Abstract SY24-02: Development of recombinant vaccines for the prevention and therapy of human carcinomas
Authors: Schlom Jeffrey , Gulley James L. , Madan Ravi A. , Tsang Kwong-Yok , Greiner John W. , Palena Claudia , Hodge James W. 
Published: June 2012

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, this survival advantage was seen in the absence of any advantage in time to progression. Toxicity in this and other TRICOM trials was minimal. A second single-arm trial with PROSTVAC demonstrated a similar survival benefit. Patients who survived longer on vaccine had higher ratios of effector-to-regulatory T cells. A phase III trial with PROSTVAC is scheduled to begin in 2011. Preliminary evidence of patient benefit is being observed in the use of PROSTVAC vaccine in ongoing randomized trials employing (a) Samarium 153 chelate (Quadramet) plus or minus vaccine in prostate cancer patients with metastatic bone lesions, (b) hormone therapy plus or minus vaccine in hormone refractory “nonmetastatic” prostate cancer patients with rising PSA, and (c) in a multicenter trial in hormone naive prostate cancer patients following treatment of their primary tumor but with rising PSA. A nonrandomized study has also provided evidence of clinical benefit for the use of PROSTVAC with anti-CTLA4 MAb in patients with metastatic prostate cancer.

Clinical trials are also ongoing in the use of CEA-MUC-1-TRICOM vaccine (PANVAC). A multicenter trial (M. Morse, H.K. Lyerly, PIs, Duke Cancer Center) in patients receiving PANVAC following surgery for metastatic colorectal cancer also provided preliminary evidence of increased patient survival in the absence of time to progression. An ongoing randomized trial at NCI in patients with metastatic breast carcinoma employing Docetaxel plus or minus PANVAC is also providing preliminary evidence of patient benefit in the vaccine arm.

Immune Trageting of Cells with Enhanced Metastatic Potential: The use of surgery, radiation and/or adjuvant chemotherapy will control most primary carcinomas. It is believed, however, that a subpopulation of cells with higher invasive and metastatic potential, and greater resistance to conventional therapy is responsible for eventual metastatic spread. The goal is to identify molecules involved in these processes of tumor progression and to target them immunologically. We have recently identified the T-box transcription factor Brachyury as a master driver of the epithelial-to-mesenchymal transition (EMT) phenotype process for a range of human carcinoma cells. The EMT process has been implicated by others as a major factor in tumor invasion and metastases. We have now demonstrated in preclinical studies that enhanced expression of Brachyury in a range of human carcinoma cells leads to a switch in phenotype from epithelial to mesenchymal, increased migration and invasion in vitro, and increased metastatic spread in vivo; silencing Brachyury RNA in carcinoma cells has shown reciprocal results. Unlike several other EMT drivers examined, Brachyury is selectively expressed in a range of human carcinomas vs. normal adult human tissues with the exception of testes. We have now demonstrated the ability to generate Brachyury-specific human T cells, which in turn have the ability to lyse human carcinoma cells expressing Brachyury in an MHC-restricted manner. We are in the process of generating clinical grade recombinant Brachyury vaccine.

References:

1. Kantoff P, Schuetz TJ, Blumenstein BA, Glode LM, Bilhartz DL, Wyand M, Manson K, Panicali DL, Laus R, Schlom J, Dahut W, Arlen PM, Gulley JL, Godfrey WR. Overall survival (OS) analysis of a Phase II randomized controlled trial (RCT) of a poxviral-based PSA targeted immunotherapy in metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2010;28:1099-1105.

2. Gulley JL, Arlen PM, Madan RA, Tsang K-Y, Pazdur MP, Skarupa L, Jones JL, Poole DJ, Higgins JP, Hodge JW, Cereda V, Vergati M, Steinberg SM, Halabi S, Jones E, Chen C, Parnes H, Wright JJ, Dahut WL, Schlom J. Immunologic and prognostic factors associated with overall survival employing a poxviral-based PSA vaccine in metastatic castrate-resistant prostate cancer. Cancer Immunol Immunother. 2010;59:663-674.

3. Palena C, Polev DE, Tsang KY, Fernando RI, Litzinger M, Krukovskaya LL, Baranova AV, Kozlov AP, and Schlom J. The human T-box mesodermal transcription factor Brachyury is a candidate target for T-cell mediated cancer immunotherapy. Clin Cancer Res. 13:2471-2478, 2007.

4. Fernando RI, Fernando RI, Litzinger M, Trono P, Hamilton DH, Schlom J, and Palena C. The T-box transcription factor Brachyury promotes epithelial-to-mesenchymal transition in human tumor cells. J Clin Invest.120:533-544, 2010.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY24-02. doi:10.1158/1538-7445.AM2011-SY24-02