@article{8827602fc2794ecd92b77df26a7e7c56,
title = "Mesenchymal stromal cell delivery of oncolytic immunotherapy improves CAR-T cell antitumor activity",
abstract = "The immunosuppressive tumor microenvironment (TME) is a formidable barrier to the success of adoptive cell therapies for solid tumors. Oncolytic immunotherapy with engineered adenoviruses (OAd) may disrupt the TME by infecting tumor cells, as well as surrounding stroma, to improve the functionality of tumor-directed chimeric antigen receptor (CAR)-T cells, yet efficient delivery of OAds to solid tumors has been challenging. Here we describe how mesenchymal stromal cells (MSCs) can be used to systemically deliver a binary vector containing an OAd together with a helper-dependent Ad (HDAd; combinatorial Ad vector [CAd]) that expresses interleukin-12 (IL-12) and checkpoint PD-L1 (programmed death-ligand 1) blocker. CAd-infected MSCs deliver and produce functional virus to infect and lyse lung tumor cells while stimulating CAR-T cell anti-tumor activity by release of IL-12 and PD-L1 blocker. The combination of this approach with administration of HER.2-specific CAR-T cells eliminates 3D tumor spheroids in vitro and suppresses tumor growth in two orthotopic lung cancer models in vivo. Treatment with CAd MSCs increases the overall numbers of human T cells in vivo compared to CAR-T cell only treatment and enhances their polyfunctional cytokine secretion. These studies combine the predictable targeting of CAR-T cells with the advantages of cancer cell lysis and TME disruption by systemic MSC delivery of oncolytic virotherapy: incorporation of immunostimulation by cytokine and checkpoint inhibitor production through the HDAd further enhances anti-tumor activity.",
keywords = "CAR-T cells, HER.2, helper dependent adenovirus, lung cancer, mesenchymal stromal cells, oncolytic adenovirus, oncolytic immunotherapy, solid tumor, systemic delivery",
author = "McKenna, {Mary K.} and Alexander Englisch and Benjamin Brenner and Tyler Smith and Valentina Hoyos and Masataka Suzuki and Brenner, {Malcolm K.}",
note = "Funding Information: Imaging for this project was supported by the Integrated Microscopy Core at Baylor College of Medicine with funding from NIH ( DK56338 and CA125123 ), CPRIT ( RP150578 and RP170719 ), the Dan L. Duncan Comprehensive Cancer Center , and the John S. Dunn Gulf Coast Consortium for Chemical Genomics . The authors extend special thanks to Ms. Hannah Johnson with the Integrated Microscopy Core. The authors thank the Baylor College of Medicine Pathology Core (HTAP) and Dr. Patricia Castro for performing immunohistochemistry and H&E staining for tissue microarray slides supported by NCI award P30 CA125123 . The authors thank Dr. Reid Powell with Texas A&M Center for Advanced Imaging for image analysis. The authors are grateful to Ms. Catherine Gillespie for editing the manuscript. This project was supported by the National Heart, Lung, and Blood Institute of The National Institutes of Health under award number 5T32HL092332-17 to Principal Investigator: Dr. Helen Heslop and The National Cancer Institute under the award 5PO1CA094237-15 . Funding Information: Imaging for this project was supported by the Integrated Microscopy Core at Baylor College of Medicine with funding from NIH (DK56338 and CA125123), CPRIT (RP150578 and RP170719), the Dan L. Duncan Comprehensive Cancer Center, and the John S. Dunn Gulf Coast Consortium for Chemical Genomics. The authors extend special thanks to Ms. Hannah Johnson with the Integrated Microscopy Core. The authors thank the Baylor College of Medicine Pathology Core (HTAP) and Dr. Patricia Castro for performing immunohistochemistry and H&E staining for tissue microarray slides supported by NCI award P30 CA125123. The authors thank Dr. Reid Powell with Texas A&M Center for Advanced Imaging for image analysis. The authors are grateful to Ms. Catherine Gillespie for editing the manuscript. This project was supported by the National Heart, Lung, and Blood Institute of The National Institutes of Health under award number 5T32HL092332-17 to Principal Investigator: Dr. Helen Heslop and The National Cancer Institute under the award 5PO1CA094237-15. Conceptualization, M.K.M and M.K.B.; investigation, M.K.M. A.E. and T.S. formal analysis, M.K.M. A.E. software, B.B. writing – original draft, M.K.M.; writing – review & editing, M.K.M. and M.K.B.; supervision, M.K.B.; funding acquisition, M.K.B. M.S. is a consultant for Tessa Therapeutic. M.K.B. is a co-founder of the following with equity: Tessa Therapeutics and Marker Therapeutics. Scientific Advisory Boards: Bluebird Bio, Turnstone, Tessa Therapeutics, Marker Therapeutics, Allogene, Walking Fish, Memgen, KUUR, Bellicum Pharmaceuticals, Tscan, Poseida, and Abintus. Research funding: Tessa Therapeutics. Publisher Copyright: {\textcopyright} 2021 The American Society of Gene and Cell Therapy",
year = "2021",
month = may,
day = "5",
doi = "10.1016/j.ymthe.2021.02.004",
language = "English (US)",
volume = "29",
pages = "1808--1820",
journal = "Molecular Therapy",
issn = "1525-0016",
publisher = "Nature Publishing Group",
number = "5",
}