A comparative study on the immunotherapeutic efficacy of recombinant Semliki Forest virus and adenovirus vector systems in a murine model for cervical cancer

Abstract

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 (AdeE6,7). 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, antivector 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.

Therapeutic immunization and local low‐dose tumor irradiation, a reinforcing combination

“…The rSFV replicon particles encode a fusion protein of E6 and E7 derived from the most prevalent HPV type, HPV type 16 (SFVeE6,7) . We have successfully shown that immunization with SFVeE6,7 particles induces strong HPV‐specific cellular responses and eradication of established HPV‐transformed tumors …”

Oncolytic Alphaviruses in Cancer Immunotherapy

“…Moreover, the transient nature of high level recombinant protein expression and rapid RNA replication with no risk of genome integration, are additional features making alphavirus vectors attractive. In relation to other viral vectors, 100–1000-fold lower doses of SFV were needed to elicit therapeutic efficacy of HPV E6-E7 immunization in comparison to vaccination with adenovirus vectors [107]. The tumor-targeting property of oncolytic alphaviruses has offered enhanced tumor growth inhibition and tumor eradication.…”

From Tumor Immunosuppression to Eradication: Targeting Homing and Activity of Immune Effector Cells to Tumors

“…A comparative study between the prime-boosting efficacy of SFVeE6,7 and that of the recombinant adenovirus type 5 vector expressing the same antigen construct (Ad-eE6,7) revealed that SFVeE6,7 vaccination lead to higher precursor CTL frequencies and activity when compared to Ad-eE6,7 vaccination. The efficacy of SFVeE6,7 vaccination in murine tumor treatment experiments was significantly higher than that of the Ad-eE6,7 counterpart [172]. Also, low doses of IL-12 expressed by a SFV virus vector (SFV-IL12) augmented the antigen-specific and antitumor responses induced by the virus vector alone [173].…”