Immunotherapy of a human papillomavirus type 16 E7-expressing tumor by administration of fusion protein comprised of Mycobacterium bovis BCG Hsp65 and HPV16 E7.
Human papillomavirus type 16 (HPV16) infection has been linked to the development of cervical and anal dysplasia and cancer. One hallmark of persistent infection is the synthesis of the viral E7 protein in cervical epithelial cells. The expression of E7 in dysplastic and transformed cells and its recognition by the immune system as a foreign antigen make it an ideal target for immunotherapy. Utilizing the E7-expressing murine tumor cell line, TC-1, as a model of cervical carcinoma, an immunotherapy based on the administration of an adjuvant-free fusion protein comprised of Mycobacterium bovis BCG Hsp65 linked to HPV16 E7 (HspE7) has been developed. Initial in vitro analyses indicate that immunization with HspE7 results in the induction of a type 1 immune response based on the pattern of secreted cytokines and the presence of cytolytic activity following antigenic recall. It has been previously shown that prophylactic immunization with HspE7 protected mice against challenge with TC-1 cells and that these tumor-free animals are also protected against rechallenge with TC-1 cells. The present report shows that a single therapeutic immunization with HspE7 induces regression of palpable tumors, confers protection against tumor rechallenge, and is associated with long-term survival (>253 days). In vivo studies using mice with targeted mutations in CD8 or MHC class II or depleted of CD8 or CD4 lymphocyte subsets demonstrate that tumor regression following therapeutic HspE7 immunization is CD8 dependent and CD4 independent. These studies extend previous observations on the induction of CTL by Hsp fusion proteins and are consistent with the clinical application of HspE7 as an immunotherapy for human cervical and anal dysplasia and cancer.
Chu
N R
NR
StressGen Biotechnologies Corp, Victoria, BC, Canada. rchu@stressgen.com
Wu
H B
HB
Wu
T C
TC
Boux
L J
LJ
Mizzen
L A
LA
Siegel
M I
MI
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001426:Bacterial Proteins; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology; D018834:Chaperonin 60; D018833:Chaperonins / Q000235:genetics* / Q000276:immunology*; D005260:Female; D015870:Gene Expression / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics / Q000276:immunology; D007167:Immunotherapy / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009163:Mycobacterium bovis / Q000235:genetics / Q000276:immunology*; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000276:immunology*; D050725:Papillomavirus E7 Proteins; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016019:Survival Analysis; D002583:Uterine Cervical Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy*
D000906:Antibodies; D001426:Bacterial Proteins; D016827:CD8 Antigens; D018834:Chaperonin 60; D000949:Histocompatibility Antigens Class II; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D011993:Recombinant Fusion Proteins; C074119:heat-shock protein 65, Mycobacterium; C059731:oncogene protein E7, Human papillomavirus type 16; D018833:Chaperonins