Precision medicine: In vivo CAR therapy as a showcase for receptor-targeted vector platforms

Michels, Alexander; Ho, Naphang; Buchholz, Christian J.

doi:10.1016/j.ymthe.2022.05.018

Cited by 42 publications

(28 citation statements)

References 115 publications

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“…The main approach involves using ex vivo genetically modified by viral vectors, T cells from patient’s blood. Viral transfection is the main way to transduce the CAR construct [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

“…Since CAR immunotherapy is an extremely costly and elaborate approach, the accessibility to this therapy remains limited [ 24 ]. Furthermore, the laborious leukapheresis needed to harvest autologous and healthy T cells that is associated with poor quality and limited quantity comes to add to the obstacles of the wide application of this therapy.…”

Section: Introductionmentioning

confidence: 99%

“…In addition, heterogeneous copy numbers can result in T cell populations with highly variable cytotoxic capabilities due to different expression levels of the CAR [ 3 ]. In vivo, and not ex vivo, CAR delivery has also been proposed; however, safety (short- and long-term) and efficacy remain challenging [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

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An Innovative PTD-IVT-mRNA Delivery Platform for CAR Immunotherapy of ErbB(+) Solid Tumor Neoplastic Cells

et al. 2022

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Chimeric antigen receptor (CAR) immunotherapy includes the genetic modification of immune cells to carry such a receptor and, thus, recognize cancer cell surface antigens. Viral transfection is currently the preferred method, but it carries the risk of off-target mutagenicity. Other transfection platforms have thus been proposed, such the in vitro transcribed (IVT)-mRNAs. In this study, we exploited our innovative, patented delivery platform to produce protein transduction domain (PTD)-IVT-mRNAs for the expression of CAR on NK-92 cells. CAR T1E-engineered NK-92 cells, harboring the sequence of T1E single-chain fragment variant (scFv) to recognize the ErbB receptor, bearing either CD28 or 4-1BB as co-stimulatory signaling domains, were prepared and assessed for their effectiveness in two different ErbB(+) cancer cell lines. Our results showed that the PTD-IVT-mRNA of CAR was safely transduced and expressed into NK-92 cells. CAR T1E-engineered NK-92 cells provoked high levels of cell death (25–33%) as effector cells against both HSC-3 (oral squamous carcinoma) and MCF-7 (breast metastatic adenocarcinoma) human cells in the co-incubation assays. In conclusion, the application of our novel PTD-IVT-mRNA delivery platform to NK-92 cells gave promising results towards future CAR immunotherapy approaches.

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“…The main approach involves using ex vivo genetically modified by viral vectors, T cells from patient’s blood. Viral transfection is the main way to transduce the CAR construct [ 24 ].…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

An Innovative PTD-IVT-mRNA Delivery Platform for CAR Immunotherapy of ErbB(+) Solid Tumor Neoplastic Cells

et al. 2022

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“…Individual immune cell subsets, including T cells and NK cells, are isolated, engineered to express a CAR and then injected into tumour-bearing immunodeficient mice 25 . In the past few years, technological developments have enabled the isolation of human immune cells (including T, NK and myeloid cells) from CD34 + HSPC-engrafted mice for transduction of CAR constructs [232][233][234] . Given that both CD4 + and CD8 + T cells are the dominant CD45 + subset in Hu-PBL mice, immunotherapies exploiting human T cells can be effectively tested in these models, although human CD4 + T reg cells are generally not abundant after PBMC engraftment 54 .…”

Section: Engraftment Strategy and Immune Cells Of Interestmentioning

confidence: 99%

Humanized mouse models for immuno-oncology research

et al. 2023

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Immunotherapy has emerged as a promising treatment paradigm for many malignancies and is transforming the drug development landscape. Although immunotherapeutic agents have demonstrated clinical efficacy, they are associated with variable clinical responses, and substantial gaps remain in our understanding of their mechanisms of action and specific biomarkers of response. Currently, the number of preclinical models that faithfully recapitulate interactions between the human immune system and tumours and enable evaluation of human-specific immunotherapies in vivo is limited. Humanized mice, a term that refers to immunodeficient mice co-engrafted with human tumours and immune components, provide several advantages for immuno-oncology research. In this Review, we discuss the benefits and challenges of the currently available humanized mice, including specific interactions between engrafted human tumours and immune components, the development and survival of human innate immune populations in these mice, and approaches to study mice engrafted with matched patient tumours and immune cells. We highlight the latest advances in the generation of humanized mouse models, with the aim of providing a guide for their application to immuno-oncology studies with potential for clinical translation.• Next-generation humanized mouse models are being generated to better recapitulate the development of human innate and adaptive immunity. The development and use of novel humanized mouse platforms will accelerate the discovery and testing of new immunotherapies for patients with cancer.Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

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“…Another challenge for patients is to receive the standard preconditioning chemotherapy, which depletes endogenous lymphocytes before the infusion of the ex vivo-expanded CAR T cells. To overcome the barriers of the current ex vivo CAR T cell therapy, intensive research efforts are in place to generate CAR T cells in vivo through direct injection of the gene vector (7)(8)(9). In vivo CAR T cell generation could make this treatment immediately accessible to patients.…”

Section: Introductionmentioning

confidence: 99%

In vivo CAR T cells and targeted gene delivery: A theme for the Pharmaceuticals and Medical Devices Agency Science Board to address

Wakao

Fukaya-Shiba

2023

Front. Med.

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Precision medicine: In vivo CAR therapy as a showcase for receptor-targeted vector platforms

Cited by 42 publications

References 115 publications

An Innovative PTD-IVT-mRNA Delivery Platform for CAR Immunotherapy of ErbB(+) Solid Tumor Neoplastic Cells

An Innovative PTD-IVT-mRNA Delivery Platform for CAR Immunotherapy of ErbB(+) Solid Tumor Neoplastic Cells

Humanized mouse models for immuno-oncology research

In vivo CAR T cells and targeted gene delivery: A theme for the Pharmaceuticals and Medical Devices Agency Science Board to address

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