Priming and Activation of Human Ovarian and Breast... : Journal of Immunotherapy (original) (raw)

Basic Studies

Priming and Activation of Human Ovarian and Breast Cancer-specific CD8+ T Cells by Polyvalent _Listeria monocytogenes_-based Vaccines

Sinnathamby, Gomathinayagam*; Lauer, Peter†; Zerfass, Jennifer*; Hanson, Bill†; Karabudak, Aykan*; Krakover, Jonathan*; Secord, Angeles Alvarez‡; Clay, Timothy M.‡; Morse, Michael A.‡; Dubensky, Thomas W. Jr†; Brockstedt, Dirk G.†; Philip, Ramila*; Giedlin, Martin†

*Immunotope, Inc, The Pennsylvania Biotechnology Center, Doylestown, PA

†Anza Therapeutics, Inc, Concord, CA

‡Duke Comprehensive Cancer Center, Duke University, Durham, NC

Financial Disclosure: Gomathinayagam Sinnathamby and Ramila Philip are employees of Immunotope, Inc. Jennifer Zerfass, Aykan Karabudak, and Jonathan Krakover were employees of Immunotope, Inc when this study was conducted. Angeles Alvarez Secord is a consultant for Immunotope, Inc and received funding for clinical trials. Peter Lauer, Bill Hanson, Thomas W. Dubensky Jr, Dirk G. Brockstedt, and Martin Giedlin were employees of Anza Therapeutics, Inc when this work was performed. This study was supported by NCI Grant 15 R43 CA109868-02 to Martin Giedlin and Ramila Philip.

Reprints: Ramila Philip, Immunotope, Inc, The Pennsylvania Biotechnology Center, 3805 Old Easton Road, Doylestown, PA 18902 (e-mail: [email protected]).

Received for publication December 15, 2008

accepted May 7, 2009

All other authors have declared that there are no conflicts of interest in regards to this work.

Current address: Martin Giedlin, Sangamo Biosciences, 501 Canal Boulevard, Suite A 100, Richmond, CA 94804.

Abstract

Immunotherapeutic vaccine is potentially an effective strategy to combat cancer. Essential components of an effective vaccine must include antigens that are processed by the major histocompatibility complex class I pathway, presented by the tumor major histocompatibility complex molecules, and an effective antigen delivery platform that is capable of breaking self-tolerance. In this study, we characterized a set of ovarian cancer-specific T-cell epitopes delivered by live-attenuated recombinant Listeria monocytogenes (Lm ΔactAΔinlB) as a vaccine vector. We present data that peptide-specific T cells recognize the human monocytic cell line THP-1 infected with recombinant Lm ΔactAΔinlB encoding the epitopes. Furthermore, we demonstrate that recombinant L. monocytogenes (Lm)-infected antigen-presenting cells can prime and expand epitope-specific CD8+ T cells in vitro and such CD8+ T cells recognize not only peptide-loaded targets but also ovarian and breast tumor cells presenting endogenous epitopes. Finally, peptide-specific T cells generated using peripheral blood mononuclear cell from ovarian cancer patients recognize target cells infected with recombinant Lm ΔactAΔinlB encoding the epitopes. Our results demonstrate that live-attenuated recombinant Lm can be used effectively as a vehicle to deliver cancer peptide antigens singly or as a multiepitope construct. Thus, the use of recombinant live-attenuated Lm strains encoding endogenously processed and presented tumor epitopes/antigens represents an attractive strategy for active cancer immunotherapy in a clinical setting.