Importance of T, NK, CAR T and CAR NK Cell Metabolic Fitness for Effective Anti-Cancer Therapy: A Continuous Learning Process Allowing the Optimization of T, NK and CAR-Based Anti-Cancer Therapies

Krug, Adrien; Martinez-Turtos, Adriana; Verhoeyen, Els

doi:10.3390/cancers14010183

Cited by 12 publications

(6 citation statements)

References 276 publications

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“… 42 Several studies have been devoted to improving the cytotoxicity and persistence of CAR-T cells and ACT products. 10 , 38 , 43 , 44 Genetic engineering and manipulation have been widely adopted to produce a superior T cell phenotype. For example, CD19 CAR-T cells with PD-1 integration showed a greater ability to eradicate tumor cells in xenograft models and clinical trials.…”

Section: Discussionmentioning

confidence: 99%

Ginsenoside Rg1 improves anti-tumor efficacy of adoptive cell therapy by enhancing T cell effector functions

Liu

Wang

et al. 2023

Blood Science

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Adoptive cell therapy (ACT) has emerged with remarkable efficacies for tumor immunotherapy. Chimeric antigen receptor (CAR) T cell therapy, as one of most promising ACTs, has achieved prominent effects in treating malignant hematological tumors. However, the insufficient killing activity and limited persistence of T cells in the immunosuppressive tumor microenvironment limit the further application of ACTs for cancer patients. Many studies have focused on improving cytotoxicity and persistence of T cells to achieve improved therapeutic effects. In this study, we explored the potential function in ACT of ginsenoside Rg1, the main pharmacologically active component of ginseng. We introduced Rg1 during the in vitro activation and expansion phase of T cells, and found that Rg1 treatment upregulated two T cell activation markers, CD69 and CD25, while promoting T cell differentiation towards a mature state. Transcriptome sequencing revealed that Rg1 influenced T cell metabolic reprogramming by strengthening mitochondrial biosynthesis. When co-cultured with tumor cells, Rg1-treated T cells showed stronger cytotoxicity than untreated cells. Moreover, adding Rg1 to the culture endowed CAR-T cells with enhanced anti-tumor efficacy. This study suggests that ginsenoside Rg1 provides a potential approach for improving the anti-tumor efficacy of ACT by enhancing T cell effector functions.

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Section: Discussionmentioning

confidence: 99%

Ginsenoside Rg1 improves anti-tumor efficacy of adoptive cell therapy by enhancing T cell effector functions

Liu

Wang

et al. 2023

Blood Science

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“…Combination therapies with multiple drugs apply two or more anti-cancer MOA with the purpose of decreasing the chance of developing resistance. Adoptive cell transfer (ACT) with immune effector cells, while directly killing cancer cells, expands the MOA by producing homeostatic cytokines and pro-inflammatory factors that in turn recruit and activate endogenous natural killer cells, - T cells, neutrophils and macrophages and other α–β T cells whose cytotoxic properties are directed against different targets on the surface of cancer cells [ 22 – 26 ]. Similarly, chemotherapeutics, pathway inhibitors or biologics that, beyond direct cancer cell killing, can redirect the MCN of the TME through the release by the dying cancer cells of proinflammatory signals, vicariously expand the original MOA and are, therefore, more likely to induce complete eradication of cancer and long-term remissions [ 2 , 3 , 5 , 6 , 27 – 29 ] (Fig.…”

Section: Direct (Primary) Versus Indirect (Secondary) Cancer Cell Kil...mentioning

confidence: 99%

Shifting the paradigm: engaging multicellular networks for cancer therapy

Hu,

Ascierto,

Cesano

et al. 2024

J Transl Med

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Most anti-cancer modalities are designed to directly kill cancer cells deploying mechanisms of action (MOAs) centered on the presence of a precise target on cancer cells. The efficacy of these approaches is limited because the rapidly evolving genetics of neoplasia swiftly circumvents the MOA generating therapy-resistant cancer cell clones. Other modalities engage endogenous anti-cancer mechanisms by activating the multi-cellular network (MCN) surrounding neoplastic cells in the tumor microenvironment (TME). These modalities hold a better chance of success because they activate numerous types of immune effector cells that deploy distinct cytotoxic MOAs. This in turn decreases the chance of developing treatment-resistance. Engagement of the MCN can be attained through activation of immune effector cells that in turn kill cancer cells or when direct cancer killing is complemented by the production of proinflammatory factors that secondarily recruit and activate immune effector cells. For instance, adoptive cell therapy (ACT) supplements cancer cell killing with the release of homeostatic and pro-inflammatory cytokines by the immune cells and damage associated molecular patterns (DAMPs) by dying cancer cells. The latter phenomenon, referred to as immunogenic cell death (ICD), results in an exponential escalation of anti-cancer MOAs at the tumor site. Other approaches can also induce exponential cancer killing by engaging the MCN of the TME through the release of DAMPs and additional pro-inflammatory factors by dying cancer cells. In this commentary, we will review the basic principles that support emerging paradigms likely to significantly improve the efficacy of anti-cancer therapy.

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“…Two strategies to metabolically improve T cell function in the TME are: i) by direct manipulation of cell metabolism during ex vivo expansion, or ii) genetically engineering T cells to better cope with the TME (89). As in the case of CAR-T cells, NK cells can also be metabolically optimized during expansion either through genetic alterations or by manipulating expansion conditions (90)(91)(92)(93).…”

Section: Fitnessmentioning

confidence: 99%

Advancements in CAR-NK therapy: lessons to be learned from CAR-T therapy

et al. 2023

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Advancements in chimeric antigen receptor engineered T-cell (CAR-T) therapy have revolutionized treatment for several cancer types over the past decade. Despite this success, obstacles including the high price tag, manufacturing complexity, and treatment-associated toxicities have limited the broad application of this therapy. Chimeric antigen receptor engineered natural killer cell (CAR-NK) therapy offers a potential opportunity for a simpler and more affordable “off-the-shelf” treatment, likely with fewer toxicities. Unlike CAR-T, CAR-NK therapies are still in early development, with few clinical trials yet reported. Given the challenges experienced through the development of CAR-T therapies, this review explores what lessons we can apply to build better CAR-NK therapies. In particular, we explore the importance of optimizing the immunochemical properties of the CAR construct, understanding factors leading to cell product persistence, enhancing trafficking of transferred cells to the tumor, ensuring the metabolic fitness of the transferred product, and strategies to avoid tumor escape through antigen loss. We also review trogocytosis, an important emerging challenge that likely equally applies to CAR-T and CAR-NK cells. Finally, we discuss how these limitations are already being addressed in CAR-NK therapies, and what future directions may be possible.

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Importance of T, NK, CAR T and CAR NK Cell Metabolic Fitness for Effective Anti-Cancer Therapy: A Continuous Learning Process Allowing the Optimization of T, NK and CAR-Based Anti-Cancer Therapies

Cited by 12 publications

References 276 publications

Ginsenoside Rg1 improves anti-tumor efficacy of adoptive cell therapy by enhancing T cell effector functions

Ginsenoside Rg1 improves anti-tumor efficacy of adoptive cell therapy by enhancing T cell effector functions

Shifting the paradigm: engaging multicellular networks for cancer therapy

Advancements in CAR-NK therapy: lessons to be learned from CAR-T therapy

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