Therapeutic HPV Cancer Vaccine Targeted to CD40 Elicits Effective CD8+ T-cell Immunity.

Wu Yin ,Dorothée Duluc,Lei Wang,Jung-Hee Woo,Hyemee Joo,Richard Ouedraogo,Zhiqing Wang,Clay Beauregard,Sandra Zurawski,Andrew G Sikora,Falguni Parikh,Luann Thompson-Snipes,Amelia Clark,Sangkon Oh,Lance Oxford,Yaming Xue,Chao Gu,Sang‐Yull Lee ,Gérard Zurawski ,Seunghee Kim‐Schulze

doi:10.1158/2326-6066.cir-16-0128

Abstract

Human papillomavirus (HPV), particularly HPV16 and HPV18, can cause cancers in diverse anatomical sites, including the anogenital and oropharyngeal (throat) regions. Therefore, development of safe and clinically effective therapeutic vaccines is an important goal. Herein, we show that a recombinant fusion protein of a humanized antibody to CD40 fused to HPV16.E6/7 (αCD40-HPV16.E6/7) can evoke HPV16.E6/7-specific CD8+ and CD4+ T-cell responses in head-and-neck cancer patients in vitro and in human CD40 transgenic (hCD40Tg) mice in vivo The combination of αCD40-HPV16.E6/7 and poly(I:C) efficiently primed HPV16.E6/7-specific T cells, particularly CD8+ T cells, in hCD40Tg mice. Inclusion of montanide enhanced HPV16.E6/7-specific CD4+, but not CD8+, T-cell responses. Poly(I:C) plus αCD40-HPV16.E6/7 was sufficient to mount both preventative and therapeutic immunity against TC-1 tumors in hCD40Tg mice, significantly increasing the frequency of HPV16-specific CD8+ CTLs in the tumors, but not in peripheral blood. In line with this, tumor volume inversely correlated with the frequency of HPV16.E6/7-specific CD8+ T cells in tumors, but not in blood. These data suggest that CD40-targeting vaccines for HPV-associated malignancies can provide a highly immunogenic platform with a strong likelihood of clinical benefit. Data from this study offer strong support for the development of CD40-targeting vaccines for other cancers in the future. Cancer Immunol Res; 4(10); 823-34. ©2016 AACR.

Highlights

Human papillomavirus (HPV) infection is the most common sexually transmitted infection in the United States, with most sexually active individuals acquiring HPV
Human CD40-transfected CHO cells were stained with different amounts (0.01–10 mg/mL) of aCD40–HPV16.E6/7 or control IgG4–HPV16.E6/7. aCD40–HPV16.E6/7 bound to CHO-hCD40 cells in a dose-dependent manner, whereas IgG4–HPV16.E6/7 did not (Supplementary Fig. S2A)
Neither aCD40–HPV16.E6/7 nor IgG4–HPV16.E6/7 bound to CHO cells transfected with a mock plasmid. aCD40–HPV16.E6/7 bound to blood CD11cþ myeloid dendritic cells (DC), while IgG4–HPV16.E6/ 7 did not

Summary

Introduction

Human papillomavirus (HPV) infection is the most common sexually transmitted infection in the United States, with most sexually active individuals acquiring HPV. 79 million people are currently infected with HPV, and 14 million are newly infected each year in the United States [1, 2]. Of the more than 150 different types of HPV [3], high-risk HPV strains (HPV16 and 18) are strongly associated with many cancers of the cervix, vagina, vulva, penis, and anus [4, 5]. Up to 22% of adults are HPV16-seropositive, but most primary infections are cleared without sequelae [6,7,8]. Note: Supplementary data for this article are available at Cancer Immunology Research Online (http://cancerimmunolres.aacrjournals.org/).

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