Chemotherapy delivered after viral immunogene therapy augments antitumor efficacy via multiple immune-mediated mechanisms

Zvi G. Fridlender, Jing Sun, Sunil Singhal, Veena Kapoor, Guanjun Cheng, Eiji Suzuki, Steven M. Albelda

Research output: Contribution to journalArticlepeer-review

109 Scopus citations

Abstract

The most widely used approach to cancer immunotherapy is vaccines. Unfortunately, the need for multiple administrations of antigens often limits the use of one of the most effective vaccine approaches, immunogene therapy using viral vectors, because neutralizing antibodies are rapidly produced. We hypothesized that after viral immunogene therapy primed an initial strong antitumor immune response, subsequent boosts could be provided by sequential courses of chemotherapy. Three adenoviral (Ad)-based immunogene therapy regimens were administered to animals with large malignant mesothelioma and lung cancer tumors followed by three weekly administrations of a drug regimen commonly used to treat these tumors (Cisplatin/Gemcitabine). Immunogene therapy followed by chemotherapy resulted in markedly increased antitumor efficacy associated with increased numbers of antigen-specific, activated CD8 T-cells systemically and within the tumors. Possible mechanisms included: (i) decreases in immunosuppressive cells such as myeloid-derived suppressor cells (MDSC), T-regulatory cells (T-regs), and B-cells, (ii) stimulation of memory cells by intratumoral antigen release leading to efficient cross-priming, (iii) alteration of the tumor microenvironment with production of danger signals and immunostimulatory cytokines, and (iv) augmented trafficking of T-cells into the tumors. This approach is currently being tested in a clinical trial and could be applied to other trials of viral immunogene therapy.

Original languageAmerican English
Pages (from-to)1947-1959
Number of pages13
JournalMolecular Therapy
Volume18
Issue number11
DOIs
StatePublished - Nov 2010
Externally publishedYes

Bibliographical note

Funding Information:
This work was funded by NCI PO1 CA 66726. We thank Dr Robert Streiter for help in measuring cytokine and chemokines from tissue samples. We thank Dr Beth Hutchens for the gift of Ad.IFNα.

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