A comparative study on the immunotherapeutic efficacy of recombinant Semliki Forest virus and adenovirus vector systems in a murine model for cervical cancer.
Currently, various therapeutic strategies are being explored as a potential means to immunize against metastatic malignant cells or even primary tumours. Using recombinant viral vectors systems or protein-based immunization approaches, we are developing immunotherapeutic strategies against cervical cancer or premalignant cervical disease, as induced by high-risk type human papillomaviruses (HPVs). We previously demonstrated that immunization of mice with recombinant replication-defective Semliki Forest virus (rSFV) encoding a fusion protein of HPV16 E6 and -E7 (SFV-eE6,7) induces strong cytotoxic T-lymphocyte (CTL) activity and eradication of established HPV-transformed tumours. In this study, we compared the antitumour efficacy of SFV-eE6,7 with that of a recombinant adenovirus (rAd) type 5 vector, expressing the same antigen construct (Ad-eE6,7). Prime-boosting with SFV-eE6,7 resulted in higher precursor CTL frequencies and CTL activity compared to prime-boosting with Ad-eE6,7 and also in murine tumour treatment experiments SFV-eE6,7 was more effective than Ad-eE6,7. To elicit a therapeutic effect with Ad-eE6,7, 100/1000-fold higher doses were needed compared to SFV-eE6,7. In vivo T-cell depletion experiments demonstrated that these differences could not be explained by the induction of a different type of effector cells, since CD8+ T cells were the main effector cells involved in the protection against tumour growth in both rSFV- and rAd-immunized mice. Also comparable amounts of in vivo transgene expression were found upon immunization with rSFV and rAd encoding the reportor gene luciferase. However, anti-vector responses induced by a single injection with rAd resulted in a more than 3-log decrease in luciferase expression after a second injection of rAd. With rSFV, transgene expression was inhibited by only one to two orders of magnitude in preinjected mice. As an antigen-specific booster immunization strongly increases the level of the CTL response and is essential for efficient induction of immunological memory, it is likely that (part of) the difference in efficacy between rSFV and rAd type 5 can be ascribed to a diminished efficacy of the booster immunization in the case of rAd due to anti-vector antibody responses.
Riezebos-Brilman
A
A
Department of Medical Microbiology, Molecular Virology Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
Walczak
M
M
Regts
J
J
Rots
M G
MG
Kamps
G
G
Dontje
B
B
Haisma
H Y
HY
Wilschut
J
J
Daemen
T
T
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D004306:Dose-Response Relationship, Immunologic; D005260:Female; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage / Q000235:genetics; D007117:Immunization, Secondary; D007267:Injections; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009856:Oncogene Proteins, Viral / Q000235:genetics / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D030361:Papillomavirus Infections / Q000276:immunology / Q000628:therapy*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology; D012097:Repressor Proteins / Q000235:genetics / Q000276:immunology; D012672:Semliki forest virus / Q000235:genetics*; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000628:therapy* / Q000821:virology; D014611:Vaccination / Q000379:methods*
C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; C059731:oncogene protein E7, Human papillomavirus type 16