Clinical evaluation of TRICOM vector therapeutic cancer vaccines

Abstract

We have developed an "off-the-shelf" vector-based vaccine platform containing transgenes for carcinoma-associated antigens and multiple costimulatory molecules (designated TRICOM). Two TRICOM platforms have been evaluated both preclinically and in clinical trials. PROSTVAC consists of rV, rF-PSA-TRICOM and is being used in prostate cancer therapy trials. PANVAC consists of rV, rF-CEA-MUC1-TRICOM; the expression of the two pan-carcinoma transgenes CEA and MUC-1 renders PANVAC vaccination applicable for therapeutic applications for a range of human carcinomas. Many new paradigms have emerged as a consequence of completed and ongoing TRICOM vaccine trials, including (1) clinical evidence of patient benefit may be delayed, because multiple vaccinations may be necessary to induce a sufficient anti-tumor immune response; (2) survival, and not strict adherence to RECIST criteria or time-to-progression, may be the most appropriate trial endpoint when TRICOM vaccines are used as monotherapy; (3) certain patient populations are more likely to benefit from vaccine therapy as compared to other therapeutics; and (4) TRICOM vaccines combined with standard-of-care therapeutics, either concomitantly or sequentially, are feasible because of the limited toxicity of vaccines.

Published by Elsevier Inc.

Figures

Figure 1. TRICOM Therapeutic Cancer Vaccine Platform

The TRICOM vaccination platform consists of a single recombinant vaccinia (rV-) prime vaccination followed by six or more monthly booster vaccinations with recombinant fowlpox (rF-). Each of these vectors contains transgenes for one or more tumor-associated antigens and transgenes for three human T-cell costimulatory molecules (designated TRICOM) to enhance T-cell activation to the tumor antigens.-, For prostate cancer trials, rV-, rF-PSA-TRICOM (also designated PROSTVAC) is employed., , For trials of other carcinomas (breast, colorectal, etc.), the pan-carcinoma antigen transgenes for carcinoembryonic antigen CEA and MUC-1 are used along with TRICOM, i.e., rV-, rF-CEA-MUC-1-TRICOM (designated PANVAC)., , Vaccinations are given subcutaneously.

Figure 2. Overall Survival Advantage Using Cancer Vaccines

A, Overall survival of a randomized, placebo (empty vector) controlled 43-center trial of PSA-TRICOM vaccine in patients with metastatic castrate-resistant prostate cancer. There was an overall survival advantage of 8.5 months (p=0.006) and a 44% reduction in death in the vaccine arm. Adapted from Kantoff et al.

Figure 3. Tumor Growth Rates Following Chemotherapy vs. Vaccine Therapy

Adapted from data in ref. 29. A, Growth rate of tumor if no therapy is initiated (a). An examination of five clinical trials (four with chemotherapy and one with PSA-TRICOM vaccine) in patients with mCRPC demonstrated that with the use of chemotherapy there was an initial tumor reduction, but that the growth rate of tumors at relapse (b) was similar to the initial tumor growth rate prior to therapy; this is contrasted with the reduction in tumor growth rate following vaccine therapy (c). Thus for patients with little or any tumor reduction (and thus virtually no increase in time to progression), an increase in survival was observed. B, This phenomenon could potentially be enhanced if vaccine therapy is initiated earlier in disease progression or in patients with low tumor burden metastatic disease (d), but would have minimal effect in patients with large tumor burden (e). C, Additional therapies received with vaccine may take advantage of both modalities. †, projected time of death.