Abstract SY24-02: Development of recombinant vaccines for the prevention and therapy of human carcinomas

• Published in: Cancer research (Chicago, Ill.) Ill.), 2011-04, Vol.71 (8_Supplement), p.SY24-02-SY24-02
• Main Authors: Schlom, Jeffrey, Gulley, James L., Madan, Ravi A., Tsang, Kwong-Yok, Greiner, John W., Palena, Claudia, Hodge, James W.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2011-SY24-02

There are several situations for which vaccines can be employed in the prevention and treatment of human carcinomas. True prevention of cervical cancer has been demonstrated in the use of the HPV vaccine (Gardasil). The Sipuleucel-T “dendritic cell”-based vaccine (Dendreon) has recently been approved by the FDA for the treatment of metastatic prostate cancer. The low levels of toxicity seen with many cancer therapeutic vaccines has led to interest in the potential use of these vaccines in patients with high-risk preneoplastic conditions such as familial adenomatous polyposis (FAP), high-grade prostatic epithelial neoplasia (PIN), and in patients with preneoplastic breast lesions. Clinical studies are ongoing and planned in the use of vaccines in adjuvant settings in patients rendered disease free radiographically, but with a high risk of developing metastatic disease. Preclinical Studies: We have developed a recombinant poxviral vaccine platform (recombinant vaccinia prime and multiple avixpox booster vaccination) with each vector containing the transgenes for one or more tumor-associated antigens and the transgenes for a triad of T-cell costimulatory molecules (TRICOM). These are “off-the-shelf” vaccines that can and have been widely distributed for clinical studies. In preclinical studies, these vaccines have demonstrated the ability to induce increased levels of high-avidity antigen-specific T cells and induce antitumor effects in several animal models. The use of a CEA-TRICOM vaccine with Celebrex was shown to enhance survival in a preneoplastic model for FAP at far greater levels than either agent alone. Preclinical studies also demonstrated the synergy in the use of TRICOM vaccines with local radiation of tumor or certain chemotherapeutic agents (both modalities have been shown to alter the phenotype of tumor cells and rendered them more susceptible to T-cell killing). Anti-CTLA4 MAb was also shown to synergize with TRICOM vectors to enhance T-cell avidity. Several of the above findings have led to completed and ongoing clinical studies. Clinical Studies: A 43-center placebo (empty vector)-controlled randomized trial employing PSA-TRICOM vaccine (PROSTVAC) in patients with metastatic prostate cancer demonstrated that PROSTVAC vaccinated patients had a superior overall survival at 3 years post-study (30% vs. 17% alive) and a longer median overall survival by 8.5 months (25.1 vs. 16.6 months, p=0.0061, HR 0.56). As with the Sipuleucel-T vaccine trial,