Pharmacologic Control of CAR T Cells

Benjamin Caulier, Jorrit M Enserink, Sébastien Wälchli, Benjamin Caulier, Jorrit M Enserink, Sébastien Wälchli

Abstract

Chimeric antigen receptor (CAR) therapy is a promising modality for the treatment of advanced cancers that are otherwise incurable. During the last decade, different centers worldwide have tested the anti-CD19 CAR T cells and shown clinical benefits in the treatment of B cell tumors. However, despite these encouraging results, CAR treatment has also been found to lead to serious side effects and capricious response profiles in patients. In addition, the CD19 CAR success has been difficult to reproduce for other types of malignancy. The appearance of resistant tumor variants, the lack of antigen specificity, and the occurrence of severe adverse effects due to over-stimulation of the therapeutic cells have been identified as the major impediments. This has motivated a growing interest in developing strategies to overcome these hurdles through CAR control. Among them, the combination of small molecules and approved drugs with CAR T cells has been investigated. These have been exploited to induce a synergistic anti-cancer effect but also to control the presence of the CAR T cells or tune the therapeutic activity. In the present review, we discuss opportunistic and rational approaches involving drugs featuring anti-cancer efficacy and CAR-adjustable effect.

Keywords: CAR T cell; chimeric antigen receptor; drugs; immunotherapy; kinase inhibitors; small molecules.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of the pharmacologic interventions exploited with CAR T cells. (i) Combinatorial anti-cancer approaches. (ii) Mitigating adverse effects. (iii) CAR T cell elimination. (iv) Reversible control of CAR. (v) Modulating CAR specificity. See the main text for description. Created with BioRender.com.
Figure 2
Figure 2
Pharmacologic strategies to reversibly control CAR function. Engineered CAR T cells can be commanded through signaling pathways and transgene expression (left panel), structural CAR component interactions (middle panel) or targeting CAR for proteolysis (right panel). See the main text for detailed descriptions. Created with BioRender.com.

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