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Full-Length Dominant-Negative Survivin for Cancer Immunotherapy

¹ University of Nebraska Medical Center Eppley Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska;
² H. Lee Moffitt Cancer Center and Department of Interdisciplinary Oncology, University of South Florida, Tampa, Florida; and
³ Cancer Center and Department of Cancer Biology, University of Massachusetts School of Medicine, Worcester, Massachusetts

Purpose: The goal of this study is to investigate the possible utility of dendritic cells (DCs) transduced with the human full-length dominant-negative survivin for cancer immunotherapy.

Experimental Design: Mononuclear cells were collected from HLA-A2-positive healthy volunteers and patients with prostate cancer. DCs were transduced with an adenoviral vector containing a full-length, dominant-negative survivin gene. After three rounds of stimulation, the T-cell response against three different survivin-derived HLA-A2-matching peptides was tested in IFN- enzyme-linked immunospot and CTL assays.

Results: Seven of eight healthy volunteers and cancer patients showed a significant response to at least two different survivin-derived epitopes in the enzyme-linked immunospot assay. One patient responded to only one peptide. All four healthy volunteers and two of three patients tested demonstrated a specific CTL response against T2 target cells loaded with one survivin-derived epitope. Two donors and two patients had a significant CTL response against two different epitopes. Significant cytotoxic activity was seen against HLA-A2-positive MCF-7 tumor cells that express survivin. That response was specific for survivin and was MHC class I restricted. Because survivin is expressed in CD34⁺ hematopoietic progenitor cells (HPCs), we tested whether the antisurvivin CTLs can recognize normal HPCs. The incubation of survivin-specific CTLs with CD34⁺ cells did not significantly decrease the colony-forming ability of HPCs.

Conclusions: DCs transduced with dominant-negative survivin induce potent survivin-specific CTL responses able to recognize and kill tumor cells. This response does not significantly affect HPCs. Thus, this study may provide rationale for immunotherapeutic clinical trials using a DC vaccine transduced with the dominant-negative survivin.

Commentary

Cancer Immunotherapy Targeting Survivin: Commentary re: V. Pisarev et al., Full-Length Dominant-Negative Survivin for Cancer Immunotherapy. Clin. Cancer Res., 9:6523–6533, 2003.

John C. Reed and Darcy B. Wilson
Clin. Cancer Res. 2003 9: 6310-6315. [Full Text] [PDF]

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