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Enhanced Generation of Cytotoxic T Lymphocytes Using Recombinant Vaccinia Virus Expressing Human Tumor-associated Antigens and B7 Costimulatory Molecules¹

Research Division, Department of Surgery, University of Basel, Center for Teaching and Research, 4031 Basel, Switzerland

In this work, we addressed the possibility to enhance the "in vitro" generation of CTLs recognizing tumor-associated antigens (TAAs) by using an inactivated recombinant vaccinia virus encoding B7.1 and B7.2 costimulatory molecules (rVV-B7.1/2). Antigen presenting cells (APCs) infected by rVV-B7.1/2 and pulsed with MART-1/Melan-A_27-35 HLA-A2.1-restricted peptide induced significantly higher specific cytotoxic activity than peptide-loaded APCs infected by wild-type VV, both in VV-sensitized and naive donors. When APCs were infected with a rVV encoding both MART-1/Melan-A_27–35 and B7-1/2 (rVV-B7.1/2-M), a significantly more effective CTL generation was observed as compared with cultures stimulated by APCs infected with a rVV encoding the TAA epitope only (rVV-M). These enhancing effects were detectable irrespective of a previous VV-specific sensitization. Most importantly, fibroblasts, devoid of antigen-presenting capacity upon peptide pulsing or infection with rVV-M, could be turned into effective APCs after infection by rVV encoding TAA epitopes and costimulatory molecules. In these experiments, by using separate recombinant viral constructs, we observed a predominant role of B7-1 as compared with B7-2 in the induction of TAA-specific CTLs. Taken together, our data indicate that replication-incompetent rVV encoding TAA epitopes and costimulatory molecules are able to induce highly effective generation of tumor-specific CTLs. Therefore, these vectors could represent valuable clinical tools for immunotherapy of melanoma patients.

¹ This work was supported by the Regional Leagues of Basel-Stadt and Basel-Land and the Swiss National Fund, Grants 31-52750.97 and 31-45560.95.

² To whom requests for reprints should be addressed, at ZLF, Hebelstrasse 20, 4031 Basel, Switzerland. Phone: 41-61-265-2330; Fax: 41-61-265-3990.

Received 5/18/98. Accepted 8/26/98.

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