Chimeric Antigen Receptor T Cell Therapy: A Comprehensive Review of Clinical Efficacy, Toxicity, and Best Practices for Outpatient Administration

Alexander, Mhairi E.; Culos, Kathryn A.; Roddy, Julianna; Shaw, J. Ryan; Bachmeier, Christina A.; Shigle, Terri Lynn; Mahmoudjafari, Zahra

doi:10.1016/j.jtct.2021.01.014

Cited by 46 publications

(39 citation statements)

References 44 publications

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“…In addition to Yescarta (axicabtagene ciloleucel) and Kymriah (tisagenlecleucel), two other CD19-targeted CAR T-cell therapies, namely, Tecartus (brexuscabtagene autoleucel) and Breyanzi (lisocatbagene maraleucel), were approved in 2020 and 2021, respectively. Finally, the first BCMA-targeted CAR T-cell therapy, Abecma (idecabtagene vicleucel), for relapsed/refractory multiple myeloma received approval in March 2021 ( 3 ).…”

Section: Introductionmentioning

confidence: 99%

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: Introductionmentioning

confidence: 99%

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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“…In recent years, immunotherapy represented by CAR-T gradually emerges as the fourth major tumor treatment mode after surgery, radiotherapy, and chemotherapy. 7 , 26 It has been widely used in clinical practice. However, the complex immunosuppressive microenvironment and physical obstacles in solid tumors, such as abnormal vasculature, increased matrix hardness, and higher tissue pressure, may impair T cell infiltration.…”

Section: Discussionmentioning

confidence: 99%

“… 5 , 6 Chimeric antigen receptor T cell (CAR-T) is a landmark achievement of tumor immunotherapy in recent years. 7 , 8 Chimeric antigen receptor (CAR) is an artificial receptor that mimics the function of a T cell receptor (TCR). It artificially integrates TCR binding signals, CD28 and CD137 co-stimulatory signals required for T cell activation into a single signal receptor composed of target recognition domains, hinge and transmembrane domains, and intracellular signal domains.…”

Section: Introductionmentioning

confidence: 99%

Oncolytic adenovirus-mediated expression of decorin facilitates CAIX-targeting CAR-T therapy against renal cell carcinoma

Zhang

Lin

Wang

et al. 2022

Molecular Therapy - Oncolytics

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Although chimeric antigen receptor T cell (CAR-T) therapy has been successful for hematological malignancies, it is less effective for solid tumors. The primary reason is that the immune microenvironment restricts CAR-T cells from infiltrating and proliferating in tumors. Oncolytic virotherapy has emerged as a novel immunogenic therapy to augment antitumor immune response. Here we combined an oncolytic adenovirus carrying decorin with a CAR-T targeting carbonic anhydrase IX (CAIX) to perform the antitumor activity for renal cancer cells. We found that OAV-Decorin combined with CAIX-CAR-T exhibited significantly reduced tumor burden, altered the composition of extracellular matrix (ECM) by inhibiting the distribution of collagen fibers, decreased the expression of TGF-β in tumor cells, enhanced IFN-γ secretion, and obtained higher numbers of CAR-T cells. The combination treatment modality showed prolonged mice survival. The intratumoral injection of OAV-Decorin into tumor-bearing immunocompetent mice activated the inflammatory immune status and resulted in tumor regression. These data supported further investigation of the combination of OAV-Decorin and CAIX-CAR-T cells in solid tumors.

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“…However, CAR T-cells can mediate severe adverse effects. Treated patients must be monitored closely for cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome [ 127 ]. ACT comprises cells that mediates cellular immunity, such as CD8 T cells, iNKT cells (invariant NK T cells), γδ T cells, cytokine-induced immune killer cells, and CAR-T cells.…”

Section: Other Immunotherapeutic Approaches Of Hccmentioning

confidence: 99%

Prospects and Challenges for T Cell-Based Therapies of HCC

Woller

Engelskircher

Wirth

et al. 2021

Cells

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The scope of therapeutic options for the treatment of hepatocellular carcinoma (HCC) has recently been expanded by immunotherapeutic regimens. T cell-based therapies, especially in combination with other treatments have achieved far better outcomes compared to conventional treatments alone. However, there is an emerging body of evidence that eliciting T cell responses in immunotherapeutic approaches is insufficient for favorable outcomes. Immune responses in HCC are frequently attenuated in the tumor microenvironment (TME) or may even support tumor progress. Hence, therapies with immune checkpoint inhibitors or adoptive cell therapies appear to necessitate additional modification of the TME to unlock their full potential. In this review, we focus on immunotherapeutic strategies, underlying molecular mechanisms of CD8 T cell immunity, and causes of treatment failure in HCC of viral and non-viral origin. Furthermore, we provide an overview of TME features in underlying etiologies of HCC patients that mediate therapy resistance to checkpoint inhibition and discuss strategies from the literature concerning current approaches to these challenges.

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Chimeric Antigen Receptor T Cell Therapy: A Comprehensive Review of Clinical Efficacy, Toxicity, and Best Practices for Outpatient Administration

Cited by 46 publications

References 44 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

Oncolytic adenovirus-mediated expression of decorin facilitates CAIX-targeting CAR-T therapy against renal cell carcinoma

Prospects and Challenges for T Cell-Based Therapies of HCC

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