Abstracts

Immunotherapy in a K14-HPV16 Transgenic Model of Cervical Carcinogenesis by Administration of a Fusion Protein Comprising Mycobacterium bovis Bacille Calmette-Guerin (BCG) Hsp65 and HPV16 E7 (HspE7).

Abstract presented at Cancer Vaccines 2000 - New York, NY October 2-4, 2000

Daniel D.(1), Hanahan D.(1), Chu N.R.(2), Wu H.B.(2), Boux L.(3), Siegel M.I.(3), Mizzen L.A.(2)

1) Hormone Research Institute, Dept. of Biochem. and Biophysics, University of California, San Francisco, San Francisco, CA, USA.
2) Stressgen Biotechnologies Corporation, Victoria, BC, Canada.
3) Stressgen Biotechnologies, Inc., Collegeville, PA, USA.

Human papillomaviruses (HPVs) have been implicated in the genesis of squamous cell carcinomas (SCC) of the cervix. Our laboratory has developed a transgenic mouse model of HPV16-induced SCC of the cervix. In the model, the early gene region of HPV16, including the E6 and E7 oncogenes, are expressed under the control of the human keratin 14 promoter/enhancer (K14).
When female mice are treated with chronic 17b-estradiol, we observe a
multi-stage progression toward invasive carcinomas at the cervix transformation zone (1,2). When the transgenic mice are immunized with HPV16-E7, they mount a CD4+ T cell response, indicating that mice are not tolerant to E7 in the CD4+ T cell compartment. However, previous studies by other investigators have demonstrated that FVB/n mice, the background strain for our K14-HPV16 mice, may be incapable of generating a class I-restricted CD8+ T cell (CTL) response to HPV16-E7 (3). In collaboration with Stressgen Biotechnologies, we tested an immunotherapy based on the administration of an adjuvant-free fusion protein comprising Mycobacterium bovis BCG heat shock protein (Hsp) 65 linked to HPV16 E7 (HspE7) in estrogen implanted female K14-HPV16 mice. HspE7 immunization has previously been shown to elicit E7-specific cellular immunity, including CTL and to induce rejection
of a subcutaneously implanted HPV16-E7-expressing carcinoma cell line, TC-1, by a mechanism requiring CD8+ T cells (4). When K14-HPV16 mice with advanced dysplasias (CIN III) or small invasive SCCs were immunized with HspE7, we observed a decreased incidence of invasive SCCs (17% in HspE7-treated mice vs. 83% in PBS-treated controls, P=0.01 Fisher's test). Thus, the mechanism(s) by which HspE7 immunotherapy elicits an anti-tumour response in K14-HPV16 mice are of considerable interest, and will be initially addressed in future studies using mice with targeted mutations in CD4 and CD8.

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2) Elson DA, Riley RR, Lacey A, Thordarson G, Talamantes FJ, Arbeit JM.
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3) Herd K, Fernando GJ, Dunn LA, Frazer IH, Lambert P, Tindle RW. 1997. E7
oncoprotein of human papillomavirus type 16 expressed constitutively in the
epidermis has no effect on E7-specific B- or Th-repertoires or on the immune
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231:155-65.
4) Chu NR, Wu HB, Wu T, Boux LJ, Siegel MI, Mizzen LA. 2000. Immunotherapy
of a human papillomavirus (HPV) type 16 E7-expressing tumour by
administration of fusion protein comprising mycobacterium bovis bacille
calmette-Guerin (BCG) hsp65 and HPV16 E7. Clin Exp Immunol. 121:216-25.