Gene modification strategies for next-generation CAR T cells against solid cancers

Tian, Yonggui; Li, Yilu; Shao, Yupei; Zhang, Yi

doi:10.1186/s13045-020-00890-6

Cited by 118 publications

(90 citation statements)

References 158 publications

(170 reference statements)

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“…Adoptive transfer therapy with chimeric antigen receptor T (CAR-T) cells has made great progresses in malignant diseases ( Minn et al, 2019 ; Tian et al, 2020 ). CAR-T cells targeting CD19, CD20, and CD22 have shown promises in treating hematological malignancies in clinical trials ( Grupp et al, 2013 ; Zhang et al, 2016 ; Fry et al, 2018 ; Li D. et al, 2019 ; Li Y. et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

Augmenting the Effectiveness of CAR-T Cells by Enhanced Self-Delivery of PD-1-Neutralizing scFv

Yü

Nan

et al. 2020

Front. Cell Dev. Biol.

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Chimeric antigen receptor T (CAR-T) cell therapy is not satisfying in solid tumors. PD-1-mediated suppression greatly hinders CART cells in the microenvironment. It has been shown that PD-1 blockade improves the effectiveness of CART cells. Herein, we designed CART cells than could secret α-PD-1 scFv by themselves. To obtain optimal secretions of scFv, we screened several signal peptides. And the segment from human increased the extracellular production of PD-1-neutralizing proteins. The secreted neutralizing scFv efficiently blocked PD-1 and enhanced T cell activation when PD-L1 was present. Further analysis showed that CART cells themselves could secret α-PD-1 scFv with bioactivity. In contrast to the prototype, the scFv-producing CART cells demonstrated decreased PD-1 but increases expansion and toxicity against solid tumor cells. In the subcutaneous and orthotopic xenograft models, the self-delivered α-PD-1 scFv increased CART cell functionalities and tumor-suppressions. Our work suggested that engineering T cells to co-express antigen-responsive receptors and checkpoint inhibitors is effective to optimize CART cell therapy for solid tumors.

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Section: Introductionmentioning

confidence: 99%

Augmenting the Effectiveness of CAR-T Cells by Enhanced Self-Delivery of PD-1-Neutralizing scFv

Yü

Nan

et al. 2020

Front. Cell Dev. Biol.

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“…Instead of decreasing T-cell inhibitory signals, another approach would be to trigger stimulatory receptors on T cells, which could be induced by administering agonistic antibodies for these receptors on T cells, such as CD28 and 4-1BB. This approach parallels the addition of a costimulatory intracellular signaling domain to improve efficacy for second generation CAR T cells [ 201 ]. The combination of CD3-BsAbs with costimulatory antibodies has been successfully used in many different tumor models in mice [ 202 , 203 ].…”

Section: Main Textmentioning

confidence: 99%

Overcoming Challenges for CD3-Bispecific Antibody Therapy in Solid Tumors

Middelburg

Kemper

Engelberts

et al. 2021

Cancers

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Immunotherapy of cancer with CD3-bispecific antibodies is an approved therapeutic option for some hematological malignancies and is under clinical investigation for solid cancers. However, the treatment of solid tumors faces more pronounced hurdles, such as increased on-target off-tumor toxicities, sparse T-cell infiltration and impaired T-cell quality due to the presence of an immunosuppressive tumor microenvironment, which affect the safety and limit efficacy of CD3-bispecific antibody therapy. In this review, we provide a brief status update of the CD3-bispecific antibody therapy field and identify intrinsic hurdles in solid cancers. Furthermore, we describe potential combinatorial approaches to overcome these challenges in order to generate selective and more effective responses.

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“…In addition, 4-1BB can ameliorate T cell exhaustion and prolong CAR-T cell survival [ 49 ]. Not only CD28 and 4-1BB but other costimulatory domains including OX40, CD27, and ICOS also regulate persistence and effector function of CAR-T cells [ 53 ]. Compared with CD28 domain, CAR-T cells harbored CD27 domain show elevated persistence in vivo while ICOS promotes Th17/Th1 cell differentiation [ 54 , 55 ].…”

Section: Development Of Car-t Cell Exhaustionmentioning

confidence: 99%

Chimeric Antigen Receptor T Cell Exhaustion during Treatment for Hematological Malignancies

Shen

Zhang

2020

BioMed Research International

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Immunotherapy, especially based on chimeric antigen receptor (CAR) T cells, has achieved prominent success in the treatment of hematological malignancies. However, approximately 30-50% of patients will have disease relapse following remission after receiving CD19-targeting CAR-T cells, with failure of maintaining a long-term effect. Mechanisms underlying CAR-T therapy inefficiency consist of loss or modulation of target antigen and CAR-T cell poor persistence which mostly results from T cell exhaustion. The unique features and restoration strategies of exhausted T cells (Tex) have been well described in solid tumors. However, the overview associated with CAR-T cell exhaustion is relatively rare in hematological malignancies. In this review, we summarize the characteristics, cellular, and molecular mechanisms of Tex cells as well as approaches to reverse CAR-T cell exhaustion in hematological malignancies, providing novel strategies for immunotherapies.

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Gene modification strategies for next-generation CAR T cells against solid cancers

Cited by 118 publications

References 158 publications

Augmenting the Effectiveness of CAR-T Cells by Enhanced Self-Delivery of PD-1-Neutralizing scFv

Augmenting the Effectiveness of CAR-T Cells by Enhanced Self-Delivery of PD-1-Neutralizing scFv

Overcoming Challenges for CD3-Bispecific Antibody Therapy in Solid Tumors

Chimeric Antigen Receptor T Cell Exhaustion during Treatment for Hematological Malignancies

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