Abstracts

A Mechanism For The Immunotherapeutic Potential Of Hspe7: Integration Of Innate And Adaptive Immunity

Abstract presented at HPV 2002 - Paris, France

Chu, N.R., Liu, H., Wu, B., Recktenwald, A., Rowse, G., Boux, H.A., Boux, L.(1), Mizzen, L. and Siegel, M.I.(1)

Stressgen Biotechnologies Corporation, Victoria, BC, Canada. and
1)Stressgen Biotechnologies, Inc., Collegeville, PA, USA

Immunotherapy is a promising approach to the treatment of HPV-associated disease. Administration of HspE7 (a protein comprised of BCG Hsp65 fused to HPV16 E7) as a soluble protein in saline provides clinical benefit in phase II immunotherapy trials of anogenital HPV diseases. To understand its intrinsic immunogenicity, the immune responses to HspE7 were compared using mice that differ in their functional expression of the innate immune receptor, Toll-like receptor 4 (Tlr4). Primed splenocytes from HspE7-immunized, Tlr4+ (C3H/HeN and C57Bl/10 ScSn) mice produce IFN-g and lyse E7 targets, respectively, upon restimulation. In contrast, primed splenocytes from Tlr4- mice (C3H/HeJ and C57Bl/10 ScNCr) produce IL-5 and do not lyse E7 targets, respectively, when restimulated. HspE7 induces TNF-a, IL-12p40 and GM-CSF production from resident peritoneal macrophages isolated from C3H/HeN and C3H/HeJ mice. Furthermore, HspE7 induces GM-CSF production from naïve splenocytes of both strains of mice and in addition, IFN-g and IL-6 from C3H/HeN splenocytes. Therefore the activity of HspE7 is largely Tlr4-dependent, providing an explanation for its intrinsic immunogenicity: via its interaction with Tlr4, HspE7 integrates innate and adaptive immune pathways resulting in the induction of cell-mediated immunity.