Optimization of metabolism to improve efficacy during CAR-T cell manufacturing

Zhang, Meng; Jin, Xin; Sun, Rui; Xiong, Xia; Wang, Jiaxi; Xie, Danni; Zhao, Mingfeng

doi:10.1186/s12967-021-03165-x

Cited by 50 publications

(41 citation statements)

References 114 publications

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“…Naïve T cells (T N ) and T SCM have the capacity to persist and proliferate long-term in cancer patients, leading to improved clinical outcome (45). Hence, enriching these cell types, especially CAR + T SCM cells, has become a central focus in the development of next-generation CAR-T therapy (28)(29)(30)(31). Our studies have demonstrated that almost all qCART™-generated CAR-T cell products contain >90% T N and T SCM (> 70% T SCM in most cases) in both CD4 CAR + and CD8 CAR + T cell populations, regardless of (1) CAR construct design, (2) GOI size, and…”

Section: Discussionmentioning

confidence: 99%

“…Another strategy for strengthening CAR-T efficacy is to enrich specific T cell subsets that possess superior capability to persist and attack cancer. Ever since Gattinoni et al described a class of immunological memory cells known as memory stem T cell (T SCM ) (27), several studies have demonstrated that T SCM is critical in facilitating successful adoptive T cell therapy (28)(29)(30)(31).…”

Section: Introductionmentioning

confidence: 99%

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Quantum CART(qCART), apiggyBac-basedsystem for development and production of virus-free multiplex CAR-T cell therapy

Chen¹,

Hua²,

Hsu³

et al. 2022

Preprint

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Chimeric antigen receptor T (CAR-T) cell therapy has the potential to transform cancer treatment. However, CAR-T therapy application is currently limited to certain types of relapse and refractory liquid tumors. To unlock the full potential of CAR-T therapy, technologic breakthroughs will be needed in multiple areas, including optimization of autologous CAR-T development, shortening the innovation cycle, and further manufacturing advancement of next-generation CAR-T therapies. Here, we established a simple and robust virus-free multiplex Quantum CART (qCART™) system that seamlessly and synergistically integrates four platforms: 1. GTailor™ for rapid identification of lead CAR construct design, 2. Quantum Nufect™ for effective but gentle electroporation-based gene delivery, 3. Quantum pBac™, featuring a virus-free transposon-based vector with large payload capacity and potentially safe integration profile, and 4. iCellar™ for robust and high-quality CAR+ T memory stem cell (TSCM) expansion. This robust, virus-free multiplex qCART™ system is expected to unleash the full potential of CAR-T therapy for treating diseases.Significance StatementChimeric antigen receptor T (CAR-T) cell therapy is currently ineffective against solid tumors. Here, we showcase Quantum CART (qCART™), a simple and robust system that seamlessly and synergistically integrates four platforms for optimal production of multiplex virus-free CAR-T cells: GTailor™ for rapid identification of lead CAR candidates; Quantum Nufect™ for effective but gentle electroporation-based gene delivery; Quantum pBac™, featuring a highly efficient, high payload capacity virus-free gene therapy vector and potentially safe integration profile; and iCellar™ for robust and high quality CAR-T cell expansion. We demonstrate that qCART™ is a simple and robust system for cost-effective and time-efficient manufacturing of T memory stem cell (TSCM) multiplex CAR-T cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Quantum CART(qCART), apiggyBac-basedsystem for development and production of virus-free multiplex CAR-T cell therapy

Chen¹,

Hua²,

Hsu³

et al. 2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Cancer cells deplete glucose in the TME, inhibiting the anticancer immunity of T cells, NK cells, macrophages, and DCs that use glucose for anti-cancer activity ( Renner et al, 2017 ; Xia et al, 2021 ). Mechanistically, glycolysis is necessary to regulate IFNγ production by T cells, and the restricted use of glucose in the TME limits Ca 2+ signaling, glycolysis, and cytokine production of TILs ( Rangel Rivera et al, 2021 ; Zhang et al, 2021 ). In fact, resistance to T cell therapy appears in cancer patients with overexpressed glycolysis enzymes.…”

Section: Cancer Metabolism and Immune Evasionmentioning

confidence: 99%

The Evasion Mechanisms of Cancer Immunity and Drug Intervention in the Tumor Microenvironment

Kim¹,

Cho

2022

Front. Pharmacol.

208

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Recently, in the field of cancer treatment, the paradigm has changed to immunotherapy that activates the immune system to induce cancer attacks. Among them, immune checkpoint inhibitors (ICI) are attracting attention as excellent and continuous clinical results. However, it shows not only limitations such as efficacy only in some patients or some indications, but also side-effects and resistance occur. Therefore, it is necessary to understand the factors of the tumor microenvironment (TME) that affect the efficacy of immunotherapy, that is, the mechanism by which cancer grows while evading or suppressing attacks from the immune system within the TME. Tumors can evade attacks from the immune system through various mechanisms such as restricting antigen recognition, inhibiting the immune system, and inducing T cell exhaustion. In addition, tumors inhibit or evade the immune system by accumulating specific metabolites and signal factors within the TME or limiting the nutrients available to immune cells. In order to overcome the limitations of immunotherapy and develop effective cancer treatments and therapeutic strategies, an approach is needed to understand the functions of cancer and immune cells in an integrated manner based on the TME. In this review, we will examine the effects of the TME on cancer cells and immune cells, especially how cancer cells evade the immune system, and examine anti-cancer strategies based on TME.

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“…This result strongly supports the idea that elevated mitochondrial FAO leads to increased antigen presentation and IFN signaling to facilitate T cell-mediated cancer cell death. Moreover, increased mitochondrial metabolism and FAO in T cells, improves T cell survival and functionality, enhancing sensitivity to anti-PD-1 therapy (Chowdhury et al, 2018;Zhang et al, 2021) in other cancer types. Interestingly, a similar induction of IFN signaling has been revealed using RNA-seq analysis in human melanoma cells and mouse B16 melanoma treated with specific inhibitors of the FA desaturase SCD1.…”

Section: Melanoma Metabolism a Tool To Boost Immunotherapymentioning

confidence: 99%

Connecting Metabolic Rewiring With Phenotype Switching in Melanoma

Falletta

Goding

Vivas-García

2022

Front. Cell Dev. Biol.

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Melanoma is a complex and aggressive cancer type that contains different cell subpopulations displaying distinct phenotypes within the same tumor. Metabolic reprogramming, a hallmark of cell transformation, is essential for melanoma cells to adopt different phenotypic states necessary for adaptation to changes arising from a dynamic milieu and oncogenic mutations. Increasing evidence demonstrates how melanoma cells can exhibit distinct metabolic profiles depending on their specific phenotype, allowing adaptation to hostile microenvironmental conditions, such as hypoxia or nutrient depletion. For instance, increased glucose consumption and lipid anabolism are associated with proliferation, while a dependency on exogenous fatty acids and an oxidative state are linked to invasion and metastatic dissemination. How these different metabolic dependencies are integrated with specific cell phenotypes is poorly understood and little is known about metabolic changes underpinning melanoma metastasis. Recent evidence suggests that metabolic rewiring engaging transitions to invasion and metastatic progression may be dependent on several factors, such as specific oncogenic programs or lineage-restricted mechanisms controlling cell metabolism, intra-tumor microenvironmental cues and anatomical location of metastasis. In this review we highlight how the main molecular events supporting melanoma metabolic rewiring and phenotype-switching are parallel and interconnected events that dictate tumor progression and metastatic dissemination through interplay with the tumor microenvironment.

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Optimization of metabolism to improve efficacy during CAR-T cell manufacturing

Cited by 50 publications

References 114 publications

Quantum CART(qCART), apiggyBac-basedsystem for development and production of virus-free multiplex CAR-T cell therapy

Quantum CART(qCART), apiggyBac-basedsystem for development and production of virus-free multiplex CAR-T cell therapy

The Evasion Mechanisms of Cancer Immunity and Drug Intervention in the Tumor Microenvironment

Connecting Metabolic Rewiring With Phenotype Switching in Melanoma

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