Combined local therapy and CAR‐GPC3 T‐cell therapy in advanced hepatocellular carcinoma: a proof‐of‐concept treatment strategy

Shi, Yaoping; Shi, Daren; Chi, Jiachang; Cui, Dan; Tang, Xiaodong; Lin, Yingsong; Wang, Siying; Li, Zonghai; Jin, Haojie; Zhai, Bo

doi:10.1002/cac2.12472

Cited by 8 publications

(3 citation statements)

References 9 publications

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“…In addition to immune checkpoint blockade, chimeric antigen receptor-T (CAR-T) cell therapy has become another appealing immunotherapy modality, even though its use for disease treatment is only in the preclinical stage of testing. Glypican-3 (GPC3) is a well-characterized HCC-associated antigen that has been shown to be a promising target for HCC CAR-T therapy [117,118]. In preclinical studies, cancer vaccines based on tumor-associated antigens, such as alphafetoprotein (AFP), Glypican-3, multidrug resistance-associated protein 3 (MRP3), etc., have also shown some effects for use in HCC treatment [119].…”

Section: Implications Of Cd4 + T Cells In the Treatment Of Nash Nash-...mentioning

confidence: 99%

The Role of CD4+T Cells in Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

Miao,

Li,

Feng

et al. 2024

IJMS

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Hepatocellular carcinoma (HCC) has become the fourth leading cause of cancer-related deaths worldwide; annually, approximately 830,000 deaths related to liver cancer are diagnosed globally. Since early-stage HCC is clinically asymptomatic, traditional treatment modalities, including surgical ablation, are usually not applicable or result in recurrence. Immunotherapy, particularly immune checkpoint blockade (ICB), provides new hope for cancer therapy; however, immune evasion mechanisms counteract its efficiency. In addition to viral exposure and alcohol addiction, nonalcoholic steatohepatitis (NASH) has become a major cause of HCC. Owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance, NASH-associated HCC patients respond much less efficiently to ICB treatment than do patients with other etiologies. In addition, abnormal inflammation contributes to NASH progression and NASH–HCC transition, as well as to HCC immune evasion. Therefore, uncovering the detailed mechanism governing how NASH-associated immune cells contribute to NASH progression would benefit HCC prevention and improve HCC immunotherapy efficiency. In the following review, we focused our attention on summarizing the current knowledge of the role of CD4+T cells in NASH and HCC progression, and discuss potential therapeutic strategies involving the targeting of CD4+T cells for the treatment of NASH and HCC.

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Section: Implications Of Cd4 + T Cells In the Treatment Of Nash Nash-...mentioning

confidence: 99%

The Role of CD4+T Cells in Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

Miao,

Li,

Feng

et al. 2024

IJMS

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“…Current (CAR)-T cell therapy targets in solid tumors. Many of these targets are found in a vast variety of tumor types, but the listed include those that have been included in published studies [33,[42][43][44][45][46][47][48][49][50][51][52][53][54].…”

Section: Solid Tumorsmentioning

confidence: 99%

Current Advancements in Anti-Cancer Chimeric Antigen Receptor T Cell Immunotherapy and How Nanotechnology May Change the Game

Ku,

Tang,

Chen

et al. 2024

IJMS

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Chimeric antigen receptor (CAR)-T cell immunotherapy represents a cutting-edge advancement in the landscape of cancer treatment. This innovative therapy has shown exceptional promise in targeting and eradicating malignant tumors, specifically leukemias and lymphomas. However, despite its groundbreaking successes, (CAR)-T cell therapy is not without its challenges. These challenges, particularly pronounced in the treatment of solid tumors, include but are not limited to, the selection of appropriate tumor antigens, managing therapy-related toxicity, overcoming T-cell exhaustion, and addressing the substantial financial costs associated with treatment. Nanomedicine, an interdisciplinary field that merges nanotechnology with medical science, offers novel strategies that could potentially address these limitations. Its application in cancer treatment has already led to significant advancements, including improved specificity in drug targeting, advancements in cancer diagnostics, enhanced imaging techniques, and strategies for long-term cancer prevention. The integration of nanomedicine with (CAR)-T cell therapy could revolutionize the treatment landscape by enhancing the delivery of genes in (CAR)-T cell engineering, reducing systemic toxicity, and alleviating the immunosuppressive effects within the tumor microenvironment. This review aims to explore how far (CAR)-T cell immunotherapy has come alone, and how nanomedicine could strengthen it into the future. Additionally, the review will examine strategies to limit the off-target effects and systemic toxicity associated with (CAR)-T cell therapy, potentially enhancing patient tolerance and treatment outcomes.

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“…Even with combination therapy, the highest attainable objective response rate remains below 40% [ 9 ]. As for ACT, encompassing the utilization of transgenic tumor antigen specific TCR-T or CAR-T, it is noteworthy that, to date, clinical benefits have exclusively been observed in advanced HCC patients through the application of CAR-T cells engineered to target Glypican-3 (GPC3) [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Atovaquone enhances antitumor efficacy of TCR-T therapy by augmentation of ROS-induced ferroptosis in hepatocellular carcinoma

Chen,

Yu,

et al. 2024

Cancer Immunol Immunother

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T-cell receptor (TCR) engineered T-cell therapy has recently emerged as a promising adoptive immunotherapy approach for tumor treatment, yet hindered by tumor immune evasion resulting in poor therapeutic efficacy. The introduction of ferroptosis-targeted inducers offers a potential solution, as they empower T cells to induce ferroptosis and exert influence over the tumor microenvironment. Atovaquone (ATO) stands as a prospective pharmaceutical candidate with the potential to target ferroptosis, effectively provoking an excessive generation and accumulation of reactive oxygen species (ROS). In this study, we evaluated the effectiveness of a combination therapy comprising ATO and TCR-T cells against hepatocellular carcinoma (HCC), both in vitro and in vivo. The results of lactate dehydrogenase and cytokine assays demonstrated that ATO enhanced cytotoxicity mediated by AFP-specific TCR-T cells and promoted the release of IFN-γ in vitro. Additionally, in an established HCC xenograft mouse model, the combined therapy with low-dose ATO and TCR-T cells exhibited heightened efficacy in suppressing tumor growth, with no apparent adverse effects, comparable to the results achieved through monotherapy. The RNA-seq data unveiled a significant activation of the ferroptosis-related pathway in the combination therapy group in comparison to the TCR-T cells group. Mechanistically, the synergy between ATO and TCR-T cells augmented the release of IFN-γ by TCR-T cells, while concurrently elevating the intracellular and mitochondrial levels of ROS, expanding the labile iron pool, and impairing the integrity of the mitochondrial membrane in HepG2 cells. This multifaceted interaction culminated in the potentiation of ferroptosis within the tumor, primarily induced by an excess of ROS. In summary, the co-administration of ATO and TCR-T cells in HCC exhibited heightened vulnerability to ferroptosis. This heightened susceptibility led to the inhibition of tumor growth and the stimulation of an anti-tumor immune response. These findings suggest that repurposing atovaquone for adoptive cell therapy combination therapy holds the potential to enhance treatment outcomes in HCC.

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Combined local therapy and CAR‐GPC3 T‐cell therapy in advanced hepatocellular carcinoma: a proof‐of‐concept treatment strategy

Cited by 8 publications

References 9 publications

The Role of CD4+T Cells in Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

The Role of CD4+T Cells in Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

Current Advancements in Anti-Cancer Chimeric Antigen Receptor T Cell Immunotherapy and How Nanotechnology May Change the Game

Atovaquone enhances antitumor efficacy of TCR-T therapy by augmentation of ROS-induced ferroptosis in hepatocellular carcinoma

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