Major scientific achievements include: (a) The completion of the first clinical trials employing an admixture of vectors containing transgenes for a costimulatory molecule and a TAA. Three clinical studies in patients with different stages of prostate cancer demonstrated that vaccine (rV-PSA + rV-B7.1 followed by rF-PSA) could be safely employed with external beam irradiation of tumor, second line hormone therapy, and Taxotere, and provided preliminary evidence of prolongation of time to disease progression, and antigen cascade post-vaccination. (b) The completion of the first clinical trials with rV-, rF-PSA-TRICOM vaccines in patients with metastatic prostate cancer. These studies provided evidence of clinical benefit that correlated with the generation of PSA-specific T-cell responses. These trials have led to planned NCI-sponsored randomized multicenter Phase II and III trials in D0 and D0.5 patients. (c) Completion of the first Phase I/II collaborative clinical trial employing vaccines containing transgenes for three costimulatory molecules (rV-, rF-CEA-TRICOM). This trial demonstrated the advantage of a diversified prime and boost vaccination schema with the inclusion of GM-CSF. Preliminary evidence was seen correlating CEA-specific T-cell responses and survival; this trial also provided evidence for the need for continued boosting with vaccine to maintain disease stabilization. (d) Completion of the first NCI clinical trial employing rV-, rF-PANVAC (CEA-MUC-1-TRICOM) vaccines plus GM-CSF. This trial provided evidence of clinical activity that has led to subsequent clinical trials at NCI and other Cancer Centers. Based on promising hypothesis-driven preclinical results, described in Projects A1-A3, science-based trials have been initiated involving (e) s.c./intratumoral vaccination, in locally advanced prostate cancer, employing i.t. vaccination of rF-PSA-TRICOM plus rF-GM-CSF, (f) CEA-TRICOM vaccination plus external beam irradiation of colon cancer metastatic lesions, (g) vaccine plus anti-CTLA-4 MAb in patients with metastatic prostate cancer, (h) the use of palliative 153Sm-chelate (to alter the phenotype of bone metastases) plus PSA-TRICOM vaccination in prostate cancer patients with bone metastases (in review). (i) The establishment of a network of collaborative clinical trials to provide a scientific-based programmatic approach to cancer vaccine clinical trial development.
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