Immunotherapy with recombinant SFV-replicons expressing the P815A tumor antigen or IL-12 induces tumor regression.
Replicons based on alphaviruses are emerging as candidate vectors for vaccination and gene therapy purposes. We have reported previously that mice vaccinated with a recombinant Semliki Forest virus (a member of the alphavirus genus) carrying the gene encoding the P815A tumor antigen (rSFV/E-P1A) were protected against a lethal challenge with the P815 tumor. In this study we investigated the anti-tumor therapeutic efficacy of rSFV/E-P1A or rSFV expressing the cytokine interleukin 12 (rSFV/IL12) on Day 5-established tumors. The results show that both antigen-specific and cytokine-mediated rSFV treatments exhibited a significant effect on P815 tumor growth, by delaying tumor progression and even inducing complete tumor regressions in several mice. The therapeutic potency of these vectors was dependent on the size of the treated tumor, as treatment of mice bearing larger tumors showed lower efficacy. In addition, rSFV treatment resulted in long-term immunity as observed by the lack of tumor recurrence in the majority of tumor-regressing mice after rechallenge with the tumor. Furthermore, the anti-tumor therapeutic effect was only achieved by local intratumoral injection of rSFV, as treatment by injection in the contralateral site resulted in tumor progression comparable to control-untreated mice. Accordingly, expression of a rSFV-RNA was localized to the tumor and draining lymph node. These results further demonstrate the potential of rSFV replicons as tumor therapeutic agents.
Colmenero
Paula
P
Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden. puacol@ki.se
Chen
Margaret
M
Castaños-Velez
Esmeralda
E
Liljeström
Peter
P
Jondal
Mikael
M
D000818:Animals; D000951:Antigens, Neoplasm / Q000235:genetics*; D002460:Cell Line; D004274:DNA, Recombinant / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015870:Gene Expression; D007167:Immunotherapy / Q000379:methods*; D018664:Interleukin-12 / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009374:Neoplasms, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D012313:RNA / Q000235:genetics / Q000378:metabolism; D012074:Remission Induction; D012672:Semliki forest virus / Q000235:genetics*; D013997:Time Factors
D000951:Antigens, Neoplasm; D004274:DNA, Recombinant; C076546:tumor rejection antigen P815A, mouse; D018664:Interleukin-12; D012313:RNA