Enhanced functionality of CD4+CD25highFoxP3+ regulatory T cells in the peripheral blood of patients with prostate cancer. CD4+CD25highFoxP3+ regulatory T cells (Treg) have been shown to inhibit the activation and function of T cells that participate in antigen-specific immune responses. Higher levels of Tregs have been reported in the peripheral blood of patients with several types of tumors. In this study, we investigated the number and functionality of CD4+CD25highFoxP3+ Tregs in patients with prostate cancer (PCa), and their potential role in inhibiting antitumor immune responses. Levels of Tregs in the peripheral blood of healthy donors and patients with biochemically progressive, localized, and metastatic PCa were each measured by flow cytometry. The functional activity of Tregs was determined by their ability to suppress the proliferation of CD4+CD25- T cells. Data were analyzed using Wilcoxon rank sum test and unpaired Students t test. Although levels of Tregs in the peripheral blood of patients with PCa were not significantly higher than those in healthy donors, Tregs in patients with PCa had significantly greater suppressive functionality than Tregs from healthy donors (P <0.05). Additionally, there was a direct correlation between the serum levels of prostaglandin E2 and Treg functionality in patients with localized PCa, using Pearsons product-moment correlation coefficient (R). These findings further show the potential importance of Tregs in modifying immune responses in patients with PCa. Although longer studies are necessary to confirm these findings, these studies also show for the first time the differences in Treg populations in patients with various stages of PCa, and thus, provide a basis for determining which PCa patient populations are best suited for immunotherapy trials involving the inhibition of Tregs. Dr. Tsang and his colleagues in the Laboratory of Tumor Immunology and Biology (LTIB) and the Medical Oncology Branch (MOB), Center for Cancer Research (CCR), NCI, have ongoing or recently completed in FY08-09 the following collaborative vaccine clinical trials at the NCI Clinical Center. A Phase I/II pilot study of sequential vaccinations with rFowlpox-PSA (L155)-TRICOM (PROSTVAC-F/TRICOM) alone, or in combination with rVaccinia-PSA (L155)-TRICOM (PROSTVAC-V/TRICOM), and the role of GM-CSF, in patients with prostate cancer, MOB, CCR, NCI. This is the first trial involving the use of a vaccine for prostate cancer containing transgenes for three costimulatory molecules. The study showed evidence of significant drops in serum PSA, objective response, prolonged stable disease and survival in patients with advanced prostate cancer which correlated with immunologic responses. This trial also provided evidence for a more appropriate prostate cancer patient population for vaccine therapy trials. A randomized Phase II trial combining vaccine therapy with PROSTVAC/TRICOM and Flutamide, vs. Flutamide alone in men with androgen insensitive non metastatic (D0.5) prostate cancer, MOB, CCR, NCI. This was the first randomized trial to combine a vaccine with this second-line hormone therapy in D0.5 prostate cancer patients. Phase I Trial of a PSA based vaccine and an anti-CTLA-4 antibody in patients with Metastatic Androgen Independent Prostate Cancer. This trial is the first clinical trial to combine an anti-CTLA-4 antibody and a vector-based vaccine in prostate cancer. A randomized phase 2.5 study of 153Sm-EDTMP (Quadramet) with or without a PSA/TRICOM vaccine in men with androgen-insensitive metastatic prostate cancer, MOB, CCR, NCI. This trial is the first clinical trial to combine vaccine with a bone seeking radionuclide for use in patients with androgen independent prostate cancer. A Phase I-II study of tumor vaccine following chemotherapy in patients with previously untreated metastatic breast cancer: Vaccine-induced bias of T-cell repertoire reconstitution after T-cell Reinfusion. (Collaboration with Dr. Sportes) MOB, CCR, NCI. This trial combines the concepts of T-cell repertoire reconstitution with vaccine therapy. An open label phase I study to evaluate the safety and tolerability of a vaccine (GI-6207) consisting of whole, heat-killed recombinant Saccharomyces cerevisiae (yeast) genetically modified to express CEA protein in adults with metastatic CEA-expressing carcinoma. This is a first in humans trial for this vaccine.

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National Cancer Institute (NCI)
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Schlom, Jeffrey; Hodge, James W; Palena, Claudia et al. (2014) Therapeutic cancer vaccines. Adv Cancer Res 121:67-124
Jochems, Caroline; Tucker, Jo A; Tsang, Kwong-Yok et al. (2014) A combination trial of vaccine plus ipilimumab in metastatic castration-resistant prostate cancer patients: immune correlates. Cancer Immunol Immunother 63:407-18
Gulley, James L; Madan, Ravi A; Tsang, Kwong Y et al. (2014) Immune impact induced by PROSTVAC (PSA-TRICOM), a therapeutic vaccine for prostate cancer. Cancer Immunol Res 2:133-41
Farsaci, Benedetto; Jochems, Caroline; Grenga, Italia et al. (2014) Identification by digital immunohistochemistry of intratumoral changes of immune infiltrates after vaccine in the absence of modifications of PBMC immune cell subsets. Int J Cancer 135:862-70
Kim, Peter S; Jochems, Caroline; Grenga, Italia et al. (2014) Pan-Bcl-2 inhibitor, GX15-070 (obatoclax), decreases human T regulatory lymphocytes while preserving effector T lymphocytes: a rationale for its use in combination immunotherapy. J Immunol 192:2622-33
Gameiro, Sofia R; Jammeh, Momodou L; Wattenberg, Max M et al. (2014) Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. Oncotarget 5:403-16
Takai, Shinji; Schlom, Jeffrey; Tucker, Joanne et al. (2013) Inhibition of TGF-?1 signaling promotes central memory T cell differentiation. J Immunol 191:2299-307
Huen, Ngar-Yee; Pang, Alan Lap-Yin; Tucker, Jo A et al. (2013) Up-regulation of proliferative and migratory genes in regulatory T cells from patients with metastatic castration-resistant prostate cancer. Int J Cancer 133:373-82
Gulley, James L; Heery, Christopher R; Madan, Ravi A et al. (2013) Phase I study of intraprostatic vaccine administration in men with locally recurrent or progressive prostate cancer. Cancer Immunol Immunother 62:1521-31
Vergati, Matteo; Schlom, Jeffrey; Tsang, Kwong Y (2011) The consequence of immune suppressive cells in the use of therapeutic cancer vaccines and their importance in immune monitoring. J Biomed Biotechnol 2011:182413

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