Minicircle DNA-Engineered CAR T Cells Suppressed Tumor Growth in Mice

Han, Jinsheng; Gao, Fei; Geng, Songsong; Ye, Xueshuai; Wang, Tie; Du, Pingping; Cai, Ziqi; Fu, Zexian; Zhao, Zhihui; Shi, Long; Li, Qingxia; Cai, Jianhui

doi:10.1158/1535-7163.mct-19-0204

Cited by 13 publications

(8 citation statements)

References 25 publications

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“…CAR T cell therapy has been nominated by the American Society of Clinical Oncology as the most important advancement in cancer research [8], and its therapeutic e cacy has been proven effective in solid tumors [9,10]. We demonstrated that the 3rdgeneration CAR T cells produced by our platform, including PSCA-CAR T cells against prostate cancer and NKG2D-CAR T cells against colorectal cancer, possess signi cant antitumor capacity both in vitro and in vivo [11,12]. CAR T cells have three components: 1) an extracellular single-chain variable fragment (scFv), which can speci cally bind tumor-associated antigens (TAAs) through human leukocyte antigen (HLA)-independent recognition; 2) a hinge domain and transmembrane fragment from human CD8α; and 3) at least one intracellular costimulatory domain such as that from human CD28, CD137 or CD3ζ to promote cell proliferation and the release of cytokines and cytotoxic granules after activation by targeted tumor signals.…”

Section: Introductionmentioning

confidence: 90%

Nonviral mcDNA-Mediated Cospecific CAR T Cells For The Treatment of Human Hepatocellular Carcinoma Xenograft in Mice

Wang

et al. 2021

Preprint

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Background: Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and the adoptive immunotherapy of which is worth studying. CD133, a kind of cancer stem cell (CSC) antigen, together with glypican-3 (GPC3) have been proved to be highly expressed in HCC cells and both of them are used as targets to generate chimeric antigen receptor (CAR) T cells. But there are limitations like “on-target, off-tumor” toxicity, low transfection efficacy and weak antitumor ability in CAR T cells treatment.Methods: First we fused anti-CD133 and anti-GPC3 single chain Fragment variable (scFv) structures with intracellular domains, respectively. Using non-viral minicircle DNA (mcDNA) vectors to generate co-specific CAR T cells (CoG133-CAR T cells) against CD133 and GPC3 double-positive HCC cells. We exhibited the transduction efficiency of CoG133-CAR T cells and the antigen expression of tumor cell lines. Finally, the antitumor efficacy of CoG133-CAR T cells both in vitro and in vivo was detected. Results: GPC3-CAR and CD133-CAR were successfully prepared using non-viral mcDNA vectors to generate effector cells. For the GPC3 and CD133 double-positive HCC (Huh7) xenograft mice, co-specific CAR T cells possessed stronger tumor growth suppression compared to single-targeted CAR (GPC3-CAR and CD133-CAR) T cells which induced only one antigen-mediated signal pathway. The same results also occurred on the in vitro experiments including cytokine secretion, cytotoxicity and proliferation ability of CAR T cells. Vital organs from CoG133-CAR T cells and normal T cells respectively treated Huh7 xenograft mice were stained by hematoxylin and eosin (H&E), the images showed no difference. Conclusions: The mcDNA vectors loading CAR structures were transfected into T cells by electroporation without genetic mutation or mismatch. Huh7 is an HCC cell line with two antigens of GPC3 and CD133 highly expressed. The antitumor efficacy of co-specific CAR (CoG133-CAR) T cells against Huh7 cells is significantly enhanced. The joint design of two specific targets and non-viral vectors leads much more safety, also.

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Section: Introductionmentioning

confidence: 90%

Nonviral mcDNA-Mediated Cospecific CAR T Cells For The Treatment of Human Hepatocellular Carcinoma Xenograft in Mice

Wang

et al. 2021

Preprint

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“…As such, these cell lines are either transfected or transduced to express PSCA. PSCA-CAR-T cells have demonstrated specific and effective cytokine release as well as cell lysis in vitro against a variety of cell lines that have been genetically transduced to express PSCA (RT4, LAPC-9, DU145 and PC-3) [75][76][77][78][79][80][81].…”

Section: Prostate Stem Cell Antigen (Psca)mentioning

confidence: 99%

“…These results have been recapitulated in vivo in immunocompromised mice using a variety of prostate cancer models (PC-3, PC-3M, mel526 and LAPC-9). CAR-T-treated mice displayed tumour regression and prolonged survival compared to mice bearing untreated tumour xenografts [76][77][78][79][80][81]. Whilst the majority of xenograft models displayed almost complete tumour volume reduction, in some cases tumour growth kinetics were only partially reduced in CAR-T cell-treated xenografts [77].…”

Section: Prostate Stem Cell Antigen (Psca)mentioning

confidence: 99%

Chimeric Antigen Receptor T-Cell Therapy in Metastatic Castrate-Resistant Prostate Cancer

Perera

Thomas

Risbridger

et al. 2022

Cancers

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Prostate cancer is the most commonly diagnosed solid-organ cancer amongst males worldwide. Metastatic castrate-resistant prostate cancer (mCRPC) is a rapidly fatal end-sequelae of prostate cancer. Therapeutic options for men with mCRPC are limited and are not curative in nature. The recent development of chimeric antigen receptor T-cell (CAR-T) therapy has revolutionised the treatment of treatment-resistant haematological malignancies, and several studies are underway investigating the utility of this technology in the treatment of solid tumours. In this review, we evaluate the current treatment options for men with mCRPC as well as the current landscape of preclinical and clinical trials of CAR-T cell therapy against prostate cancer. We also appraise the various prostate cancer-specific tumour-associated antigens that may be targeted by CAR-T cell technology. Finally, we examine the potential translational barriers of CAR-T cell therapy in solid tumours. Despite preclinical success, preliminary clinical trials in men with prostate cancer have had limited efficacy. Therefore, further clinically translatable preclinical models are required to enhance the understanding of the role of this investigational therapeutic in men with mCRPC. In the era of precision medicine, tailored immunotherapy administered to men in a tumour-agnostic approach provides hope to a group of men who otherwise have few treatment options available.

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“…16,17 DNA mini-circles (devoid of bacterial DNA) are also efficient vectors and have yielded functional CAR T cells persisting in vivo for more than 28 days. 18 They, however, still carry a risk of random genomic insertion.…”

Section: Current Stage Of Cell Therapy With Retargeted T Cells (Car T Cells)mentioning

confidence: 99%

Immunotherapy perspectives in the new era of B-cell editing

et al. 2021

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Since the early days of vaccination, targeted immunotherapy has gone through multiple conceptual changes and challenges. It now provides the most efficient and up-to-date strategies for either preventing or treating infections and cancer. Its most recent and successful weapons are autologous T cells carrying chimeric antigen receptors, engineered purposely for binding cancer-specific antigens and therefore used for so-called adoptive immunotherapy. We now face the merger of such achievements in cell therapy: using lymphocytes redirected on purpose to bind specific antigens and the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) revolution, which conferred genome-editing methodologies with both safety and efficacy. This unique affiliation will soon and considerably expand the scope of diseases susceptible to adoptive immunotherapy and of immune cells available for being reshaped as therapeutic tools, including B cells. Following the monumental success story of passive immunotherapy with monoclonal antibodies (mAbs), we are thus entering into a new era, where a combination of gene therapy/cell therapy will enable reprogramming of the patient’s immune system and notably endow his B cells with the ability to produce therapeutic mAbs on their own.

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Minicircle DNA-Engineered CAR T Cells Suppressed Tumor Growth in Mice

Cited by 13 publications

References 25 publications

Nonviral mcDNA-Mediated Cospecific CAR T Cells For The Treatment of Human Hepatocellular Carcinoma Xenograft in Mice

Nonviral mcDNA-Mediated Cospecific CAR T Cells For The Treatment of Human Hepatocellular Carcinoma Xenograft in Mice

Chimeric Antigen Receptor T-Cell Therapy in Metastatic Castrate-Resistant Prostate Cancer

Immunotherapy perspectives in the new era of B-cell editing

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