In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers

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Abstract

DNA-carrying nanoparticles can efficiently introduce leukaemia-targeting CAR genes into T cell nuclei, thereby inducing long-term disease remission.

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Most cited references 20

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Enhanced CAR T-cell engineering using non-viral Sleeping Beauty transposition from minicircle vectors

R Monjezi, C Miskey, T Gogishvili … (2017)

Immunotherapy with T cell modified with gamma-retroviral or lentiviral (LV) vectors to express a chimeric antigen receptor (CAR) has shown remarkable efficacy in clinical trials. However, the potential for insertional mutagenesis and genotoxicity of viral vectors is a safety concern, and their cost and regulatory demands a roadblock for rapid and broad clinical translation. Here, we demonstrate that CAR T cells can be engineered through non-viral Sleeping Beauty (SB) transposition of CAR genes from minimalistic DNA vectors called minicircles (MCs). We analyzed genomic distribution of SB and LV integrations and show that a significantly higher proportion of MC-derived CAR transposons compared with LV integrants had occurred outside of highly expressed and cancer-related genes into genomic safe harbor loci that are not expected to cause mutagenesis or genotoxicity. CD19-CAR T cells engineered with our enhanced SB approach conferred potent reactivity in vitro and eradicated lymphoma in a xenograft model in vivo. Intriguingly, electroporation of SB MCs is substantially more effective and less toxic compared with conventional plasmids, and enables cost-effective rapid preparation of therapeutic CAR T-cell doses. This approach sets a new standard in advanced cellular and gene therapy and will accelerate and increase the availability of CAR T-cell therapy to treat hematologic malignancies.

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Cell transfer immunotherapy for metastatic solid cancer--what clinicians need to know.

Steven Rosenberg (2011)

Cancer immunotherapy using the adoptive transfer of autologous tumor-infiltrating lymphocytes results in objective cancer regression in 49-72% of patients with metastatic melanoma. In a pilot trial combining cell transfer with a maximum lymphodepleting regimen, complete durable responses were seen in 40% of patients, with complete responses ongoing beyond 3 to 7 years. Current approaches to cell transfer therapy using autologous cells genetically engineered to express conventional or chimeric T-cell receptors have mediated cancer regression in patients with metastatic melanoma, synovial sarcoma, neuroblastoma and refractory lymphoma. Adoptive cell transfer immunotherapy is a rapidly developing new approach to the therapy of metastatic cancer in humans. This Review will emphasize the current available applications of cell transfer immunotherapy for patients with cancer.

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A novel chimeric antigen receptor against prostate stem cell antigen mediates tumor destruction in a humanized mouse model of pancreatic cancer.

Daniel Abate-Daga, Kiran Lagisetty, Eric Tran … (2014)

Despite advances in the understanding of its molecular pathophysiology, pancreatic cancer remains largely incurable, highlighting the need for novel therapies. We developed a chimeric antigen receptor (CAR) specific for prostate stem cell antigen (PSCA), a glycoprotein that is overexpressed in pancreatic cancer starting at early stages of malignant transformation. To optimize the CAR design, we used antigen-recognition domains derived from mouse or human antibodies, and intracellular signaling domains containing one or two T cell costimulatory elements, in addition to CD3zeta. Comparing multiple constructs established that the CAR based on human monoclonal antibody Ha1-4.117 had the greatest reactivity in vitro. To further analyze this CAR, we developed a human pancreatic cancer xenograft model and adoptively transferred CAR-engineered T cells into animals with established tumors. CAR-engineered human lymphocytes induced significant antitumor activity, and unlike what has been described for other CARs, a second-generation CAR (containing CD28 cosignaling domain) induced a more potent antitumor effect than a third-generation CAR (containing CD28 and 41BB cosignaling domains). While our results provide evidence to support PSCA as a target antigen for CAR-based immunotherapy of pancreatic cancer, the expression of PSCA on selected normal tissues could be a source of limiting toxicity.

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Author and article information

Journal

Title: Nature Nanotechnology

Abbreviated Title: Nature Nanotech

Publisher: Springer Nature

ISSN (Print): 1748-3387

ISSN (Electronic): 1748-3395

Publication date Created: April 17 2017

Publication date (Print): April 17 2017

Volume: 12

Issue: 8

Pages: 813-820

Article

DOI: 10.1038/nnano.2017.57

PMC ID: 5646367

PubMed ID: 28416815

SO-VID: 94fb012c-9ede-4023-97af-b88fd8b8fe82

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In situ programming of leukaemia-specific T cells using synthetic DNA nanocarriers

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Most cited references 20

Enhanced CAR T-cell engineering using non-viral Sleeping Beauty transposition from minicircle vectors

Cell transfer immunotherapy for metastatic solid cancer--what clinicians need to know.

A novel chimeric antigen receptor against prostate stem cell antigen mediates tumor destruction in a humanized mouse model of pancreatic cancer.

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