1. ¹Department of Obstetrics and Gynecology, National Taiwan University Hospital, Taipei, Taiwan
2. ²Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan
3. ³Department of Pathology, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
4. ⁴Vaccines Research, Chiron Corporation, Emeryville, CA, USA
5. ⁵Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
6. ⁶Department of Obstetrics and Gynecology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
7. ⁷Department of Molecular Microbiology and Immunology, Johns Hopkins Medical Institutions, Baltimore, MD, USA
8. ⁸Department of Oncology, Johns Hopkins Medical Institutions, Baltimore, MD, USA

Correspondence: Dr C-A Chen, Department of Obstetrics and Gynecology, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan. E-mail: cachen@ha.mc.ntu.edu.tw

Received 11 July 2005; Revised 7 December 2005; Accepted 1 March 2006; Published online 28 April 2006.

Abstract

Alphavirus vectors have emerged as a promising strategy for the development of cancer vaccines and gene therapy applications. In this study, we used the replication-defective vaccine vector SIN replicon particles from a new packaging cell line (PCL) to develop SIN replicon particles encoding calreticulin (CRT) linked to a model tumor antigen, human papillomavirus type 16 (HPV16) E7 protein. The linkage of CRT to E7 in SIN replicon particles resulted in a significant increase in E7-specific CD8⁺ T-cell precursors and a strong antitumor effect against E7-expressing tumors in vaccinated mice. SINrep5-CRT/E7 replicon particles enhanced presentation of E7 through the major histocompatibility complex (MHC) class I pathway by infecting dendritic cells (DCs) directly and pulsing DCs with lysates of cells infected by SINrep5-CRT/E7 replicons. Vaccination of immunocompromised (BALB/c nu/nu) mice with SINrep5-CRT/E7 replicon particles also generated significant reduction of lung tumor nodules, suggesting that antiangiogenesis may contribute to the antitumor effect of SINrep5-CRT/E7 replicon particles. Furthermore, SINrep5-CRT/E7 replicon particles generated long-term in vivo tumor protection effects and antigen-specific memory immunities. We concluded that the CRT strategy used in the context of SIN replicon particles facilitated the generation of a highly effective vaccine for cancer prophylaxis and immunotherapy.