Improving CAR-T immunotherapy: Overcoming the challenges of T cell exhaustion

Abstract

Chimeric antigen receptor (CAR) T cell therapy has emerged as a cancer treatment with enormous potential, demonstrating impressive antitumor activity in the treatment of hematological malignancies. However, CAR T cell exhaustion is a major limitation to their efficacy, particularly in the application of CAR T cells to solid tumors. CAR T cell exhaustion is thought to be due to persistent antigen stimulation, as well as an immunosuppressive tumor microenvironment, and mitigating exhaustion to maintain CAR T cell effector function and persistence and achieve clinical potency remains a central challenge. Here, we review the underlying mechanisms of exhaustion and discuss emerging strategies to prevent or reverse exhaustion through modifications of the CAR receptor or CAR independent pathways. Additionally, we discuss the potential of these strategies for improving clinical outcomes of CAR T cell therapy.

Keywords: CAR T; Cancer; Chimeric antigen receptor; Immunotherapy; T cell exhaustion.

Figure 1

The T cell response during acute and persistent antigen stimulation. For acute antigen stimulation, the expansion of Teff cells is followed by antigen clearance. After the antigen is cleared, the majority of antigen specific T cells die off, leaving a small number of Tmem cells. For persistent antigen stimulation, the antigen is not cleared leading to the differentiation of the Teff cells to an exhausted state. MPECs: memory precursor effector cells, Teff: effector T cells, Tmem: memory T cells. Original figure.

Figure 2

Intrinsic T cell approaches to overcoming exhaustion in CAR T cell therapy. Inhibition of T cell activation and promotion of exhaustion by the (a) PD-1, (b) TOX/NR4A, (c) TGF-β, and (d) CBL-B pathways. Means of targeting these pathways to resist exhaustion are depicted in red. KO: knockout, KD: knock down, MI: molecular inhibitor, dnPD-1: dominant negative PD-1, dnC-CBL: dominant negative C-CBL, dnTGFBR2: dominant negative TGFBR2. Original figure.

Figure 3

CAR construct approaches to overcoming exhaustion in CAR T cell therapy. (a) Diagram of the conventional construction of a CAR. Post-transcriptional regulation of CAR at the surface of the T cell include drug-induced stabilization (b) and de-stabilization (c). Methods of regulating CAR expression at the transcriptional level include inducible systems (d), self-driving CAR promoters (e), and tumor microenvironment (TME) factor driven CAR promoters. Switchable CARs (g) and split CARs (h) uncouple the antigen recognition or co-stimulation from the CD3ζ domain. TM: transmembrane domain, co-stim: co-stimulatory domain, TME: tumor microenvironment. Original figure.