Construction of an anti‑programmed death‑ligand 1 chimeric antigen receptor and determination of its antitumor function with transduced cells

Xie, Jiasen; Zhou, Zishan; Jiao, Shunchang; Li, Xiaokun

doi:10.3892/ol.2018.8617

Cited by 9 publications

(9 citation statements)

References 72 publications

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“…A similar study also used MUC16-ecto targeting CARs secreting anti-PD-1 scFvs in syngeneic and xenograft mouse models of PD-L1 + metastatic ovarian cancers, and showed superiority over CAR T cells plus PD-1 checkpoint inhibitors (134). Along a similar line of thinking, an anti-PD-L1 CAR has shown in vitro cytotoxicity (135); it has yet to be seen whether these CARs might be successful in vivo , either alone or as adjuvant therapy. CAR T cells engineered to secrete PD-1, CTLA-4, or PD-L1 antibodies have gone to clinical trials for MUC1, EGFR, EGFRvIII, and mesothelin expressing cancers (136).…”

Section: Til Survival In the Tumor Microenvironmentmentioning

confidence: 99%

CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment

2019

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Chimeric antigen receptor (CAR) T cells, T cells that have been genetically engineered to express a receptor that recognizes a specific antigen, have given rise to breakthroughs in treating hematological malignancies. However, their success in treating solid tumors has been limited. The unique challenges posed to CAR T cell therapy by solid tumors can be described in three steps: finding, entering, and surviving in the tumor. The use of dual CAR designs that recognize multiple antigens at once and local administration of CAR T cells are both strategies that have been used to overcome the hurdle of localization to the tumor. Additionally, the immunosuppressive tumor microenvironment has implications for T cell function in terms of differentiation and exhaustion, and combining CARs with checkpoint blockade or depletion of other suppressive factors in the microenvironment has shown very promising results to mitigate the phenomenon of T cell exhaustion. Finally, identifying and overcoming mechanisms associated with dysfunction in CAR T cells is of vital importance to generating CAR T cells that can proliferate and successfully eliminate tumor cells. The structure and costimulatory domains chosen for the CAR may play an important role in the overall function of CAR T cells in the TME, and “armored” CARs that secrete cytokines and third- and fourth-generation CARs with multiple costimulatory domains offer ways to enhance CAR T cell function.

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Section: Til Survival In the Tumor Microenvironmentmentioning

confidence: 99%

CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment

2019

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“…The PD-L1/B7-H1 antigen is preferentially expressed in many different types of cancer cells but minimally expressed on normal tissues [ 16 ], indicating its potential as an ideal target for designing CAR-T cells to combat multiple solid tumors [ 18 – 20 ]. Therefore, we tested whether we can design a CAR or CCR incorporating a humanized scFv specific for PD-L1 that can be used for cell-based immunotherapy.…”

Section: Resultsmentioning

confidence: 99%

PD-L1 chimeric costimulatory receptor improves the efficacy of CAR-T cells for PD-L1-positive solid tumors and reduces toxicity in vivo

Liao

Mao

et al. 2020

Biomark Res

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Background On-target off-tumor toxicity impedes the clinical application of chimeric antigen receptor-modified T cells (CAR-T cells) in the treatment of solid tumors. Previous reports proved that the combinatorial antigen recognition strategy could improve the safety profile of CAR-T cells by targeting two different tumor-associated antigens (TAAs), one as a CAR-T targeted antigen and the other as a chimeric costimulatory receptor (CCR) ligand. The programmed death-ligand 1 (PD-L1, also known as B7-H1) is preferentially overexpressed on multiple tumors, it will be highly interesting to explore the potential of PD-L1 as a universal target for designing CCR. Methods A novel dual-targeted CAR, which is composed of first-generation CD19/HER2 CAR with CD3ζ signaling domain and PD-L1 CCR containing the CD28 costimulatory domain, was constructed and delivered into T cells by pseudotyped lentivirus. The cytokine release, cytotoxicity and proliferation of dual-targeted CAR-T cells were tested in vitro, and their safety and therapeutic efficacy were evaluated using a human tumor xenograft mouse model in vivo. Results The dual-targeted CAR-T cells exerted a similar cytotoxic activity against CD19/HER2+ tumor cells with or without PD-L1 in vitro, however, enhanced cytokine releases and improved proliferative capacity were only observed in the presence of both CD19/HER2 and PD-L1. Importantly, the dual-targeted CAR-T cells displayed no cytotoxicity against PD-L1+ cells alone in the absence of tumor antigen CD19/HER2. In addition, the dual-targeted CAR-T cells preferably destroyed tumor xenografts bearing both CD19/HER2 and PD-L1, but spared only antigen-positive tumor xenografts without PD-L1 in vivo. Furthermore, PD-L1 CCR also improved the antitumor efficacy of the low-affinity HER2 CAR-T cells against PD-L1+ tumors expressing high levels of HER2. Conclusion Our observations demonstrated that PD-L1 could be used as a universal target antigen for designing CCR, and the dual-targeted CAR-T cells equipped with PD-L1 CCR could be used to reduce the risk of on-target off-tumor toxicity while retaining their potent antitumor efficacy in the treatment of PD-L1+ solid tumors.

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“…Characterization of the PD-L1 scFv-based CAR and CCR in Jurkat T cells The PD-L1/B7-H1 antigen is preferentially expressed in many different types of cancer cells but minimally expressed on normal tissues [16], indicating its potential as an ideal target for designing CAR-T cells to combat multiple solid tumors [18][19][20]. Therefore, we tested whether we can design a CAR or CCR incorporating a humanized scFv speci c for PD-L1 that can be used for cell-based immunotherapy.…”

Section: Resultsmentioning

confidence: 99%

PD-L1 chimeric costimulatory receptor improves the efficacy of CAR-T cells for PD-L1-positive solid tumors and reduces toxicity in vivo

Liao

Mao

et al. 2020

Preprint

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Background: On-target off-tumor toxicity impedes the clinical application of chimeric antigen receptor-modified T cells (CAR-T cells) in the treatment of solid tumors. Previous reports proved that the combinatorial antigen recognition strategy could improve the safety profile of CAR-T cells by targeting two different tumor-associated antigens (TAAs), one as a CAR-T targeted antigen and the other as a chimeric costimulatory receptor (CCR) ligand. The programmed death-ligand 1 (PD-L1, also known as B7-H1) is preferentially overexpressed on multiple tumors, it will be highly interesting to explore the potential of PD-L1 as a universal target for designing CCR.Methods: A novel dual-targeted CAR, which is composed of first-generation CD19/HER2 CAR with CD3ζ signaling domain and PD-L1 CCR containing the CD28 costimulatory domain, was constructed and delivered into T cells by pseudotyped lentivirus. The cytokine release, cytotoxicity and proliferation of dual-targeted CAR-T cells were tested in vitro, and their safety and therapeutic efficacy were evaluated using a human tumor xenograft mouse model in vivo.Results: The dual-targeted CAR-T cells exerted a similar cytotoxic activity against CD19/HER2+ tumor cells with or without PD-L1 in vitro, however, enhanced cytokine releases and improved proliferative capacity were only observed in the presence of both CD19/HER2 and PD-L1. Importantly, the dual-targeted CAR-T cells displayed no cytotoxicity against PD-L1+ cells alone in the absence of tumor antigen CD19/HER2. In addition, the dual-targeted CAR-T cells preferably destroyed tumor xenografts bearing both CD19/HER2 and PD-L1, but spared only antigen-positive tumor xenografts without PD-L1 in vivo. Furthermore, PD-L1 CCR also improved the antitumor efficacy of the low-affinity HER2 CAR-T cells against PD-L1+ tumors expressing high levels of HER2.Conclusion: Our observations demonstrated that PD-L1 could be used as a universal target antigen for designing CCR, and the dual-targeted CAR-T cells equipped with PD-L1 CCR could be used to reduce the risk of on-target off-tumor toxicity while retaining their potent antitumor efficacy in the treatment of PD-L1+ solid tumors.

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Construction of an anti‑programmed death‑ligand 1 chimeric antigen receptor and determination of its antitumor function with transduced cells

Cited by 9 publications

References 72 publications

CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment

CAR T Cells for Solid Tumors: New Strategies for Finding, Infiltrating, and Surviving in the Tumor Microenvironment

PD-L1 chimeric costimulatory receptor improves the efficacy of CAR-T cells for PD-L1-positive solid tumors and reduces toxicity in vivo

PD-L1 chimeric costimulatory receptor improves the efficacy of CAR-T cells for PD-L1-positive solid tumors and reduces toxicity in vivo

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