Patient-derived glioblastoma stem cells are killed by CD133-specific CAR T cells but induce the T cell aging marker CD57

Zhu, Xuekai; Prasad, Shruthi; Gaedicke, Simone; Hettich, Michael; Firat, Elke; Niedermann, Gabriele

doi:10.18632/oncotarget.2767

Cited by 143 publications

(126 citation statements)

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“…28 In this study, simple models were used, including co-culture of CAR T cells with tumor cells in vitro and treatment of tumor-bearing immunodeficient mice with human CAR T cells, as used before. 14,20,29 Although a CD133 highly expressed U251 cell line cannot be a very suitable model to represent the patient situation, it was used to judge the CAR T cells' capability of killing tumors on a quantified level. Furthermore, though the tumor cells used expressed high levels of PD-L1, it is not clear whether the PD-1/ PD-L1 pathway is the main negative regulator of CAR T cells in the models.…”

mentioning

confidence: 99%

Nucleofection with Plasmid DNA for CRISPR/Cas9-Mediated Inactivation of Programmed Cell Death Protein 1 in CD133-Specific CAR T Cells

et al. 2019

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CRISPR/Cas9-mediated programmed cell death protein 1 (PD-1) disruption in chimeric antigen receptor (CAR) T cells could be an appealing choice to improve the therapeutic efficacy of CAR T cells in an immunosuppressive tumor microenvironment. In most of the reported cases, Cas9 was delivered into T cells by way of electroporation with RNA or protein. However, transient expression of Cas9 by transfection with a plasmid encoding its gene is apparently simpler, as it avoids the steps of in vitro transcription of DNA or protein production. This study tried nucleofection into human primary T cells of plasmids encoding both CRISPR/Cas9 for disrupting the PD-1 gene and the piggyBac transposon system for expressing CD133-specific CAR in one reaction. Based on drug selection, CD133-specific CAR T cells were obtained in which, on average, 91.5% of the PD-1 gene sites were disrupted, but almost no Cas9 gene expression was found in the final engineered CAR T cells. The PD-1-deficient CD133-specific CAR T cells showed similar levels of cytokine secretion and improved proliferation and cytotoxicity in vitro, and enhanced inhibition of tumor growth in an orthotopic mouse model of glioma, compared to conventional CD133-CAR T cells. The described method could be useful for the production of PD-1-deficient CAR T cells for cancer immunotherapy.

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confidence: 99%

Nucleofection with Plasmid DNA for CRISPR/Cas9-Mediated Inactivation of Programmed Cell Death Protein 1 in CD133-Specific CAR T Cells

et al. 2019

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“…It is inserted between the binding domain and the transmembrane (TM) domain and is important for CAR expression on the cell surface [66]. The hinge region is usually derived from CD8, IgG1, or IgG4 molecules [30,[67][68][69][70]. It mediates flexibility of the scFV, and its length may influence the quality of the interaction between scFV and antigen, depending on the location of the epitope on the target antigen.…”

Section: Car Hinge and Transmembranementioning

confidence: 99%

“…The TM domain is usually derived from CD3ζ [74], CD4 [75,76], CD8 [47,60,68], or CD28 [70,75,77] molecules and is inserted between the hinge region and the signaling endodomains. It has significant effects on the cell surface expression of CARs.…”

Section: Car Hinge and Transmembranementioning

confidence: 99%

CARTs for Solid Tumors: Feasible or Infeasible?

Song²,

Jin

et al. 2017

Oncol Res Treat

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Adoptive transfer of chimeric antigen receptor-engineered T cells (CARTs) is a novel approach to cancer therapy as CARTs combine with the antigen specificity of an antibody and the activating functions of T lymphocytes. Recent results from preclinical and clinical trials with CARTs for B-cell malignancies are exciting, although different groups selected different tumor-associated antigens, binding domains, and signal domains, which make up the chimeric antigen receptor (CAR) configuration. However, there are few clinical trials with CARTs for solid tumors compared to hematologic malignancies. In this brief review, we discuss the basic principles of CAR design and clinical studies of CARTs for solid tumors.

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“…CAR T cells are capable to eliminate those CSCs in experimental models including melanoma; one trial is going to explore the clinical efficacy [36][37][38][39][40].…”

Section: Car Targetable Antigens: Neo-antigen Tumor-associated Antigmentioning

confidence: 99%

CARs on the Highway: Chimeric Antigen Receptor Modified T Cells for the Adoptive Cell Therapy of Malignant Diseases

Holzinger¹,

Abken²

2017

Immunotherapy - Myths, Reality, Ideas, Future

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Adoptive therapy of malignant diseases by chimeric antigen receptor (CAR) redirected T cells takes advantage of the patient's own immune system to recognize and destroy cancer cells. This is impressively demonstrated by the induction of complete and lasting remissions of leukemia with CAR-engineered T cells in early phase trials. Recent developments in optimizing the CAR design, in the recognition of target cells and the production of modified cells for clinical use, have paved the path for a broader application than currently explored. The chapter reviews the differences in CAR design, the success in the treatment of hematologic malignancies, the challenges in treating solid cancer, the treatment-related toxicities, and strategies to improve safety of CAR T cell therapy. Challenges for future applications are discussed.

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Patient-derived glioblastoma stem cells are killed by CD133-specific CAR T cells but induce the T cell aging marker CD57

Cited by 143 publications

References 50 publications

Nucleofection with Plasmid DNA for CRISPR/Cas9-Mediated Inactivation of Programmed Cell Death Protein 1 in CD133-Specific CAR T Cells

Nucleofection with Plasmid DNA for CRISPR/Cas9-Mediated Inactivation of Programmed Cell Death Protein 1 in CD133-Specific CAR T Cells

CARTs for Solid Tumors: Feasible or Infeasible?

CARs on the Highway: Chimeric Antigen Receptor Modified T Cells for the Adoptive Cell Therapy of Malignant Diseases

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