Excessive Costimulation Leads to Dysfunction of Adoptively Transferred T Cells

Wijewarnasuriya, Dinali; Bebernitz, Christina; Lopez, Andrea V.; Rafiq, Sarwish; Brentjens, Renier J.

doi:10.1158/2326-6066.cir-19-0908

Cited by 22 publications

(21 citation statements)

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“…These data support previous work, which shows the quality of co-stimulatory signaling based on the positioning of the signaling domains, not the overall quantity of signaling, results in enhanced CAR T-cell persistence and efficacy (36). Another study also finds that balancing activation signals through optimizing CD28 co-stimulation results in CAR T cells with a more effective antitumor function (37). Together these results suggest a model of CAR co-stimulation in which some signaling pathways are critical and others expendable for enhanced function.…”

Section: Mut06 Has Reduced Exhaustion-related Gene Expression and Accsupporting

confidence: 87%

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: Mut06 Has Reduced Exhaustion-related Gene Expression and Accsupporting

confidence: 87%

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

Boucher

Kotani

et al. 2021

Cancer Immunology Research

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“…Resistance to CD19 CAR T-cell often develops in patients with high tumor burdens (48). Excess costimulation or CAR with very high target affinity does not always translate to better clinical outcomes (18,49). Consistent with this observation, increasing CAR affinity is known to promote T cell exhaustion and decrease the generation of memory-phenotype cells (50).…”

Section: Discussionmentioning

confidence: 99%

“…Down-regulation of tumor antigen can lead to resistance to CAR-T cell therapy (17). However, continuously challenging CAR-T cells with antigen often results in dampened CAR-T function (18). Reduced CAR-T cell function at high target cells and tumor antigen densities have been shown in cell lysis assays and the per-unit diminution of CAR-T cell lytic capacity is evident as target density approaches an upper boundary (Figure 1A) (19)(20)(21)(22)(23)(24).…”

Section: The Iffl Recapitulates Negative Regulatory Mechanisms Of Car-t Cell Functionmentioning

confidence: 99%

Speed and Location Both Matter: Antigen Stimulus Dynamics Controls CAR-T Cell Response

Liu

Milner

et al. 2021

Front. Immunol.

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Despite the success in B-cell malignancies, chimeric antigen receptor (CAR)-T cell therapies have not yet demonstrated consistent efficacy across all patients and tumor types, particularly against solid tumors. Higher rates of T cell exhaustion are associated with inferior clinical outcomes following CAR-T cell therapy, which is prevalent in solid tumors. T cell exhaustion may originate from persistent and chronic antigen stimulation by tumor cells that resist and/or evade T cell-mediated killing. We exploited CAR-T exhaustion with a classic negative feedback model (incoherent feedforward loop, IFFL) to investigate the balance between CAR-T cell activation and exhaustion under different antigen presentation dynamics. Built upon the experimental and clinical data, we hypothesize that the speed and anatomical location of antigenic stimulation are both crucial to CAR-T cell response. Chronic antigenic stimulation as well as the harsh tumor microenvironment present multiple barriers to CAR-T cell efficacy in solid tumors. Many therapeutic strategies are individually insufficient to improve of CAR-T responses against solid tumors, as they clear but one of the many barriers CAR-T cells face in solid tumors. A combination strategy targeting multiple barriers holds promise to improve CAR-T therapy in solid tumors.

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“…For example, CARs with two of three mutated immunoreceptor tyrosine-based activation motifs (ITAMs) in the CD3z chain endow CAR T cells with improved effector function. 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.…”

Section: Design Of Carsmentioning

confidence: 99%