Chimeric antigen receptor T cells are vulnerable to immunosuppressive mechanisms present within the tumor microenvironment

Beatty, Gregory L.; Moon, Edmund K.

doi:10.4161/21624011.2014.970027

Cited by 68 publications

(50 citation statements)

References 6 publications

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“…The potential to achieve transient CAR expression in T cells through transfection of mRNA has been demonstrated and results in CAR surface expression for up to several days which can be sufficient to induce an anti-tumor effect, especially when high doses of CAR T cells are administered (Beatty & Moon, 2014;Caruso et al, 2016). However, because of the rapid decline in CAR expression, multiple subsequent administrations are required to sustain the therapeutic effect.…”

Section: Viral Gene Transfer Vectors Dominate Pre-clinical and Clinicmentioning

confidence: 97%

Going non-viral: theSleeping Beautytransposon system breaks on through to the clinical side

Hudecek

Izsvák

Johnen

et al. 2017

Critical Reviews in Biochemistry and Molecular Biology

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Molecular medicine has entered a high-tech age that provides curative treatments of complex genetic diseases through genetically engineered cellular medicinal products. Their clinical implementation requires the ability to stably integrate genetic information through gene transfer vectors in a safe, effective and economically viable manner. The latest generation of Sleeping Beauty (SB) transposon vectors fulfills these requirements, and may overcome limitations associated with viral gene transfer vectors and transient non-viral gene delivery approaches that are prevalent in ongoing pre-clinical and translational research. The SB system enables high-level stable gene transfer and sustained transgene expression in multiple primary human somatic cell types, thereby representing a highly attractive gene transfer strategy for clinical use. Here we review several recent refinements of the system, including the development of optimized transposons and hyperactive SB variants, the vectorization of transposase and transposon as mRNA and DNA minicircles (MCs) to enhance performance and facilitate vector production, as well as a detailed understanding of SB's genomic integration and biosafety features. This review also provides a perspective on the regulatory framework for clinical trials of gene delivery with SB, and illustrates the path to successful clinical implementation by using, as examples, gene therapy for age-related macular degeneration (AMD) and the engineering of chimeric antigen receptor (CAR)-modified T cells in cancer immunotherapy.

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Section: Viral Gene Transfer Vectors Dominate Pre-clinical and Clinicmentioning

confidence: 97%

Going non-viral: theSleeping Beautytransposon system breaks on through to the clinical side

Hudecek

Izsvák

Johnen

et al. 2017

Critical Reviews in Biochemistry and Molecular Biology

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“…In recent years, CD19-targeted CAR T-cell therapy has yielded spectacular clinical responses against hematologic liquid tumors (44), including up to 90% complete response in relapsed or treatment-refractory acute lymphoblastic leukemia (ALL) patients (45). In the solid TME, however, T-cells face a battery of physical and immunometabolic barriers (46, 47), to which CAR T-cells, like endogenous T-cells, are vulnerable (48, 49). CAR T-cells may thus similarly require combinatorial regimens of immunomodulation such as kinase inhibitors (50), chemotherapy (51), radiotherapy (RT) (52), or checkpoint blockade (53), to unleash their full therapeutic potential (54–56).…”

Section: Natural Tumor Immunity and Response To Immunotherapymentioning

confidence: 99%

Engineering Chimeric Antigen Receptor T-Cells for Racing in Solid Tumors: Don’t Forget the Fuel

et al. 2017

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T-cells play a critical role in tumor immunity. Indeed, the presence of tumor-infiltrating lymphocytes is a predictor of favorable patient prognosis for many indications and is a requirement for responsiveness to immune checkpoint blockade therapy targeting programmed cell death 1. For tumors lacking immune infiltrate, or for which antigen processing and/or presentation has been downregulated, a promising immunotherapeutic approach is chimeric antigen receptor (CAR) T-cell therapy. CARs are hybrid receptors that link the tumor antigen specificity and affinity of an antibody-derived single-chain variable fragment with signaling endodomains associated with T-cell activation. CAR therapy targeting CD19 has yielded extraordinary clinical responses against some hematological tumors. Solid tumors, however, remain an important challenge to CAR T-cells due to issues of homing, tumor vasculature and stromal barriers, and a range of obstacles in the tumor bed. Protumoral immune infiltrate including T regulatory cells and myeloid-derived suppressor cells have been well characterized for their ability to upregulate inhibitory receptors and molecules that hinder effector T-cells. A critical role for metabolic barriers in the tumor microenvironment (TME) is emerging. High glucose consumption and competition for key amino acids by tumor cells can leave T-cells with insufficient energy and biosynthetic precursors to support activities such as cytokine secretion and lead to a phenotypic state of anergy or exhaustion. CAR T-cell expansion protocols that promote a less differentiated phenotype, combined with optimal receptor design and coengineering strategies, along with immunomodulatory therapies that also promote endogenous immunity, offer great promise in surmounting immunometabolic barriers in the TME and curing solid tumors.

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“…This is achieved through a variety of mechanisms including cell-cell signaling and release of soluble cytokines. Importantly, like the endogenous immune system, adoptively transferred T cells are also susceptible to tumor-mediated immunosuppression 144 . Further, chronic T cell activation induces upregulation of inhibitory ligands on the activated cells 145 .…”

Section: Building Smarter Redirected T Cellsmentioning

confidence: 99%

Engineered T cells: the promise and challenges of cancer immunotherapy

2016

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Chimeric antigen receptor T cells are vulnerable to immunosuppressive mechanisms present within the tumor microenvironment

Cited by 68 publications

References 6 publications

Going non-viral: theSleeping Beautytransposon system breaks on through to the clinical side

Going non-viral: theSleeping Beautytransposon system breaks on through to the clinical side

Engineering Chimeric Antigen Receptor T-Cells for Racing in Solid Tumors: Don’t Forget the Fuel

Engineered T cells: the promise and challenges of cancer immunotherapy

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