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Front. Immunol. | doi: 10.3389/fimmu.2018.02268

Regional Delivery of Chimeric Antigen Receptor (CAR)-Engineered T cells with 4-1BB Co-Stimulation Effectively Targets TAG72-Positive Peritoneal Ovarian Tumors

 John P. Murad1,  Anna K. Kozlowska1,  Hee Jun Lee1,  Maya Ramamurthy1, Wen-Chung Chang1,  Paul Yazaki1, David Colcher1, John Shively1, Mihaela Cristea1, Stephen J. Forman1* and  Saul J. Priceman1*
  • 1City of Hope National Medical Center, United States

Impressive clinical efficacy of chimeric antigen receptor (CAR)-engineered T cell therapy for hematological malignancies have prompted significant efforts in achieving similar responses in solid tumors. The lack of truly restricted and uniform expression of tumor-associated antigens, as well as limited T cell persistence and/or tumor trafficking pose major challenges for successful translation of CAR T cell therapy in solid tumors. Recent studies have demonstrated that aberrantly glycosylated cell surface proteins on tumor cells are amenable CAR targets. Tumor- associated glycoprotein 72 (TAG72) antigen is the sialyl-Tn found on multiple O-glycoproteins expressed at high levels on the surface of several cancer types, including ovarian cancer. Here, we developed a humanized TAG72-specific CAR containing a 4-1BB intracellular co-stimulatory signaling domain (TAG72-BBζ). TAG72-BBζ CAR T cells showed potent antigen-dependent cytotoxicity and cytokine production against multiple TAG72+ ovarian cancer cell lines and patient-derived ovarian cancer ascites. Using in vivo xenograft models of peritoneal ovarian tumors, regional intraperitoneal delivery of TAG72-BBζ CAR T cells significantly reduced tumor growth, extended overall survival of mice, and was further improved with repeat infusions of CAR T cells. However, reduced TAG72 expression was observed in early recurring tumors, which coincided with a lack of T cell persistence. Taken together, we demonstrate efficacy with TAG72- CAR T cells in ovarian cancer, warranting further investigations as a CAR T cell therapeutic strategy for this disease.

Keywords: Chimeric Antigen Receptor, ovarian cancer, regional intraperitoneal delivery, TAG72, tumor-associated glycoproteins, adoptive cell theraphy

Received: 02 Jul 2018; Accepted: 12 Sep 2018.

Edited by:

Avery D. Posey, Jr., University of Pennsylvania, United States

Reviewed by:

Maksim Mamonkin, Baylor College of Medicine, United States
Catharina Steentoft, University of Copenhagen, Denmark  

Copyright: © 2018 Murad, Kozlowska, Lee, Ramamurthy, Chang, Yazaki, Colcher, Shively, Cristea, Forman and Priceman. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
MD. Stephen J. Forman, City of Hope National Medical Center, Duarte, United States, SForman@coh.org
PhD. Saul J. Priceman, City of Hope National Medical Center, Duarte, United States, sjpriceman@yahoo.com