Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability

Guedan, Sonia; Madar, Aviv; Casado‐Medrano, Victoria; Shaw, Carolyn E.; Wing, Anna; Liu, Fang; Young, Regina M.; June, Carl H.; Posey, Avery D.

doi:10.1172/jci133215

Cited by 128 publications

(98 citation statements)

References 76 publications

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“…CD28 directly activates PI3K and Grb2 signaling through YMNM (14,15), which drives terminal T-cell differentiation to short-lived effectors (16,17). Previous work finds that mutation of YMNM to YMFM increases CAR T-cell persistence and antitumor durability in xenograft models (18). The PRRP motif can associate with ITK, which then signals through PLC and Erk, resulting in T-cell proliferation and IL2 production (19).…”

Section: Introductionmentioning

confidence: 99%

CD28 Costimulatory Domain–Targeted Mutations Enhance Chimeric Antigen Receptor T-cell Function

Boucher

Kotani

et al. 2021

Cancer Immunology Research

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An obstacle to the development of chimeric antigen receptor (CAR) T cells is the limited understanding of CAR T-cell biology and the mechanisms behind their antitumor activity. We and others have shown that CARs with a CD28 costimulatory domain drive high T-cell activation, which leads to exhaustion and shortened persistence. This work led us to hypothesize that by incorporating null mutations of CD28 subdomains (YMNM, PRRP, or PYAP), we could optimize CAR T-cell costimulation and enhance function. In vivo, we found that mice given CAR T cells with only a PYAP CD28 endodomain had a significant survival advantage, with 100% of mice alive after 62 days compared with 50% for mice with an unmutated endodomain. We observed that mutant CAR T cells remained more sensitive to antigen after ex vivo antigen and PD-L1 stimulation, as demonstrated by increased cytokine production. The mutant CAR T cells also had a reduction of exhaustion-related transcription factors and genes such as Nfatc1, Nr42a, and Pdcd1. Our results demonstrated that CAR T cells with a mutant CD28 endodomain have better survival and function. This work allows for the development of enhanced CAR T-cell therapies by optimizing CAR T-cell costimulation.

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Section: Introductionmentioning

confidence: 99%

CD28 Costimulatory Domain–Targeted Mutations Enhance Chimeric Antigen Receptor T-cell Function

Boucher

Kotani

et al. 2021

Cancer Immunology Research

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“…61 In addition, excessive CD28 costimulation has detrimental effects, 62 and mutations in the YMXM motif of CD28 that reduce its signaling activity improve T cell function. 63 In addition to CAR signaling after activation, baseline (aka tonic) signaling determines CAR T cell activity. 64,65 Recently, investigators have also focused on studying the immunological synapse that is formed between CAR T cells and target cells, and they have correlated synapse formation with CAR T cell effectiveness.…”

Section: Design Of Carsmentioning

confidence: 99%

CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?

et al. 2020

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“…Recently, Posey et al reported that a single asparagine (Asn) amino acid in the intracellular domain of CD28 is responsible for CD28-mediated exhaustion in CAR T cells. Substituting this Asn to phenylalanine hindered cell exhaustion and led to a durable antitumor response [100].…”

Section: Costimulation Induction and Cytokine Exposurementioning

confidence: 99%

“…Based on these findings, although induction of CD28 signaling will apparently restore the immunocompetence of senescent CAR T cells [101], it might drive the cells into states of exhaustion and dysfunction. Therefore, the mutant-type CD28 (with substituted Asn in the YMNM motif) costimulation in CAR T cells may result in more benefits [100].…”

Section: Costimulation Induction and Cytokine Exposurementioning

confidence: 99%

Counteracting CAR T cell dysfunction

et al. 2021

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In spite of high rates of complete remission following chimeric antigen receptor (CAR) T cell therapy, the efficacy of this approach is limited by generation of dysfunctional CAR T cells in vivo, conceivably induced by immunosuppressive tumor microenvironment (TME) and excessive antigen exposure. Exhaustion and senescence are two critical dysfunctional states that impose a pivotal hurdle for successful CAR T cell therapies. Recently, modified CAR T cells with an “exhaustion-resistant” phenotype have shown superior antitumor functions and prolonged lifespan. In addition, several studies have indicated the feasibility of senescence delay in CAR T cells. Here, we review the latest reports regarding blockade of CAR T cell exhaustion and senescence with a particular focus on the exhaustion-inducing pathways. Subsequently, we describe what potential these latest insights offer for boosting the potency of adoptive cell transfer (ACT) therapies involving CAR T cells. Furthermore, we discuss how induction of costimulation, cytokine exposure, and TME modulation can impact on CAR T cell efficacy and persistence, while potential safety issues associated with reinvigorated CAR T cells will also be addressed.

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Single residue in CD28-costimulated CAR-T cells limits long-term persistence and antitumor durability

Cited by 128 publications

References 76 publications

CD28 Costimulatory Domain–Targeted Mutations Enhance Chimeric Antigen Receptor T-cell Function

CD28 Costimulatory Domain–Targeted Mutations Enhance Chimeric Antigen Receptor T-cell Function

CAR T Cell Therapy for Solid Tumors: Bright Future or Dark Reality?

Counteracting CAR T cell dysfunction

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