HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jimmunol.0901747v1 183/10/6800    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Radfar, S. Articles by Khong, H. T. PubMed PubMed Citation Articles by Radfar, S. Articles by Khong, H. T.

Activated CD4⁺ T Cells Dramatically Enhance Chemotherapeutic Tumor Responses In Vitro and In Vivo

Mitchell Cancer Institute, University of South Alabama, Mobile, Alabama 36604

Chemoimmunotherapy has been widely studied in melanoma, with various degrees of success. One of the most common approaches is the so-called biochemotherapy, which is associated with increased toxicities, but without overall survival benefit. Another conventional strategy is the use of chemotherapy as an immunomodulator to enhance the effect of cancer vaccines or adoptive cell transfer therapy. Based on this approach, recent studies using chemotherapy to prepare the host before the infusion of ex vivo-activated, melanoma Ag-specific tumor-infiltrating lymphocytes and high dose IL-2 resulted in an impressive response rate. However, the development of immunotherapy for the treatment of a broad range of cancer type is still lacking. In this study, we report the development of a simple yet universal approach termed "chemocentric chemoimmunotherapy" that has potential application in the treatment of all cancer types. This technique uses nonspecifically activated CD4⁺ T cells as a chemosensitizer before the administration of chemotherapy. Dramatic enhancement of the cytotoxic effect of chemotherapeutic drugs, either active or nonactive as single agents, was observed both in in vitro and in vivo human tumor xenograft models. Soluble factors secreted from activated CD4⁺ T cells, likely acting on the tumor and its microenvironment, were responsible for the observed effect. Although IFN- played a major role in the therapeutic outcome, it was consistently found to be inferior to the use of activated CD4⁺ T cells in tumor chemosensitization. Our model may provide a plausible mechanism to facilitate further understanding, design and development of improved chemoimmunotherapy in the treatment of cancer.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Current address: Yale University School of Medicine, Department of Internal Medicine, Hematology Section, 333 Cedar Street, P.O. Box 208021, New Haven, Connecticut 06520-8021.

² Current address: Research Laboratory of Oral and Maxillofacial Surgery, Peking University School of Stomatology, Beijing, China.

³ Address correspondence and reprint requests to Dr. Hung T. Khong, M.D., Mitchell Cancer Institute, University of South Alabama, 1660 Springhill Avenue, Mobile, Alabama 36604. E-mail address: hkhong{at}usouthal.edu

⁴ Abbreviations used in this paper: aCD4, activated CD4⁺ T cell; CM, complete medium; TMZ, temozolomide; Carbo, carboplatin; Pax, paclitaxel; RFU, relative fluorescence signal; CI, combination index; AU, arbitrary unit.