Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape

Suzuki, Motoshi; Cao, Ke; Kato, Seiichi; Komizu, Yuji; Mizutani, Naoki; Tanaka, Kouji; Arima, Chinatsu; Tai, Mei Chee; Yanagisawa, Kiyoshi; Togawa, Norie; Shiraishi, Takahiro; Usami, Noriyasu; Taniguchi, Tetsuo; Fukui, Takayuki; Yokoi, Kohei; Wakahara, Keiko; Hasegawa, Yoshinori; Mizutani, Yukiko; Igarashi, Yasuyuki; Inokuchi, Jin-ichi; Iwaki, Soichiro; Fujii, Satoshi; Satou, Akira; Matsumoto, Yōko; Ueoka, Ryuichi; Tamiya‐Koizumi, Keiko; Murate, Takashi; Nakamura, Mitsuhiro; Kyogashima, Mamoru; Takahashi, Takashi

doi:10.1172/jci131246

Cited by 123 publications

(175 citation statements)

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“…In a separate trial, a patient with glioblastoma treated with an IL-13 receptor α 2 (IL13Rα 2)-specific CAR had recurrent tumour with decreased antigen expresssion 170 . These clinical data, alongside preclinical studies demonstrating the emergence of antigen loss variants, underscore the need for targeting multiple antigens 119,161,164,[171][172][173] .…”

Section: Nature Biomedical Engineeringmentioning

confidence: 96%

“…4c) 172 . Tandem bispecific CARs can be constructed by linking two scFv domains in series 174,175 ; these constructs may require optimization of the orientation of the heavy and light chains to achieve correct pairing and a favourable conformation for binding, and the linker length needed for targeting each antigen must be taken into consideration.…”

Section: Nature Biomedical Engineeringmentioning

confidence: 99%

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Programming CAR-T cells to kill cancer

2018

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T cells engineered to express chimeric antigen receptors (CARs) that are specific for tumour antigens have led to high complete response rates in patients with haematologic malignancies. Despite this early success, major challenges to the broad application of CAR-T cells as cancer therapies remain, including treatment-associated toxicities and cancer relapse with antigen-negative tumours. Targeting solid tumours with CAR-T cells poses additional obstacles because of the paucity of tumourspecific antigens and the immunosuppressive effects of the tumour microenvironment. To overcome these challenges, T cells can be programmed with genetic modules that increase their therapeutic potency and specificity. In this Review Article, we survey major advances in the engineering of next-generation CAR-T therapies for haematologic cancers and solid cancers, with particular emphasis on strategies for the control of CAR specificity and activity and on approaches for improving CAR-T-cell persistence and overcoming immunosuppression. We also lay out a roadmap for the development of off-the-shelf CAR-T cells.

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Section: Nature Biomedical Engineeringmentioning

confidence: 96%

Section: Nature Biomedical Engineeringmentioning

confidence: 99%

Programming CAR-T cells to kill cancer

2018

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“…Compared with unispecific CARs, tandem CARs showed enhanced anti-tumor effect in a murine gliobastoma model. Furthermore, bispecific targeting might reduce antigen escape mechanisms [53].…”

Section: Limiting Off-tumor Toxicitymentioning

confidence: 99%

Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: Clinical data to date, current limitations and perspectives

Gauthier

Yakoub-Agha

2017

Current Research in Translational Medicine

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“…88 Tandem CAR T cells designed to target both HER2 and IL13Ra2 from a single CAR molecule exhibited improved T-cell activity without increased T-cell exhaustion and had better tumor control in a mouse glioblastoma model, likely due to reduced antigen escape of tumor cells. 89 The feasibility of creating a CAR T-cell therapy, in which two entire CAR molecules are expressed in each CAR T cell, was recently demonstrated by transduction with two lentiviral constructs designed to express second-generation CARs containing a CD8 hinge, 4-1BB costimulatory domain, and a CD3f signaling domain via the elongation factor-1a (EF-1a) promoter. 21 Dual CART123/CART19 cells showed greater control of B-ALL than either CAR T-cell alone or a mixture of both CAR T-cell types.…”

Section: Vector Developments For Carsmentioning

confidence: 99%

Chimeric Antigen Receptor T Cells: Extending Translation from Liquid to Solid Tumors

Morgan

Schambach

2018

Human Gene Therapy

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Successful translation of chimeric antigen receptor (CAR) T cells designed to target and eradicate CD19+ lymphomas has emboldened scientists and physicians worldwide to explore the possibility of applying CAR T-cell technology to other tumor entities, including solid tumors. Next-generation strategies such as fourth-generation CARs (CAR T cells redirected for universal cytokine killing, also known as TRUCKs) designed to deliver immunomodulatory cytokines to the tumor microenvironment, dual CAR designs to improve tumor control, inclusion of suicide genes as safety switches, and precision genome editing are currently being investigated. One major ongoing goal is to determine how best to generate CAR T cells that modulate the tumor microenvironment, overcome tumor survival mechanisms, and thus allow broader applicability as universal allogeneic T-cell therapeutics. Development of state-of-the-art and beyond viral vector systems to deliver designer CARs coupled with targeted genome editing is expected to generate more effective off-the-shelf CAR T cells with activity against a greater number of cancer types and importantly solid tumors.

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Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape

Cited by 123 publications

References 1 publication

Programming CAR-T cells to kill cancer

Programming CAR-T cells to kill cancer

Chimeric antigen-receptor T-cell therapy for hematological malignancies and solid tumors: Clinical data to date, current limitations and perspectives

Chimeric Antigen Receptor T Cells: Extending Translation from Liquid to Solid Tumors

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