A multicenter, randomized Phase II trial employing PROSTVAC-VF provided evidence of enhanced median overall survival (OS) (p = 0.0061) in patients with metastatic castration-resistant prostate cancer (mCRPC). Thirty-two patients were vaccinated once with recombinant vaccinia containing the transgenes for prostate-specific antigen (PSA) and three costimulatory molecules. Patients received boosters with recombinant fowlpox containing the same four transgenes. Twelve of 32 patients showed declines in serum PSA post-vaccination and 2/12 showed decreases in index lesions. Median OS was 26.6 months (predicted median OS by the Halabi nomogram was 17.4 months). Patients with greater PSA-specific T-cell responses showed a trend (p = 0.055) toward enhanced survival. There was no difference in T-cell responses or survival in cohorts of patients receiving GM-CSF versus no GM-CSF. Patients with a Halabi predicted survival of <18 months (median predicted 12.3 months) had an actual median OS of 14.6 months, while those with a Halabi predicted survival of greater than or equal to 18 months (median predicted survival 20.9 months) will meet or exceed 37.3 months, with 12/15 patients living longer than predicted (p = 0.035). Treg suppressive function was shown to decrease following vaccine in patients surviving longer than predicted, and increase in patients surviving less than predicted. This hypothesis-generating study provides evidence that patients with more indolent mCRPC (Halabi predicted survival of greater than or equal to 18 months) may best benefit from vaccine therapy. A recently completed study in mCRPC demonstrated that when ipilimumab (anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) monoclonal antibody) was combined with PSA-TRICOM (PROSTVAC) at escalating doses, the median survival was 34 months, which compares favorably to previous vaccine trials in mCRPC that resulted in median survivals of approximately 26 months. These and other data support the rationale for randomized studies employing immune checkpoint inhibitors in combination with TRICOM-based vaccines.Two of the most widely studied human tumor-associated antigens (TAAs) are CEA and mucin-1 (MUC-1). CEA is overexpressed in a wide range of human carcinomas, including gastrointestinal, breast, lung, pancreatic, medullary thyroid, ovarian, and prostate. MUC-1 is a tumor-associated mucin, which is overexpressed and hypoglycosylated in all human carcinomas as well as in acute myeloid leukemia (AML) and multiple myeloma. Studies have demonstrated that the C-terminus of MUC-1 functions as an oncogene. A study was conducted to obtain preliminary evidence of clinical response in metastatic breast and ovarian cancer patients with PANVAC (rV,rF-CEA-MUC1-TRICOM). Twenty-six patients were enrolled and given monthly vaccinations. These patients were heavily pretreated, with 21 of 26 patients having had three or more prior chemotherapy regimens. Side effects were largely limited to mild injection-site reactions. For the 12 breast cancer patients enrolled, median time to progression was 2.5 months (1-37+) and median OS was 13.7 months. Four patients had stable disease. One patient had a complete response by RECIST (Response Evaluation Criteria on Solid Tumors) and remained on study for over 37 months. Another patient with metastatic disease confined to the mediastinum had a 17% reduction in mediastinal mass and was on study for 10 months. Patients with stable or responding disease had fewer prior therapies and lower tumor marker levels than patients with no evidence of response. Patients were also monitored for generation of T-cell responses and antibody responses to tumor-associated antigens expressed by the vaccine. Further studies to confirm these results are warranted. A randomized multicenter study has been initiated evaluating docetaxel vs docetaxel plus PANVAC vaccine (rV-, rF-CEA-MUC1-TRICOM) in patients (n=48) with metastatic breast carcinoma. Preliminaryfindings to date indicate a substantial increase in time to progression in the combination arm vs the docetaxel alone arm.Identification of tumor antigens is essential in advancing immune-based therapeutic interventions in cancer. Particularly attractive targets are those molecules that are selectively expressed by malignant cells and that are also essential for tumor progression. We have used a computer-based differential display analysis tool for mining of expressed sequence tag clusters in the human Unigene database and identified Brachyury as a novel tumor antigen. Brachyury, a member of the T-box transcription factor family, is a key player in mesoderm specification during embryonic development. Moreover, transcription factors that control mesoderm have been implicated in the epithelial-to-mesenchymal transition (EMT), which has been postulated to be a key step during tumor progression to metastasis. Reverse transcription-PCR analysis validated the in silico predictions and showed Brachyury expression in tumors of the small intestine, stomach, kidney, bladder, uterus, ovary, and testis, as well as in cell lines derived from lung, colon, and prostate carcinomas, but not in the vast majority of the normal tissues tested. An HLA-A0201epitope of human Brachyury was identified that was able to expand T lymphocytes from blood of cancer patients and normal donors with the ability to lyse Brachyury-expressing tumor cells. To our knowledge, this is the first demonstration that (a) a T-box transcription factor and (b) a molecule implicated in mesodermal development, i.e., EMT, can be a potential target for human T-cell-mediated cancer immunotherapy. Metastatic disease is responsible for the majority of human cancer deaths. Understanding the molecular mechanisms of metastasis is a major step in designing effective cancer therapeutics. We have shown that the T-box transcription factor Brachyury induces in tumor cells EMT, an important step in the progression of primary tumors toward metastasis. Overexpression of Brachyury in human carcinoma cells induced changes characteristic of EMT, including upregulation of mesenchymal markers, downregulation of epithelial markers, and an increase in cell migration and invasion. Conversely, inhibition of Brachyury resulted in downregulation of mesenchymal markers and loss of cell migration and invasion and diminished the ability of human tumor cells to form lung metastases in a xenograft model. Furthermore, we found Brachyury to be overexpressed in various human tumor tissues and tumor cell lines compared with normal tissues. The selective expression of Brachyury in tumor cells and its role in EMT and cancer progression suggest that Brachyury may be an attractive target for antitumor therapies. We have also evaluated Brachyury as a potential target for lung cancer therapy. Our results showed Brachyury protein expression in 41% of primary lung carcinomas, including 48% of adenocarcinomas and 25% of squamous cell carcinomas. With the exception of normal testis and some thyroid tissues, the majority of normal tissues evaluated in this study were negative for the expression of Brachyury protein. Brachyury-specific T cells could lyse Brachyury-positive tumors and the level of Brachyury corresponded to resistance of tumor cells to EGFR kinase inhibition. We hypothesize that the elimination of Brachyury-positive tumor cells may be able to prevent and/or diminish tumor dissemination and the establishment of metastases. The ability of Brachyury-specific T-cell lines to lyse Brachyury-positive tumor cells, in vitro, supports the development of Brachyury-based immunotherapeutic approaches for the treatment of lung cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010972-05
Application #
8552906
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2012
Total Cost
$887,872
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
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