Transient rest restores functionality in exhausted CAR-T cells through epigenetic remodeling

Weber, Evan W.; Parker, Kevin R.; Sotillo, Elena; Lynn, Rachel C.; Anbunathan, Hima; Lattin, John; Good, Zinaida; Belk, Julia A.; Dániel, Bence; Klysz, Dorota D.; Malipatlolla, Meena; Xu, Peng; Bashti, Malek; Heitzeneder, Sabine; Labanieh, Louai; Vandris, Panayiotis; Majzner, Robbie G.; Qi, Yanyan; Sandor, Katalin; Chen, Ling-Chun; Prabhu, Snehit; Gentles, Andrew J.; Wandless, Thomas J.; Satpathy, Ansuman T.; Chang, Howard Y.; Mackall, Crystal L.

doi:10.1126/science.aba1786

Cited by 374 publications

(318 citation statements)

References 83 publications

(124 reference statements)

Supporting

Mentioning

269

Contrasting

Order By: Relevance

“…In this way SIRT1 acts as an epigenetic promoter of immune exhaustion ( 18 , 194 ). In a follow-up CAR T study, the incorporation of a titratable FK506 binding protein 12 (FKBP) destabilizing domain (DD) emphasized the importance of timing and rest ( 195 ). Simply put, this engineered CAR T cell model demonstrated that interrupting tonic T cell activation, either through the titratable FK506 DD or through dasatinib, a tyrosine kinase inhibitor, could block epigenetic-mediated immune exhaustion.…”

Section: Bioengineering Approaches To Reverse Epigenetic-mediated Immune Exhaustion and Suppressionmentioning

confidence: 99%

Reversing Post-Infectious Epigenetic-Mediated Immune Suppression

et al. 2021

View full text Add to dashboard Cite

The immune response must balance the pro-inflammatory, cell-mediated cytotoxicity with the anti-inflammatory and wound repair response. Epigenetic mechanisms mediate this balance and limit host immunity from inducing exuberant collateral damage to host tissue after severe and chronic infections. However, following treatment for these infections, including sepsis, pneumonia, hepatitis B, hepatitis C, HIV, tuberculosis (TB) or schistosomiasis, detrimental epigenetic scars persist, and result in long-lasting immune suppression. This is hypothesized to be one of the contributing mechanisms explaining why survivors of infection have increased all-cause mortality and increased rates of unrelated secondary infections. The mechanisms that induce epigenetic-mediated immune suppression have been demonstrated in-vitro and in animal models. Modulation of the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR), nuclear factor of activated T cells (NFAT) or nuclear receptor (NR4A) pathways is able to block or reverse the development of detrimental epigenetic scars. Similarly, drugs that directly modify epigenetic enzymes, such as those that inhibit histone deacetylases (HDAC) inhibitors, DNA hypomethylating agents or modifiers of the Nucleosome Remodeling and DNA methylation (NuRD) complex or Polycomb Repressive Complex (PRC) have demonstrated capacity to restore host immunity in the setting of cancer-, LCMV- or murine sepsis-induced epigenetic-mediated immune suppression. A third clinically feasible strategy for reversing detrimental epigenetic scars includes bioengineering approaches to either directly reverse the detrimental epigenetic marks or to modify the epigenetic enzymes or transcription factors that induce detrimental epigenetic scars. Each of these approaches, alone or in combination, have ablated or reversed detrimental epigenetic marks in in-vitro or in animal models; translational studies are now required to evaluate clinical applicability.

show abstract

Section: Bioengineering Approaches To Reverse Epigenetic-mediated Immune Exhaustion and Suppressionmentioning

confidence: 99%

Reversing Post-Infectious Epigenetic-Mediated Immune Suppression

et al. 2021

View full text Add to dashboard Cite

show abstract

“…Here, we focus on the development of more specific and potent next-generation engineered T cell therapies for mesothelioma and ovarian cancer. Mesothelioma is a highly aggressive chronic inflammationdriven cancer with an exceedingly poor prognosis that has three histological subtypes: epithelioid (69% of cases, median overall survival ~14 months), biphasic (12%, ~10 months), and sarcomatoid (19%, ~4 months) (7,8). Mesothelioma is inherently hard to treat with traditional modes of cancer therapy, and recent trials exploring mono-or combination immune checkpoint inhibitors (ICIs) have also had limited impact (10,11).…”

Section: Introductionmentioning

confidence: 99%

SynNotch CAR circuits enhance solid tumor recognition and promote persistent antitumor activity in mouse models

et al. 2021

View full text Add to dashboard Cite

The first clinically approved engineered chimeric antigen receptor (CAR) T cell therapies are remarkably effective in a subset of hematological malignancies with few therapeutic options. Although these clinical successes have been exciting, CAR T cells have hit roadblocks in solid tumors that include the lack of highly tumor-specific antigens to target, opening up the possibility of life-threatening “on-target/off-tumor” toxicities, and problems with T cell entry into solid tumor and persistent activity in suppressive tumor microenvironments. Here, we improve the specificity and persistent antitumor activity of therapeutic T cells with synthetic Notch (synNotch) CAR circuits. We identify alkaline phosphatase placental-like 2 (ALPPL2) as a tumor-specific antigen expressed in a spectrum of solid tumors, including mesothelioma and ovarian cancer. ALPPL2 can act as a sole target for CAR therapy or be combined with tumor-associated antigens such as melanoma cell adhesion molecule (MCAM), mesothelin, or human epidermal growth factor receptor 2 (HER2) in synNotch CAR combinatorial antigen circuits. SynNotch CAR T cells display superior control of tumor burden when compared to T cells constitutively expressing a CAR targeting the same antigens in mouse models of human mesothelioma and ovarian cancer. This was achieved by preventing CAR-mediated tonic signaling through synNotch-controlled expression, allowing T cells to maintain a long-lived memory and non-exhausted phenotype. Collectively, we establish ALPPL2 as a clinically viable cell therapy target for multiple solid tumors and demonstrate the multifaceted therapeutic benefits of synNotch CAR T cells.

show abstract

“…Recent work has demonstrated that transient rest in CAR expression potentiates T cell function by reversing premature exhaustion driven by CAR signaling in the absence of tumor antigen. 7 Consistent with this notion, both manuscripts argue that synNotchgated CAR expression maintains T cells in a less differentiated and exhausted state, resulting in enhanced anti-tumor immunity. However, it is worth noting that while constitutively expressed bispecific IL-13Ra2/EphA2 CAR-T and EGFRvIII CAR-T cells exhibit comparably high exhaustion marker expression, EGFRvIII CAR-T cells retain functionality in vivo whereas bispecific IL-13Ra2/EphA2 CAR-T cells are completely ineffective.…”

mentioning

confidence: 75%