Potential lung attack and lethality generated by EpCAM-specific CAR-T cells in immunocompetent mouse models

Qin, Diyuan; Li, Dan; Zhang, Benxia; Chen, Yue; Liao, Xuelian; Li, Xiaoyü; Alexander, Peter; Wang, Yongsheng; Li, Qi-Jing

doi:10.1080/2162402x.2020.1806009

Cited by 26 publications

(31 citation statements)

References 45 publications

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“…In this regard, CAR-T cells targeting epithelial cell adhesion molecule (EpCAM), a tumor-associated antigen overtly presented on the cell surface of various carcinomas, is a typical precedent. Although anti-human EpCAM CAR-T cells unable of recognizing mouse EpCAM eradicated established tumor xenografts without toxicities in the immunodeficient animal models, anti-mouse EpCAM CAR-T cells induced severe pulmonary immunopathology in theimmunocompetent mice due to CAR-T recognition of basal EpCAM expression in normal lung ( 49 ). In addition, we may learn from the experience of targeting ROR1 by CAR T cells as these two molecules have similar expression profiles in both normal and tumor tissues ( 10 , 50 ).…”

Section: Discussionmentioning

confidence: 99%

PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies

et al. 2021

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In spite of impressive success in treating hematologic malignancies, adoptive therapy with chimeric antigen receptor modified T cells (CAR T) has not yet been effective in solid tumors, where identification of suitable tumor-specific antigens remains a major obstacle for CAR T-cell therapy due to the “on target off tumor” toxicity. Protein tyrosine kinase 7 (PTK7) is a member of the Wnt-related pseudokinases and identified as a highly expressed antigen enriched in cancer stem cells (CSCs) from multiple solid tumors, including but not limited to triple-negative breast cancer, non-small-cell lung cancer, and ovarian cancer, suggesting it may serve as a promising tumor-specific target for CAR T-cell therapy. In this study, we constructed three different PTK7-specific CAR (PTK7-CAR1/2/3), each comprising a humanized PTK7-specific single-chain variable fragment (scFv), hinge and transmembrane (TM) regions of the human CD8α molecule, 4-1BB intracellular co-stimulatory domain (BB-ICD), and CD3ζ intracellular domain (CD3ζ-ICD) sequence, and then prepared the CAR T cells by lentivirus-mediated transduction of human activated T cells accordingly, and we sequentially evaluated their antigen-specific recognition and killing activity in vitro and in vivo. T cells transduced with all three PTK7-CAR candidates exhibited antigen-specific cytokine production and potent cytotoxicity against naturally expressing PTK7-positive tumor cells of multiple cancer types without mediating cytotoxicity of a panel of normal primary human cells; meanwhile, in vitro recursive cytotoxicity assays demonstrated that only PTK7-CAR2 modified T cells retained effective through multiple rounds of tumor challenge. Using in vivo xenograft models of lung cancers with different expression levels of PTK7, systemic delivery of PTK7-CAR2 modified T cells significantly prevented tumor growth and prolonged overall survival of mice. Altogether, our results support PTK7 as a therapeutic target suitable for CAR T-cell therapy that could be applied for lung cancers and many other solid cancers with PTK7 overexpression.

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Section: Discussionmentioning

confidence: 99%

PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies

et al. 2021

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“…Recent research has also suggested that EpCAM can be utilized as a target antigen for CAR-T cell therapy, potentially selectively eliminating CTCs. However, their reported efficacy seems to also be accompanied by an unfavorable toxicity profile [157].…”

Section: Ctcs As a Therapeutic Targetmentioning

confidence: 99%

An Immunological Perspective of Circulating Tumor Cells as Diagnostic Biomarkers and Therapeutic Targets

Dotse

Lim

Wang

et al. 2022

Life

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Immune modulation is a hallmark of cancer. Cancer–immune interaction shapes the course of disease progression at every step of tumorigenesis, including metastasis, of which circulating tumor cells (CTCs) are regarded as an indicator. These CTCs are a heterogeneous population of tumor cells that have disseminated from the tumor into circulation. They have been increasingly studied in recent years due to their importance in diagnosis, prognosis, and monitoring of treatment response. Ample evidence demonstrates that CTCs interact with immune cells in circulation, where they must evade immune surveillance or modulate immune response. The interaction between CTCs and the immune system is emerging as a critical point by which CTCs facilitate metastatic progression. Understanding the complex crosstalk between the two may provide a basis for devising new diagnostic and treatment strategies. In this review, we will discuss the current understanding of CTCs and the complex immune-CTC interactions. We also present novel options in clinical interventions, targeting the immune-CTC interfaces, and provide some suggestions on future research directions.

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“…Then, tissues are stained with hematoxylin and eosin, and other antibodies to check for CAR-T cell infiltration and organ damages. [147]…”

Section: Safety Profiles Of Car-t Therapymentioning

confidence: 99%

“…For intra-tumoral T cell numbers, tumors are first sectioned and digested to determine the numbers of tumorinfiltrating lymphocytes via flow cytometry. [147]…”

Section: T Cell Proliferationmentioning

confidence: 99%

Materials for Improving Immune Cell Transfection

et al. 2021

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recognize and bind to tumor-associated antigens such as CD19 and epidermal growth factor receptor (EGFR) before releasing cytotoxic granules and effector cytokines to destroy cancer cells. [3] CAR-T therapy has shown remarkable success against CD19 expressing B cell hematological malignancies and, thus far, five products (Kymriah from Novartis; Yescarta and Tecartus from Kite Pharma/Gilead Sciences; and Breyanzi and Abecma from Bristol-Myers Squibb) have been approved by the US Food and Drug Administration (FDA) for clinical use. [4,5] Currently, there are at least 500 clinical trials registered on ClinicalTrials.gov database using engineered immune cells to treat various cancers including that of the brain, lungs, and skin.Despite the clinical success of CAR-T cells against B cell leukemia, CAR-T therapy still face tremendous challenges in manufacturing, safety, and affordability before it can become a viable clinical option. [6] One of the biggest technical difficulties is to transfect sensitive, primary T cells whereby biomolecules like oligonucleotides and proteins have to be delivered intracellularly and into the nuclei of cells. FDA-approved gold standard viruses and bulk electroporation suffer from low transfection efficiency while also perturbing the critical biological attributes of cells such as proliferation, metabolism, and gene expression. [7] This increases the time and costs for cell expansion, and without an efficient and cost-friendly transfection technology, the price (between USD 0.4-0.5 million per patient) for FDA-approved CAR treatments (Kymriah and Yescarta) will remain unaffordable and untimely. [8] The limitations in conventional transfection techniques have motivated the development of micro-and nanoplatforms such as microfluidics, nanoparticles, and high-aspect-ratio nanostructures to improve immune cell viability and throughput during transfection.Herein, we first provide an overview of CAR-T cell manufacturing, with emphasis on the science of transfection and limitations of traditional technology using viruses and bulk electroporation. There will also be discussion of other cell-based cancer immunotherapy using other types of promising immune cell types. Next, we describe emerging transfection platforms and companies that have been established to overcome gaps in CAR-T transfection. We then provide a list of assays constituting the polyfunctionalities of immune cells that we believe will help the field better assess the robustness and suitability of their transfection methods. Finally, we end off with existing challenges in CAR-T transfection and how overcoming these challenges can significantly enhance the clinical impact of CAR-T therapy.Chimeric antigen receptor T cell (CAR-T) therapy holds great promise for preventing and treating deadly diseases such as cancer. However, it remains challenging to transfect and engineer primary immune cells for clinical cell manufacturing. Conventional tools using viral vectors and bulk electroporation suffer from low efficiency while posing risks ...

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Potential lung attack and lethality generated by EpCAM-specific CAR-T cells in immunocompetent mouse models

Cited by 26 publications

References 45 publications

PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies

PTK7-Targeting CAR T-Cells for the Treatment of Lung Cancer and Other Malignancies

An Immunological Perspective of Circulating Tumor Cells as Diagnostic Biomarkers and Therapeutic Targets

Materials for Improving Immune Cell Transfection

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