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 (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. Access through your institution Buy or subscribe This is a preview of subscription content, access via your institution ACCESS OPTIONS Access through your institution

Subscribe to this journal Receive 6 print issues and online access $259.00 per year only $43.17 per issue Learn more Buy this article * Purchase on SpringerLink * Instant access to full

article PDF Buy now Prices may be subject to local taxes which are calculated during checkout ADDITIONAL ACCESS OPTIONS: * Log in * Learn about institutional subscriptions * Read our FAQs *

Contact customer support SIMILAR CONTENT BEING VIEWED BY OTHERS COMBINATION IMMUNOTHERAPY WITH TWO ATTENUATED _LISTERIA_ STRAINS CARRYING SHUFFLED HPV-16 E6E7 PROTEIN CAUSES TUMOR REGRESSION

IN A MOUSE TUMOR MODEL Article Open access 28 June 2021 VIRUS AGAINST VIRUS: STRATEGIES FOR USING ADENOVIRUS VECTORS IN THE TREATMENT OF HPV-INDUCED CERVICAL CANCER Article 25 February 2021

A SAFE AND POTENTIATED MULTI-TYPE HPV L2-E7 NANOPARTICLE VACCINE WITH COMBINED PROPHYLACTIC AND THERAPEUTIC ACTIVITY Article Open access 26 June 2024 REFERENCES * Daemen T, Regts J, Holtrop

M, Wilschut J . Immunization strategy against cervical cancer involving an alphavirus vector expressing high levels of a stable fusion protein of human papillomavirus 16 E6 and E7. _Gene

Therapy_ 2002; 9: 85–94. Article  CAS  PubMed  Google Scholar  * Daemen T, Riezebos-Brilman A, Bungener L, Regts J, Dontje B, Wilschut J . Eradication of established HPV16-transformed

tumours after immunisation with recombinant Semliki Forest virus expressing a fusion protein of E6 and E7. _Vaccine_ 2003; 21: 1082–1088. Article  CAS  PubMed  Google Scholar  * Daemen T,

Riezebos-Brilman A, Regts J, Dontje B, van der Zee A, Wilschut J . Superior therapeutic efficacy of alphavirus-mediated immunization against human papilloma virus type 16 antigens in a

murine tumour model: effects of the route of immunization. _Antivir Ther_ 2004; 9: 733–742. PubMed  Google Scholar  * Riezebos-Brilman A, Regts J, Freyschmidt EJ, Dontje B, Wilschut J,

Daemen T . Induction of human papilloma virus E6/E7-specific cytotoxic T-lymphocyte activity in immune-tolerant, E6/E7-transgenic mice. _Gene Therapy_ 2005; 12: 1410–1414. Article  CAS 

PubMed  Google Scholar  * Riezebos-Brilman A, de Mare A, Bungener L, Huckriede A, Wilschut J, Daemen T . Recombinant alphaviruses as vectors for anti-tumour and anti-microbial immunotherapy.

_J Clin Virol_ 2006; 35: 233–243. Article  CAS  PubMed  Google Scholar  * Bungener L, de Mare A, de Vries-Idema J, Sehr P, van der Zee A, Wilschut J _et al_. A virosomal immunization

strategy against cervical cancer and pre-malignant cervical disease. _Antivir Ther_ 2006; 11: 717–727. CAS  PubMed  Google Scholar  * Bosch FX, Lorincz A, Munoz N, Meijer CJ, Shah KV . The

causal relation between human papillomavirus and cervical cancer. _J Clin Pathol_ 2002; 55: 244–265. Article  CAS  PubMed  PubMed Central  Google Scholar  * Walboomers JM, Jacobs MV, Manos

MM, Bosch FX, Kummer JA, Shah KV _et al_. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. _J Pathol_ 1999; 189: 12–19. Article  CAS  PubMed  Google Scholar 

* Doorbar J . The papillomavirus life cycle. _J Clin Virol_ 2005; 32 (Suppl 1): S7–S15. Article  CAS  PubMed  Google Scholar  * Munger K, Howley PM . Human papillomavirus immortalization and

transformation functions. _Virus Res_ 2002; 89: 213–228. Article  CAS  PubMed  Google Scholar  * Eiben GL, Velders MP, Kast WM . The cell-mediated immune response to human

papillomavirus-induced cervical cancer: implications for immunotherapy. _Adv Cancer Res_ 2002; 86: 113–148. Article  CAS  PubMed  Google Scholar  * Dummer R, Hassel JC, Fellenberg F,

Eichmuller S, Maier T, Slos P _et al_. Adenovirus-mediated intralesional interferon-gamma gene transfer induces tumor regressions in cutaneous lymphomas. _Blood_ 2004; 104: 1631–1638.

Article  CAS  PubMed  Google Scholar  * Nemunaitis J, Sterman D, Jablons D, Smith JW, Fox B, Maples P _et al_. Granulocyte-macrophage colony-stimulating factor gene-modified autologous tumor

vaccines in non-small-cell lung cancer. _J Natl Cancer Inst_ 2004; 96: 326–331. Article  CAS  PubMed  Google Scholar  * Reid T, Warren R, Kirn D . Intravascular adenoviral agents in cancer

patients: lessons from clinical trials. _Cancer Gene Ther_ 2002; 9: 979–986. Article  CAS  PubMed  PubMed Central  Google Scholar  * Jooss K, Yang Y, Fisher KJ, Wilson JM . Transduction of

dendritic cells by DNA viral vectors directs the immune response to transgene products in muscle fibers. _J Virol_ 1998; 72: 4212–4223. CAS  PubMed  PubMed Central  Google Scholar  * Tatsis

N, Ertl HC . Adenoviruses as vaccine vectors. _Mol Ther_ 2004; 10: 616–629. Article  CAS  PubMed  Google Scholar  * Nwanegbo E, Vardas E, Gao W, Whittle H, Sun H, Rowe D _et al_. Prevalence

of neutralizing antibodies to adenoviral serotypes 5 and 35 in the adult populations of The Gambia, South Africa, and the United States. _Clin Diagn Lab Immunol_ 2004; 11: 351–357. CAS 

PubMed  PubMed Central  Google Scholar  * Vogels R, Zuijdgeest D, van Rijnsoever R, Hartkoorn E, Damen I, de Bethune MP _et al_. Replication-deficient human adenovirus type 35 vectors for

gene transfer and vaccination: efficient human cell infection and bypass of preexisting adenovirus immunity. _J Virol_ 2003; 77: 8263–8271. Article  CAS  PubMed  PubMed Central  Google

Scholar  * Shayakhmetov DM, Li ZY, Ni S, Lieber A . Analysis of adenovirus sequestration in the liver, transduction of hepatic cells, and innate toxicity after injection of fiber-modified

vectors. _J Virol_ 2004; 78: 5368–5381. Article  CAS  PubMed  PubMed Central  Google Scholar  * St George JA . Gene therapy progress and prospects: adenoviral vectors. _Gene Therapy_ 2003;

10: 1135–1141. Article  CAS  PubMed  Google Scholar  * Colmenero P, Berglund P, Kambayashi T, Biberfeld P, Liljestrom P, Jondal M . Recombinant Semliki Forest virus vaccine vectors: the

route of injection determines the localization of vector RNA and subsequent T cell response. _Gene Therapy_ 2001; 8: 1307–1314. Article  CAS  PubMed  Google Scholar  * Sato Y, Shiraishi Y,

Furuichi T . Cell specificity and efficiency of the Semliki forest virus vector- and adenovirus vector-mediated gene expression in mouse cerebellum. _J Neurosci Methods_ 2004; 137: 111–121.

Article  CAS  PubMed  Google Scholar  * Bronte V, Cingarlini S, Apolloni E, Serafini P, Marigo I, De Santo C _et al_. Effective genetic vaccination with a widely shared endogenous retroviral

tumor antigen requires CD40 stimulation during tumor rejection phase. _J Immunol_ 2003; 171: 6396–6405. Article  CAS  PubMed  Google Scholar  * Lin CT, Hung CF, Juang J, He L, Lin KY, Kim

TW _et al_. Boosting with recombinant vaccinia increases HPV-16 E7-Specific T cell precursor frequencies and antitumor effects of HPV-16 E7-expressing Sindbis virus replicon particles. _Mol

Ther_ 2003; 8: 559–566. Article  CAS  PubMed  Google Scholar  * Sutmuller RP, van Duivenvoorde LM, van Elsas A, Schumacher TN, Wildenberg ME, Allison JP _et al_. Synergism of cytotoxic T

lymphocyte-associated antigen 4 blockade and depletion of CD25(+) regulatory T cells in antitumor therapy reveals alternative pathways for suppression of autoreactive cytotoxic T lymphocyte

responses. _J Exp Med_ 2001; 194: 823–832. Article  CAS  PubMed  PubMed Central  Google Scholar  * Fitzgerald JC, Gao GP, Reyes-Sandoval A, Pavlakis GN, Xiang ZQ, Wlazlo AP _et al_. A simian

replication-defective adenoviral recombinant vaccine to HIV-1 gag. _J Immunol_ 2003; 170: 1416–1422. Article  CAS  PubMed  Google Scholar  * Barouch DH, Pau MG, Custers JH, Koudstaal W,

Kostense S, Havenga MJ _et al_. Immunogenicity of recombinant adenovirus serotype 35 vaccine in the presence of pre-existing anti-Ad5 immunity. _J Immunol_ 2004; 172: 6290–6297. Article  CAS

  PubMed  Google Scholar  * Casimiro DR, Chen L, Fu TM, Evans RK, Caulfield MJ, Davies ME _et al_. Comparative immunogenicity in rhesus monkeys of DNA plasmid, recombinant vaccinia virus,

and replication-defective adenovirus vectors expressing a human immunodeficiency virus type 1 gag gene. _J Virol_ 2003; 77: 6305–6313. Article  CAS  PubMed  PubMed Central  Google Scholar  *

Berglund P, Fleeton MN, Smerdou C, Liljestrom P . Immunization with recombinant Semliki Forest virus induces protection against influenza challenge in mice. _Vaccine_ 1999; 17: 497–507.

Article  CAS  PubMed  Google Scholar  * Huckriede A, Bungener L, Holtrop M, de Vries J, Waarts BL, Daemen T _et al_. Induction of cytotoxic T lymphocyte activity by immunization with

recombinant Semliki Forest virus: indications for cross-priming. _Vaccine_ 2004; 22: 1104–1113. Article  CAS  PubMed  Google Scholar  * Chen M, Barnfield C, Naslund TI, Fleeton MN,

Liljestrom P . MyD88 expression is required for efficient cross-presentation of viral antigens from infected cells. _J Virol_ 2005; 79: 2964–2972. Article  CAS  PubMed  PubMed Central 

Google Scholar  * Fournier P, Zeng J, Schirrmacher V . Two ways to induce innate immune responses in human PBMCs: paracrine stimulation of IFN-alpha responses by viral protein or dsRNA. _Int

J Oncol_ 2003; 23: 673–680. CAS  PubMed  Google Scholar  * Wang L, Smith D, Bot S, Dellamary L, Bloom A, Bot A . Noncoding RNA danger motifs bridge innate and adaptive immunity and are

potent adjuvants for vaccination. _J Clin Invest_ 2002; 110: 1175–1184. Article  CAS  PubMed  PubMed Central  Google Scholar  * Mercier S, Gahery-Segard H, Monteil M, Lengagne R, Guillet JG,

Eloit M _et al_. Distinct roles of adenovirus vector-transduced dendritic cells, myoblasts, and endothelial cells in mediating an immune response against a transgene product. _J Virol_

2002; 76: 2899–2911. Article  CAS  PubMed  PubMed Central  Google Scholar  * Tillman BW, de Gruijl TD, Luykx-de Bakker SA, Scheper RJ, Pinedo HM, Curiel TJ _et al_. Maturation of dendritic

cells accompanies high-efficiency gene transfer by a CD40-targeted adenoviral vector. _J Immunol_ 1999; 162: 6378–6383. CAS  PubMed  Google Scholar  * Rea D, Schagen FH, Hoeben RC, Mehtali

M, Havenga MJ, Toes RE _et al_. Adenoviruses activate human dendritic cells without polarization toward a T-helper type 1-inducing subset. _J Virol_ 1999; 73: 10245–10253. CAS  PubMed 

PubMed Central  Google Scholar  * de Gruijl TD, Ophorst OJ, Goudsmit J, Verhaagh S, Lougheed SM, Radosevic K _et al_. Intradermal delivery of adenoviral type-35 vectors leads to high

efficiency transduction of mature, CD8+ T cell-stimulating skin-emigrated dendritic cells. _J Immunol_ 2006; 177: 2208–2215. Article  CAS  PubMed  Google Scholar  * Wherry EJ, Teichgraber V,

Becker TC, Masopust D, Kaech SM, Antia R _et al_. Lineage relationship and protective immunity of memory CD8 T cell subsets. _Nat Immunol_ 2003; 4: 225–234. Article  CAS  PubMed  Google

Scholar  * Lanzavecchia A, Sallusto F . Understanding the generation and function of memory T cell subsets. _Curr Opin Immunol_ 2005; 17: 326–332. Article  CAS  PubMed  Google Scholar  *

Gourley TS, Wherry EJ, Masopust D, Ahmed R . Generation and maintenance of immunological memory. _Semin Immunol_ 2004; 16: 323–333. Article  CAS  PubMed  Google Scholar  * Visser J, van

Baarle D, Hoogeboom BN, Reesink N, Klip H, Schuuring E _et al_. Enhancement of human papilloma virus type 16 E7 specific T cell responses by local invasive procedures in patients with

(pre)malignant cervical neoplasia. _Int J Cancer_ 2006; 118: 2529–2537. Article  CAS  PubMed  Google Scholar  * Visser JTJ, Hoogenboom BN, Jager P, Nijhuis E, Klip H, Nijman HW _et al_.

CD4+/CD25+ regulatory T cells are increased in cervical cancer patients and suppress T cell responses against human papilloma virus 16 E6 and E7. _Clin Exp Immunol_ 2007; in press. *

Feltkamp MC, Smits HL, Vierboom MP, Minnaar RP, de Jongh BM, Drijfhout JW _et al_. Vaccination with cytotoxic T lymphocyte epitope-containing peptide protects against a tumor induced by

human papillomavirus type 16- transformed cells. _Eur J Immunol_ 1993; 23: 2242–2249. Article  CAS  PubMed  Google Scholar  * van der Burg SH, Kwappenberg KM, O'Neill T, Brandt RM,

Melief CJ, Hickling JK _et al_. Pre-clinical safety and efficacy of TA-CIN, a recombinant HPV16 L2E6E7 fusion protein vaccine, in homologous and heterologous prime-boost regimens. _Vaccine_

2001; 19: 3652–3660. Article  CAS  PubMed  Google Scholar  * Ji H, Chang EY, Lin KY, Kurman RJ, Pardoll DM, Wu TC . Treatment of established tumors with a novel vaccine that enhances major

histocompatibility class II presentation of tumor antigen. _Cancer Res_ 1996; 56: 21–26. Google Scholar  * Gommans WM, van Eert SJ, McLaughlin PM, Harmsen MC, Yamamoto M, Curiel DT _et al_.

The carcinoma-specific epithelial glycoprotein-2 promoter controls efficient and selective gene expression in an adenoviral context. _Cancer Gene Ther_ 2006; 13: 150–158. Article  CAS 

PubMed  Google Scholar  * He TC, Zhou S, da Costa LT, Yu J, Kinzler KW, Vogelstein B . A simplified system for generating recombinant adenoviruses. _Proc Natl Acad Sci USA_ 1998; 95:

2509–2514. Article  CAS  PubMed  PubMed Central  Google Scholar  * Alemany R, Curiel DT . CAR-binding ablation does not change biodistribution and toxicity of adenovirus vectors. _Gene

Therapy_ 2001; 8: 1347–1353. Article  CAS  PubMed  Google Scholar  Download references AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Medical Microbiology, Molecular Virology

Section, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands A Riezebos-Brilman, M Walczak, J Regts, B Dontje, J Wilschut & T Daemen * Department of

Therapeutic Gene Modulation, Groningen University Institute for Drug Exploration (GUIDE), Groningen, The Netherlands M G Rots, G Kamps & H Y Haisma Authors * A Riezebos-Brilman View

author publications You can also search for this author inPubMed Google Scholar * M Walczak View author publications You can also search for this author inPubMed Google Scholar * J Regts

View author publications You can also search for this author inPubMed Google Scholar * M G Rots View author publications You can also search for this author inPubMed Google Scholar * G Kamps

View author publications You can also search for this author inPubMed Google Scholar * B Dontje View author publications You can also search for this author inPubMed Google Scholar * H Y

Haisma View author publications You can also search for this author inPubMed Google Scholar * J Wilschut View author publications You can also search for this author inPubMed Google Scholar

* T Daemen View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to T Daemen. RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Riezebos-Brilman, A., Walczak, M., Regts, J. _et al._ A comparative study on the immunotherapeutic efficacy of recombinant Semliki Forest

virus and adenovirus vector systems in a murine model for cervical cancer. _Gene Ther_ 14, 1695–1704 (2007). https://doi.org/10.1038/sj.gt.3303036 Download citation * Received: 01 January

2007 * Revised: 27 August 2007 * Accepted: 29 August 2007 * Published: 11 October 2007 * Issue Date: December 2007 * DOI: https://doi.org/10.1038/sj.gt.3303036 SHARE THIS ARTICLE Anyone you

share the following link with will be able to read this content: Get shareable link Sorry, a shareable link is not currently available for this article. Copy to clipboard Provided by the

Springer Nature SharedIt content-sharing initiative KEYWORDS * Semliki Forest virus * adenovirus * HPV * immunotherapy * viral vector * cervical