Immunotherapy Against HPV16/18 Generates Potent TH1 and Cytotoxic Cellular Immune Responses

被引：240

作者：

Bagarazzi, Mark L. ^{[1
]}

Yan, Jian ^{[1
]}

Morrow, Matthew P. ^{[1
]}

Shen, Xuefei ^{[1
]}

Parker, R. Lamar ^{[2
]}

Lee, Jessica C. ^{[1
]}

Giffear, Mary ^{[1
]}

Pankhong, Panyupa ^{[3
]}

Khan, Amir S. ^{[1
]}

Broderick, Kate E. ^{[1
]}

Knott, Christine ^{[1
]}

Lin, Feng ^{[1
]}

Boyer, Jean D. ^{[3
]}

Draghia-Akli, Ruxandra ^{[1
]}

White, C. Jo ^{[1
]}

Kim, J. Joseph ^{[1
]}

Weiner, David B. ^{[3
]}

Sardesai, Niranjan Y. ^{[1
]}

机构：

[1] Inovio Pharmaceut Inc, Blue Bell, PA 19422 USA

[2] Lyndhurst Clin Res, Winston Salem, NC 27103 USA

[3] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2012年 / 4卷 / 155期

关键词：

HUMAN-PAPILLOMAVIRUS TYPE-16; CERVICAL INTRAEPITHELIAL NEOPLASIA; ENZYME-LINKED IMMUNOSPOT; PHASE-I TRIAL; DNA-VACCINE; T-CELLS; CANCER PATIENTS; DOUBLE-BLIND; RECOMBINANT VACCINIA; MEDIATED-IMMUNITY;

D O I：

10.1126/scitranslmed.3004414

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Despite the development of highly effective prophylactic vaccines against human papillomavirus (HPV) serotypes 16 and 18, prevention of cervical dysplasia and cancer in women infected with high-risk HPV serotypes remains an unmet medical need. We report encouraging phase 1 safety, tolerability, and immunogenicity results for a therapeutic HPV16/18 candidate vaccine, VGX-3100, delivered by in vivo electroporation (EP). Eighteen women previously treated for cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) received a three-dose (intramuscular) regimen of highly engineered plasmid DNA encoding HPV16 and HPV18 E6/E7 antigens followed by EP in a dose escalation study (0.3, 1, and 3 mg per plasmid). Immunization was well tolerated with reports of mild injection site reactions and no study-related serious or grade 3 and 4 adverse events. No dose-limiting toxicity was noted, and pain was assessed by visual analog scale, with average scores decreasing from 6.2/10 to 1.4 within 10 min. Average peak interferon-gamma enzyme-linked immunospot magnitudes were highest in the 3 mg cohort in comparison to the 0.3 and 1 mg cohorts, suggesting a trend toward a dose effect. Flow cytometric analysis revealed the induction of HPV-specific CD8(+) T cells that efficiently loaded granzyme B and perforin and exhibited full cytolytic functionality in all cohorts. These data indicate that VGX-3100 is capable of driving robust immune responses to antigens from high-risk HPV serotypes and could contribute to elimination of HPV-infected cells and subsequent regression of the dysplastic process.

引用

页数：14

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[1] THE CTLS KISS OF DEATH [J].