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As T cell therapies for cancer and viral disease enter mainstream medicine ([ 1 ][1]-[ 3 ][2]), identifying impediments to their therapeutic activity is crucial. Persistent stimulation of virus- or tumor-specific T cells through their antigen-specific T cell receptor (TCR) can lead to progressive loss of effector function, a phenomenon called functional exhaustion ([ 4 ][3], [ 5 ][4]). A similar outcome may occur in therapeutic T cells engineered with synthetic chimeric antigen receptors (CARs), which bypass the native TCR and directly activate T cells upon binding to surface tumor antigen. In both cases, exhaustion is associated with continuous stimulation through the antigen receptor, impairing expansion and target cell lysis. On page 49 of this issue, Weber et al. ([ 6 ][5]) show that continuous CAR stimulation induces profound functional, transcriptional, and epigenetic changes in CAR-T cells that are reversed by intermittent blockade of CAR signaling. One of their approaches to reversal uses an approved drug (dasatinib), enabling its rapid clinical evaluation. When T cells are exposed to tumors or chronic viral infections, sustained positive stimulation from antigen through the TCR (signal 1) and negative costimulatory signals (signal 2) from immune checkpoint receptors that suppress T cell activity, such as programmed cell death protein 1 (PD-1), can lead to functional exhaustion ([ 4 ][3]). Exposure to inhibitory cytokines (signal 3) such as transforming growth factor-β (TGF-β) often compounds the problem. These conflicting signals render T cells progressively more inert, coupling their continuing recognition of tumor or viral antigens to an inability to lyse antigen-expressing cells, secrete effector molecules, or proliferate. The magnitude and duration of inhibitory signals 2 and 3 regulate the intensity of T cell exhaustion, and the effects can initially be reversed--for example, by disrupting negative signal 2 with antibodies against PD-1 or PD-1 ligand (PD-L1) ([ 5 ][4]). CARs bypass both the endogenous TCR specificity (signal 1) and the dependence on a separate and positive costimulatory signal 2 by incorporating both signals in one artificial molecule, which is triggered upon binding to a target antigen that it is engineered to recognize. High CAR expression and structural attributes of the receptor can promote their spontaneous, persistent, and ligand-independent signaling ([ 7 ][6], [ 8 ][7]). Such tonic stimulation produces a state resembling persistent T cell stimulation by cognate antigen. Prolonged tonic CAR signaling alone is often sufficient to accelerate terminal T cell differentiation to short-lived effector subsets and induce a gene expression signature associated with exhausted T cells. These changes substantially reduce the antitumor activity of CAR-expressing T cells in preclinical models ([ 8 ][7]). The T cell dysfunction induced by tonic CAR signaling was thought to be similar to the prolonged and hard-to-reverse functional exhaustion observed in tumor- and virus-specific T cells. It was therefore assumed that only extensive and time-consuming CAR optimization could avert the problem. Weber et al. challenge this concept, demonstrating that the transcriptional, and even the epigenetic, changes induced in engineered T cells by unrelenting CAR activation can be reversed by temporarily blocking CAR signaling (see the figure). The authors controlled spontaneous signaling either by adjusting turnover of the CAR itself or by pharmacologically inhibiting key kinases involved in proximal TCR and CAR signaling with dasatinib. In both models, transient rest from CAR signaling restored their gene expression profile and phenotype. The rescued CAR-T cells had increased antitumor function in mouse xenograft models of human leukemia and osteosarcoma. Although ceasing CAR signaling for up to 3 weeks provided the greatest benefit, even brief inhibition of CAR signaling for 3 days prior to in vivo administration significantly improved anti-leukemia activity of CAR-T cells. Moreover, Weber et al. demonstrated the benefit of in vivo pulsatile inhibition of CAR signaling: An intermittent 3-days ON/4-days OFF regimen produced superior leukemia control compared with conventional, always-ON CAR-T cells. This observation is surprising because suppressing CAR-mediated target cell killing could potentially facilitate tumor growth during the OFF period. Given intermittent signal-starvation-enhanced tumor control even in T cells expressing a CAR without tonic signaling, functional reinvigoration induced by interrupting constant antigenic stimulation may have additional but unidentified benefits. ![Figure][8] Reinvigorating engineered T cells Chimeric antigen receptor (CAR)-expressing T cells are engineered to recognize antigens expressed by tumor cells. Upon chronic stimulation of the CAR, T cells can become functionally exhausted. This can be reversed by temporary cessation of CAR signaling, which induces enhancer of zeste homolog 2 (EZH2)-dependent chromatin remodeling. GRAPHIC: V. ALTOUNIAN/ SCIENCE Weber et al. revealed that the epigenetic changes (mostly transcriptional silencing) observed in hypofunctional CAR-T cells is primarily associated with histone methylation, rather than the more stable DNA methylation associated with "conventionally" exhausted T cells ([ 9 ][9]). The mechanism of these histone methylation changes is unknown, but they were reversable with "signal starvation" and required the activity of the histone methyltransferase, enhancer of zeste homolog 2 (EZH2). This may indicate that exhaustion resulting from hyperactive CAR signaling may differ from conventional exhaustion associated with overstimulated TCR and negative costimulation with immune checkpoints and inhibitory cytokines. Whether the authors' approach can be more broadly applied to tumor- and virus-specific T cells that have become exhausted in situ, or whether it will be used to prevent and reverse dysfunction primarily in CAR-T cells should be investigated in clinical studies. It will also be important to ascertain if reversal occurs even in the tumor microenvironment, where inhibitory checkpoint and cytokine signals are abundant. The study by Weber et al. has important immediate implications for CAR-T cell therapy, providing a rationale for intermittently inhibiting CAR-T cell signaling. For example, licensed drugs such as dasatinib that interrupt the tyrosine kinase pathways of CAR signaling could be given as pulses after CAR-T cell administration. Preclinical studies showed the feasibility of this approach and demonstrated that in vivo administration of dasatinib would mitigate excessive CAR-T cell-mediated inflammation ([ 10 ][10], [ 11 ][11]). Any ON/OFF schedule must, however, avoid excessive periods of unopposed tumor growth or waves of inflammatory cytokines similar to the immune reconstitution syndrome observed in patients with some chronic infections, such as HIV and tuberculosis, where reinvigoration of T cell immunity may cause lethal hyperinflammation. These concerns may be addressable by alternating inhibition of different CAR-T cell populations using orthogonal systems of conditional CAR signaling. If T cell exhaustion due to tonic CAR signaling can indeed be avoided in cancer patients merely by inducing pulsatile CAR activation, accelerated development of optimized CAR-T cells and substantive benefits to their in vivo potency are anticipated. 1. [↵][12]1. C. H. June, 2. M. Sadelain , N. Engl. J. Med. 379, 64 (2018). [OpenUrl][13][CrossRef][14][PubMed][15] 2. 1. C. M. Bollard, 2. H. E. Heslop , Blood 127, 3331 (2016). [OpenUrl][16][Abstract/FREE Full Text][17] 3. [↵][18]1. S. Guedan et al ., Annu. Rev. Immunol. 37, 145 (2019). [OpenUrl][19][CrossRef][20][PubMed][21] 4. [↵][22]1. L. M. McLane et al ., Annu. Rev. Immunol. 37, 457 (2019). [OpenUrl][23][CrossRef][24][PubMed][25] 5. [↵][26]1. M. Hashimoto et al ., Annu. Rev. Med. 69, 301 (2018). [OpenUrl][27][CrossRef][28][PubMed][25] 6. [↵][29]1. E. W. Weber et al ., Science 371, aba1786 (2021). [OpenUrl][30] 7. [↵][31]1. D. Gomes-Silva et al ., Cell Rep. 21, 17 (2017). [OpenUrl][32] 8. [↵][33]1. A. H. Long et al ., Nat. Med. 21, 581 (2015). [OpenUrl][34][CrossRef][35][PubMed][36] 9. [↵][37]1. H. E. Ghoneim et al ., Cell 170, 142 (2017). [OpenUrl][38][CrossRef][39] 10. [↵][40]1. E. W. Weber et al ., Blood Adv. 3, 711 (2019). [OpenUrl][41][Abstract/FREE Full Text][42] 11. [↵][43]1. K. Mestermann et al ., Sci. Transl. Med. 11, eaau5907 (2019). [OpenUrl][44][Abstract/FREE Full Text][45] Acknowledgments: M.K.B. has equity or advisory board interests in Allovir, Allogene, Marker Therapeutics, Tessa Therapeutics, Walking Fish Therapeutics, Abintus, Memgen Kuur, and Poseida Therapeutics. M.M. has licensing or advisory board interests with Fate Therapeutics, Allogene, and Xenetic Biosciences. M.K.B. and M.M. receive research support from NIH/NCI P50 CA7019-19, LLS 126752, and SU2C-AACR-DT-29-19. 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