4-1BB Costimulation Ameliorates T Cell Exhaustion Induced by Tonic Signaling of Chimeric Antigen Receptors

By Adrienne H. Long, Waleed Haso, J. Shern, Kelsey Wanhainen, Meera Murgai, María C. Ingaramo, Jillian P. Smith, A. Walker, M. Kohler, Vikas R Venkateshwara and 5 more. Nature Medicine, 2015

1,618 citations recorded by the source corpus.

Chimeric antigen receptors (CARs) targeting CD19 have mediated dramatic antitumor responses in hematologic malignancies, but tumor regression has rarely occurred using CARs targeting other antigens. It remains unknown whether the impressive effects of CD19 CARs relate to greater susceptibility of hematologic malignancies to CAR therapies, or superior functionality of the CD19 CAR itself. We show that tonic CAR CD3-ζ phosphorylation, triggered by antigen-independent clustering of CAR single-chain variable fragments, can induce early exhaustion of CAR T cells that limits antitumor efficacy. Such activation is present to varying degrees in all CARs studied, except the highly effective CD19 CAR. We further determine that CD28 costimulation augments, whereas 4-1BB costimulation reduces, exhaustion induced by persistent CAR signaling. Our results provide biological explanations for the antitumor effects of CD19 CARs and for the observations that CD19 CAR T cells incorporating the 4-1BB costimulatory domain are more persistent than those incorporating CD28 in clinical trials.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/b1cd570d9e4e2f4a1f9460d46de8af75a3257b47

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Citations in the corpus

• Immunological Synapse Predicts Effectiveness of Chimeric Antigen Receptor Cells (2018, background): “The role of 4-1BB co-stimulation in other CAR constructs, including CD20-CAR, CD30-CAR, EGFR-CAR, and GD2-CAR, has not been documented and may be either functionally beneficial or deleterious for certain CAR constructs.(59) No clinical direct comparisons between 4-1BB-CAR and CD28-CAR efficacy exist”
• A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma (2017, positive): “CAR T cells carrying the 4-1BB costimulation domain have been observed to have tonic signaling (42) and increased oxidative phosphorylation (43), which could facilitate the observed engraftment.”
• Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. (2016, background): “recently described CAR T cell exhaustion in a model of osteosarcoma (60) in that they describe an antigen-independent phenomenon that results from tonic signaling of aggregated CAR receptors.”
• CAR T cells targeting tumor-associated exons of glypican 2 regress neuroblastoma in mice (2021, methodology): “Incorporation of 4-1BB endodomain in a lentiviral vector could reduce this functional exhaustion.(25,26) Here, we examined tonic signaling from CT3 CAR T cells during ex vivo expansion.”
• Distinct Signaling of Coreceptors Regulates Specific Metabolism Pathways and Impacts Memory Development in CAR T Cells. (2016, background): “In addition, the incorporation of 4-1BB signaling domains in certain CARs ameliorates exhaustion (Long et al., 2015).”
• Global Manufacturing of CAR T Cell Therapy (2016, background): “It has been shown recently that the reduction of an exhausted T cell phenotype is associated with improved CAR T cell efficacy.(62) Therefore, the choice of CAR-signaling domains, selection of cell subsets, and adjustment of cell culture conditions to decrease the percentage of cells that become exh”
• CD22-CAR T Cells Induce Remissions in CD19-CAR Naïve and Resistant B-ALL (2017, positive): “BB.z) as previously described and as illustrated in Figure 1A. 19,35 All patients received the identical preparative regimen consisting of fludarabine 25 mg/m 2 /d on Days −4, −3, −2 and cyclophosphamide 900 mg/m 2 on day −2, with CD22-CAR T cell infusion on Day 0.”