Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells

Singh, Nathan; Frey, Noelle V.; Engels, Boris; Barrett, David M.; Shestova, Olga; Ravikumar, Pranali; Cummins, Katherine D.; Lee, Yong Gu; Pajarillo, Raymone; Chun, Inkook; Shyu, Amy; Highfill, Steven L.; Price, Andrew; Zhao, Linlin; Peng, Liaomin; Granda, Brian; Ramones, Melissa; Lu, Xueqing Maggie; Christian, David A.; Perazzelli, Jessica; Lacey, Simon F.; Roy, Nathan H.; Burkhardt, Janis K.; Colomb, Florent; Damra, Mohammad; Abdel‐Mohsen, Mohamed; Liu, Ting; Liu, Dongfang; Standley, Daron M.; Young, Regina M.; Brogdon, Jennifer L.; Grupp, Stephan A.; June, Carl H.; Maude, Shannon L.; Gill, Saar; Ruella, Marco

doi:10.1038/s41591-021-01326-5

Cited by 95 publications

(89 citation statements)

References 40 publications

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“…The mechanism of CAR T cell exhaustion remains poorly understood and may be affected by the donor properties, the scFv [ 49 , 50 ], the co-stimulatory domain [ 49 , 51 ] or other features. Murine models demonstrated a higher risk of CD8 CAR T cell exhaustion following TCR-mediated ligand binding of CD8 but not CD4 cells [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Molecular and Functional Signatures Associated with CAR T Cell Exhaustion and Impaired Clinical Response in Patients with B Cell Malignancies

Beider

Itzhaki

Schachter

et al. 2022

Cells

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Despite the high rates of complete remission following chimeric antigen receptor (CAR) T cell therapy, its full capacity is currently limited by the generation of dysfunctional CAR T cells. Senescent or exhausted CAR T cells possess poor targeting and effector functions, as well as impaired cell proliferation and persistence in vivo. Strategies to detect, prevent or reverse T cell exhaustion are therefore required in order to enhance the effectiveness of CAR T immunotherapy. Here we report that CD19 CAR T cells from non-responding patients with B cell malignancies show enrichment of CD8+ cells with exhausted/senescent phenotype and display a distinct transcriptional signature with dysregulation of genes associated with terminal exhaustion. Furthermore, CAR T cells from non-responding patients exhibit reduced proliferative capacity and decreased IL-2 production in vitro, indicating functional impairment. Overall, our work reveals potential mediators of resistance, paving the way to studies that will enhance the efficacy and durability of CAR T therapy in B cell malignancies.

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Section: Discussionmentioning

confidence: 99%

Molecular and Functional Signatures Associated with CAR T Cell Exhaustion and Impaired Clinical Response in Patients with B Cell Malignancies

Beider

Itzhaki

Schachter

et al. 2022

Cells

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“…Our model only considers the antigendependent CAR-T cell simulation. Antigen-independent CAR-T cell activation (55) and high levels of tonic signaling due to CAR aggregation (56,57) can also induce CAR-T cell exhaustion. This further obfuscates the balance between CAR-T cell activation and exhaustion.…”

Section: Discussionmentioning

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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“…As an example, replacement of the CD8 hinge-transmembrane region of a 4-1BBζ CAR with a CD28-hinge-transmembrane region lowered the threshold for CAR reactivity and enhanced the killing of CD19-low leukemic cells [ 36 ]. These approaches may be particularly beneficial in the context of CD22 and BCMA CAR T cells because patients often relapse with CD22dim [ 37 , 38 ] or BCMAdim [ 22 ] upon these immunotherapies whereas relapses upon CD19 CAR T cells mostly exhibit complete CD19 loss.…”

Section: Loss Of Target-agmentioning

confidence: 99%

Born to survive: how cancer cells resist CAR T cell therapy

2021

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Although chimeric antigen receptor T cells demonstrated remarkable efficacy in patients with chemo-resistant hematologic malignancies, a significant portion still resist or relapse. This immune evasion may be due to CAR T cells dysfunction, a hostile tumor microenvironment, or resistant cancer cells. Here, we review the intrinsic resistance mechanisms of cancer cells to CAR T cell therapy and potential strategies to circumvent them.

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Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells

Cited by 95 publications

References 40 publications

Molecular and Functional Signatures Associated with CAR T Cell Exhaustion and Impaired Clinical Response in Patients with B Cell Malignancies

Molecular and Functional Signatures Associated with CAR T Cell Exhaustion and Impaired Clinical Response in Patients with B Cell Malignancies

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

Born to survive: how cancer cells resist CAR T cell therapy

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