Large-scale expansion of Vγ9Vδ2 T cells with engineered K562 feeder cells in G-Rex vessels and their use as chimeric antigen receptor–modified effector cells

Xiao, Lin; Chen, Can; Li, Zhendong; Zhu, Sumin; Tay, Johan Chin-Kang; Zhang, Xi; Zha, Shijun; Zeng, Jieming; Tan, Wee Kiat; Liu, Clementine Xin; Chng, Wee Joo; Wang, Shu

doi:10.1016/j.jcyt.2017.12.014

Cited by 49 publications

(60 citation statements)

References 48 publications

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“… 25 However, pulsing PBMCs with high concentrations (100 μM) of ZOL for four hours with subsequent washing steps was found to result in more efficient Vδ2 T cell expansion. 148 Moreover, the use of bisphosphonate prodrugs rather than ZOL 152 and the use of artificial APCs in addition to ZOL 153 were also found to enhance the proliferative expansion and functional activity of Vδ2 γδ T cells. It should be mentioned that cellular cross-talk can significantly modulate the efficacy of Vδ2 T cell expansion and overall antitumor activity.…”

Section: How To Improve the In Vitro Expansion And Effector Activity mentioning

confidence: 97%

Cancer immunotherapy with γδ T cells: many paths ahead of us

et al. 2020

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γδ T cells play uniquely important roles in stress surveillance and immunity for infections and carcinogenesis. Human γδ T cells recognize and kill transformed cells independently of human leukocyte antigen (HLA) restriction, which is an essential feature of conventional αβ T cells. Vγ9Vδ2 γδ T cells, which prevail in the peripheral blood of healthy adults, are activated by microbial or endogenous tumor-derived pyrophosphates by a mechanism dependent on butyrophilin molecules. γδ T cells expressing other T cell receptor variable genes, notably Vδ1, are more abundant in mucosal tissue. In addition to the T cell receptor, γδ T cells usually express activating natural killer (NK) receptors, such as NKp30, NKp44, or NKG2D which binds to stress-inducible surface molecules that are absent on healthy cells but are frequently expressed on malignant cells. Therefore, γδ T cells are endowed with at least two independent recognition systems to sense tumor cells and to initiate anticancer effector mechanisms, including cytokine production and cytotoxicity. In view of their HLA-independent potent antitumor activity, there has been increasing interest in translating the unique potential of γδ T cells into innovative cellular cancer immunotherapies. Here, we discuss recent developments to enhance the efficacy of γδ T cell-based immunotherapy. This includes strategies for in vivo activation and tumor-targeting of γδ T cells, the optimization of in vitro expansion protocols, and the development of gene-modified γδ T cells. It is equally important to consider potential synergisms with other therapeutic strategies, notably checkpoint inhibitors, chemotherapy, or the (local) activation of innate immunity.

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Section: How To Improve the In Vitro Expansion And Effector Activity mentioning

confidence: 97%

Cancer immunotherapy with γδ T cells: many paths ahead of us

et al. 2020

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“…Costimulation domain-CAR γδ-T cells have been considered a safer therapy because the CAR follows only one pathway to stimulate the immune response, and the cytotoxicity was limited to the reaction induced by the IPP antigen [121,122]. Furthermore, a large expansion platform has been successfully established, which has the potential to make γδ-T cells an off-the-shelf product and a possible source of U-CAR-T cell therapy [123]. Another method to generate cells that avoid the host immune system is gene editing.…”

Section: The Sources Of T Cellsmentioning

confidence: 99%

Recent advances in CAR-T cell engineering

et al. 2020

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Chimeric antigen receptor T (CAR-T) cell therapy is regarded as an effective solution for relapsed or refractory tumors, particularly for hematological malignancies. Although the initially approved anti-CD19 CART therapy has produced impressive outcomes, setbacks such as high relapse rates and resistance were experienced, driving the need to discover engineered CART cells that are more effective for therapeutic use. Innovations in the structure and manufacturing of CART cells have resulted in significant improvements in efficacy and persistence, particularly with the development of fourth-generation CART cells. Paired with an immune modifier, the use of fourthgeneration and next-generation CART cells will not be limited because of cytotoxic effects and will be an efficient tool for overcoming the tumor microenvironment. In this review, we summarize the recent transformations in the ectodomain, transmembrane domain, and endodomain of the CAR structure, which, together with innovative manufacturing technology and improved cell sources, improve the prospects for the future development of CART cell therapy.

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“…17,33 In addition, the feeder cell-based expansion method for Vγ9Vδ2 T cells has also been investigated. 34 Moreover, gene modification-related technologies have been used to generate potent γδ T cells, including T-cell receptor (TCR) transfer or chimeric antigen receptor (CAR) expression. 14,35,36 Previously, our investigation on γδ T-cell expansion discovered that vitamin C could greatly promote the proliferation and effector functions of Vγ9Vδ2 T cells.…”

Section: Introductionmentioning

confidence: 99%

Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer

et al. 2020

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Vγ9Vδ2 T cells are promising candidates for cellular tumor immunotherapy. Due to their HLA-independent mode of action, allogeneic Vγ9Vδ2 T cells can be considered for clinical application. To apply allogeneic Vγ9Vδ2 T cells in adoptive immunotherapy, the methodology used to obtain adequate cell numbers with optimal effector function in vitro needs to be optimized, and clinical safety and efficacy also need to be proven. Therefore, we developed a novel formula to improve the expansion of peripheral γδ T cells from healthy donors. Then, we used a humanized mouse model to validate the therapeutic efficacy of expanded γδ T cells in vivo; furthermore, the expanded γδ T cells were adoptively transferred into late-stage liver and lung cancer patients. We found that the expanded cells possessed significantly improved immune effector functions, including proliferation, differentiation, and cancer cell killing, both in vitro and in the humanized mouse model. Furthermore, a phase I clinical trial in 132 late-stage cancer patients with a total of 414 cell infusions unequivocally validated the clinical safety of allogeneic Vγ9Vδ2 T cells. Among these 132 patients, 8 liver cancer patients and 10 lung cancer patients who received ≥5 cell infusions showed greatly prolonged survival, which preliminarily verified the efficacy of allogeneic Vγ9Vδ2 T-cell therapy. Our clinical studies underscore the safety and efficacy of allogeneic Vγ9Vδ2 T-cell immunotherapy, which will inspire further clinical investigations and eventually benefit cancer patients.

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Large-scale expansion of Vγ9Vδ2 T cells with engineered K562 feeder cells in G-Rex vessels and their use as chimeric antigen receptor–modified effector cells

Cited by 49 publications

References 48 publications

Cancer immunotherapy with γδ T cells: many paths ahead of us

Cancer immunotherapy with γδ T cells: many paths ahead of us

Recent advances in CAR-T cell engineering

Allogeneic Vγ9Vδ2 T-cell immunotherapy exhibits promising clinical safety and prolongs the survival of patients with late-stage lung or liver cancer

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