New gene expressed in prostate (NGEP) is a prostate-specific gene encoding either a small cytoplasmic protein (NGEP-S) or a larger polytopic membrane protein (NGEP-L). NGEP-L expression is detectable only in prostate cancer, benign prostatic hyperplasia and normal prostate. We have identified an HLA-A2 binding NGEP epitope (designated P703) which was used to generate T cell lines from several patients with localized and metastatic prostate cancer. These T cell lines were able to specifically lyse HLA-A2 and NGEP-expressing human tumor cells. NGEPP703 tetramer binding assays demonstrated that metastatic prostate cancer patients had a higher frequency of NGEP-specific T cells when compared with healthy donors. Moreover, an increased frequency of NGEP-specific T cells was detected in the peripheral blood mononuclear cells of prostate cancer patients post-vaccination with a PSA-based vaccine, further indicating the immunogenicity of NGEP. These studies thus identify NGEP as a potential target for T cell-mediated immunotherapy of prostate cancer. Tumor-associated antigens are weakly immunogenic. Human carcinoembryonic antigen (CEA) is overexpressed on a wide range of human carcinomas and represents an attractive target for cancer immunotherapy. This project analyzes the ability of a Saccharomyces cerevisiae vector containing the transgene encoding CEA (yeast-CEA) to activate human dendritic cells (DCs) and stimulate CEA-specific T-cell responses. We demonstrate for the first time that treatment with yeast-CEA can activate human DCs, resulting in increases in surface expression of CD80, CD83, CD54, CD58, and MHC class II, and increased production by DCs of IL-12p70, TNF-alpha, IFN-gamma, IL-8, IL-2, IL-13, IL-10, and IL-1beta. We also show that human DCs treated with yeast-CEA can activate CEA-specific T-cell lines and can act as antigen-presenting cells (APCs) to generate CEA-specific T-cell lines capable of lysing CEA+ human tumor cells. Gene expression profiles of human DCs treated with yeast-CEA show increased expression of numerous genes involved in the production of chemokines and cytokines and their receptors, and genes related to antigen uptake, antigen presentation, and signal transduction. 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 analyzed immune responses of patients from ongoing or recently completed clinical trials at the NCI Clinical Center in FY08-09. 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 Phase I feasibility study of an intraprostatic PSA-based vaccine in prostate cancer patients with local failure following radiotherapy, MOB/Urologic Oncology Branch, CCR, NCI. This clinical trial is the first to employ sequential systemic and intratumoral vaccination. This trial is ongoing with no significant toxicities to date. Moreover this strategy has been associated with significant drops in serum PSA in these patients. 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 randomized Pilot Phase II study of Docetaxel alone or in combination with PANVAC-V (vaccinia) and PANVAC-F (fowlpox) in adults with metastatic breast cancer. MOB, CCR, NCI. This is the first randomized trial to combine vaccine with Docetaxel in this breast cancer patient population. 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 pilot study to evaluate the safety and tolerability of PANVAC-V (Vaccinia) and PANVAC-F (Fowlpox) in combination with Sargramostim (GM-CSF) in patients with metastatic adenocarcinoma, MOB, CCR, NCI. This trial employed vectors with transgenes of both multiple tumor antigens and multiple costimulatory molecules. A recent amendment allowed additional patients to further analyze the efficacy of the vaccine. 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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010972-02
Application #
7965889
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2009
Total Cost
$896,832
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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