On Immunotherapy against Prostate Cancer

Prostate cancer (PC) is the most frequently diagnosed cancer in Swedish men, with an incidence of around 9000 cases per year, and the main cause of cancer related death. Standard treatment includes surgery, radiotherapy and hormonal therapy. However, once the PC becomes androgen independent and metastatic there are currently no curative treatments available. Cancer immunotherapy, i.e. the activation of the body’s own immune system to fight cancer, represents a promising approach investigated in this thesis. We demonstrate that CD4CD25 regulatory T cells are present in higher frequencies in peripheral blood and tumors of early stage PC patients undergoing prostatectomy, in comparison to healthy donors and benign prostate. These cells were further shown to suppress the proliferation of CD4CD25 T cells in vitro. Our results suggest that the presence of regulatory T cells in the prostate microenvironment might hamper the desired effects of immunotherapy and therefore, inhibition of such cells could enhance anti-tumor immune responses. In preparation for a clinical trial to evaluate a xenogenic DNA vaccine encoding rhesus macaque PSA, we modified by a single amino acid substitution a PSA epitope exhibiting three important properties; high HLA-A*0201 affinity, ability to induce CD8 human T cell responses in all subjects tested in vitro as well as being naturally processed and presented. Finally, we generated a transgenic mouse, expressing human PSA (hPSA) confined to the prostate. Detailed characterization revealed that this mouse does not reject PSA expressing tumors when vaccinated with hPSA plasmid by the intramuscular route, indicating presence of peripheral tolerance to PSA. However, we show that intradermal administration of PSA plasmid in combination with electroporation induces a potent T cell response, resulting not only in infiltration of the healthy prostate, but also the ability to eliminate PSA expressing tumor cells after in vivo challenge. List of Publications I. Miller AM, Lundberg K, Özenci V, Banham AH, Hellström M, Egevad L, Pisa P. CD4CD25high T cells are enriched in the tumor and peripheral blood of prostate cancer patients. Journal of Immunology, 2006, Nov 15; 177(10): 7398-405 II. Lundberg K*, Roos AK*, Pavlenko M, Leder C, Wehrum D, GuevaraPatiño J, Andersen RS, Pisa P. A modified epitope identified for generation and monitoring of PSA-specific T cells in patients on early phases of PSAbased immunotherapeutic protocols. Vaccine, 2009, Mar 4; 27(10): 1557-65. III. Eriksson F*, Lundberg K*, Tsagozis P, Roos AK, Egevad L, Pisa P. Intradermal electroporation enhances tumor protection in PSA transgenic mice after PSA DNA vaccination. (Manuscript). *Shared first authorship Related publication: Eriksson F, Tsagozis P, Lundberg K, Parsa R, Mangsbo SM, Persson MA, Harris RA, Pisa P. Tumor-specific bacteriophages induce tumor destruction through activation of tumor-associated macrophages. Journal of Immunology, 2009, Mar 1; 182(5): 3105-11.