ZIA BC 010598 (ZIA) | |||
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Title | Human Immune Responses to Tumor Antigens for Cancer Vaccine Development | ||
Institution | NCI, Bethesda, MD | ||
Principal Investigator | Schlom, Jeffrey | NCI Program Director | N/A |
Cancer Activity | N/A | Division | CCR |
Funded Amount | $594,675 | Project Dates | 10/01/2003 - 00/00/0000 |
Fiscal Year | 2014 | Project Type | Intramural |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Digestive Diseases (20.0%) |
Breast (15.0%) Colon/Rectum (20.0%) Hodgkins disease (5.0%) Leukemia (5.0%) Lung (5.0%) Multiple Myeloma (5.0%) Non Hodgkins Lymphoma (5.0%) Ovarian Cancer (5.0%) Prostate (30.0%) |
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Research Type | |||
Vaccines Systemic Therapies - Discovery and Development |
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Abstract | |||
[] We have continued our preclinical and clinical investigations of two diverse recombinant (rec.) vaccine platforms (each with demonstrated unique properties): (a) recombinant poxviral vectors employing a recombinant vaccinia prime followed by multiple recombinant fowlpox booster vaccinations; each vector contains the transgenes for one or more tumor-associated antigens (TAAs) and three T-cell costimulatory molecules (designated TRICOM); and (b) heat-killed rec. Saccharomyces cerevisiae (yeast) containing TAA protein via the insertion of a yeast plasmid. [] We have analyzed peripheral blood mononuclear cells from cancer patients both prior to and during standard-of-care therapies to determine whether specific regimens are suitable for use in combination with immunotherapeutics.Breast carcinoma patients undergoing treatment with docetaxel were shown to have some reductionin CD4+ and CD8+ T cells, but the even greater reduction in Tregs during therapy revealed greater eff:Treg ratios. [] Peripheral blood mononuclear cells were evaluated from non-small cell lung cancer patients prior to and during cisplatin/vinorelbine therapy. No differences during therapy were seen in CD4+ T cells, but the level of Tregs was decreased, and the suppressive activity of Tregs was decreased in the majority of patients. Similar findings were observed in metastatic prostate cancer patients treated with docetaxel. [] Numerous immune analyses pre- vs. post-treatment have been/are being employed in clinical studies in an attempt to identify which patients would most likely benefit from a given immunotherapy, and to evaluate potential immune correlates of clinical benefit early in the treatment cycle. It is emphasized that any correlations with clinical outcome using any of the immune assays described must be considered only exploratory. True correlations will require the use of validated assays in larger randomized trials. [] In addition to the use of the Elispot assay to define CD8+ responses in peripheral blood mononuclear cells to an immunodominant HLA-A2 epitope, we have now developed a FACS-based assay using 15-mer peptides reflecting entire TAA gene to simultaneously measure both CD4 and CD8 responses; this assay is not restricted by HLA allele. [] We have also analyzed the number, phenotype and suppressive function of Tregs and function of natural killer cells post- vs. pre-vaccination. [] We have developed assays to analyze numerous soluble factors in sera pre- and post-immunotherapy. In collaboration with Dr. J. Gildersleeve in the NCI Center for Cancer Research, we have profiled anti-glycan antibodies using glycan arrays in several of our PROSTVAC trials. Pre-vaccination levels of Abs to one specific glycan highly significantly (P=0.005) correlated with overall survival, while no correlations were seen in patients receiving empty vector placebo. Production of antibodies to a second glycan post- vs. pre-vaccination also correlated with overall survival. [] We have analyzed post- vs. pre-serum samples for a range of cytokines as well as two potential immunomodulatory molecules. We have shown that soluble CD40L (sCD40L) is elevated in the sera of patients with prostate cancer and metastatic breast and lung cancers. In vitro studies demonstrated sCD40L could enrich myeloid derived suppressor cells and expand Tregs. [] We have shown that soluble CD27 (sCD27) sera levels are decreased in carcinoma patients vs. healthy donors. Metastatic castration-resistant prostate cancer patients treated with PROSTVAC + ipilimumab showed a significant increase (P<0.0005) in sCD27 post-vaccination, which was associated with increased overall survival (P=0.022). In vitro studies demonstrated that sCD27 provides strong proliferative signals to lymphocytes. [] We have now developed a multi-laser/multi-color FACS-based assay to analyze up to 50 different immune cell subsets in PBMCs pre- vs. post-treatment. In one example, there were associations with overall survival" |