSMAC) (red), and distal SMAC (dSMAC) (orange). (B) CAR immune synapse (right) displays disorganized structure with no/reduced actin ring and microclusters of CAR/tumor antigen in a disorganized pattern. Major components of the TCR and CAR immune synapse are listed below the figures.

Figure 2

Schema to illustrate therapeutic window of CAR T cell therapies. (A). Therapeutic window (red area) is determined as a range between the minimum effective dose (“MED”) and the maximum tolerated dose (“MTD”), where the therapy can achieve the highest therapeutic benefit without resulting in unacceptable toxicity. Blue lines show the kinetics of CAR T cells. (B). Red area shows an expanded therapeutic window with decreased “MED” and/or increased “MTD,” which increase a chance for the CAR T cells to induce sufficient efficacy without toxicity. (C). Red area shows a narrowed therapeutic window with increased “MED” and/or decreased “MTD,” which can cause toxicity and/or suboptimal efficacy. (D). Factors that can narrow the therapeutic window and possible strategies to expand the window are listed.