Approaches to augment CAR T-cell therapy by targeting the apoptotic machinery

Karlsson, Hannah

doi:10.1042/bst20150253

Cited by 7 publications

(4 citation statements)

References 59 publications

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“…Nevertheless, considering the role of BCL-2 family members in B-cell lymphoma therapy ( 56 ), it is not surprising that combinations of CAR T-cell therapy with compounds targeting apoptosis regulators, like BH3 mimetics (e.g., ABT-737) or pan-BCL-2 inhibitors, are currently discussed for mature B-cell malignancies. Our results provide a rationale for extending this combinatorial approach to solid cancers in the future, especially if members of the BCL-2 family are dysregulated in the malignant cells ( 50 , 57 ).…”

Section: Discussionmentioning

confidence: 88%

Epigenetic Priming of Bladder Cancer Cells With Decitabine Increases Cytotoxicity of Human EGFR and CD44v6 CAR Engineered T-Cells

et al. 2021

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BackgroundTreatment of B-cell malignancies with CD19-directed chimeric antigen receptor (CAR) T-cells marked a new era in immunotherapy, which yet has to be successfully adopted to solid cancers. Epigenetic inhibitors of DNA methyltransferases (DNMTi) and histone deacetylases (HDACi) can induce broad changes in gene expression of malignant cells, thus making these inhibitors interesting combination partners for immunotherapeutic approaches.MethodsUrothelial carcinoma cell lines (UCC) and benign uroepithelial HBLAK cells pretreated with the DNMTi decitabine or the HDACi romidepsin were co-incubated with CAR T-cells directed against EGFR or CD44v6, and subsequent cytotoxicity assays were performed. Effects on T-cell cytotoxicity and surface antigen expression on UCC were determined by flow cytometry. We also performed next-generation mRNA sequencing of inhibitor-treated UCC and siRNA-mediated knockdown of potential regulators of CAR T-cell killing.ResultsExposure to decitabine but not romidepsin enhanced CAR T-cell cytotoxicity towards all UCC lines, but not towards the benign HBLAK cells. Increased killing could neither be attributed to enhanced target antigen expression (EGFR and CD44v6) nor fully explained by changes in the T-cell ligands PD-L1, PD-L2, ICAM-1, or CD95. Instead, gene expression analysis suggested that regulators of cell survival and apoptosis were differentially induced by the treatment. Decitabine altered the balance between survival and apoptosis factors towards an apoptosis-sensitive state associated with increased CAR T-cell killing, while romidepsin, at least partially, tilted this balance in the opposite direction. Knockdown experiments with siRNA in UCC confirmed BID and BCL2L1/BCLX as two key factors for the altered susceptibility of the UCC.ConclusionOur data suggest that the combination of decitabine with CAR T-cell therapy is an attractive novel therapeutic approach to enhance tumor-specific killing of bladder cancer. Since BID and BCL2L1 are essential determinants for the susceptibility of a wide variety of malignant cells, their targeting might be additionally suitable for combination with immunotherapies, e.g., CAR T-cells or checkpoint inhibitors in other malignancies.

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Section: Discussionmentioning

confidence: 88%

Epigenetic Priming of Bladder Cancer Cells With Decitabine Increases Cytotoxicity of Human EGFR and CD44v6 CAR Engineered T-Cells

et al. 2021

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“…2 and 3 . Finally, therapies including PD-1 checkpoint blockade, which can overcome the immune evasion of tumor cells from CAR-T cells within the tumor microenvironment, and the use of apoptosis inhibitor blockade agents, to increase the effect of CAR-T cell therapy, can significantly improve CAR-T cell effectiveness [ 58 , 61 , 95 , 96 ].…”

Section: Introductionmentioning

confidence: 99%

T cell senescence and CAR-T cell exhaustion in hematological malignancies

2018

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T cell senescence has been recognized to play an immunosuppressive role in the aging population and cancer patients. Strategies dedicated to preventing or reversing replicative and premature T cell senescence are required to increase the lifespan of human beings and to reduce the morbidity from cancer. In addition, overcoming the T cell terminal differentiation or senescence from lymphoma and leukemia patients is a promising approach to enhance the effectiveness of adoptive cellular immunotherapy (ACT). Chimeric antigen receptor T (CAR-T) cell and T cell receptor-engineered T (TCR-T) cell therapy highly rely on functionally active T cells. However, the mechanisms which drive T cell senescence remain unclear and controversial. In this review, we describe recent progress for restoration of T cell homeostasis from age-related senescence as well as recovery of T cell activation in hematological malignancies.

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“…Apoptosis has been a hot topic in recent years, which is of great significance in the occurrence and development of many diseases. Tumors usually upregulate anti-apoptotic proteins or silence pro-apoptotic proteins resulting in an imbalance of apoptosis [80,81]. CAR-T cells kill tumor cells via apoptosis induction.…”

Section: Apoptosis Regulatorsmentioning

confidence: 99%

Small-Molecule Compounds Boost CAR-T Cell Therapy in Hematological Malignancies

Cao

Jin

Zhang

et al. 2023

Curr. Treat. Options in Oncol.

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Opinion statementAlthough chimeric antigen receptor T cell immunotherapy has been successfully applied in patients with hematological malignancies, several obstacles still need to be overcome, such as high relapse rates and side effects. Overcoming the limitations of CAR-T cell therapy and boosting the efficacy of CAR-T cell therapy are urgent issues that must be addressed. The exploration of small-molecule compounds in combination with CAR-T cell therapies has achieved promising success in pre-clinical and clinical studies in recent years. Protein kinase inhibitors, demethylating drugs, HDAC inhibitors, PI3K inhibitors, immunomodulatory drugs, Akt inhibitors, mTOR inhibitors, and Bcl-2 inhibitors exhibited potential synergy in combination with CAR-T cell therapy. In this review, we will discuss the recent application of these combination therapies for improved outcomes of CAR-T cell therapy.

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Approaches to augment CAR T-cell therapy by targeting the apoptotic machinery

Cited by 7 publications

References 59 publications

Epigenetic Priming of Bladder Cancer Cells With Decitabine Increases Cytotoxicity of Human EGFR and CD44v6 CAR Engineered T-Cells

Epigenetic Priming of Bladder Cancer Cells With Decitabine Increases Cytotoxicity of Human EGFR and CD44v6 CAR Engineered T-Cells

T cell senescence and CAR-T cell exhaustion in hematological malignancies

Small-Molecule Compounds Boost CAR-T Cell Therapy in Hematological Malignancies

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