Intravaginal Administration of Fc-Fused IL7 Suppresses the Cervicovaginal Tumor by Recruiting HPV DNA Vaccine-Induced CD8 T Cells

Abstract

Purpose: The induction of tissue-localized virus-specific CD8 T-cell response is essential for the development of an effective therapeutic vaccine against genital diseases, such as cervical cancer and genital herpes. Here, we aimed to elucidate the immunologic role of IL7 in the induction of mucosal cellular immunity.Experimental Design: IL7 was engineered through Fc fusion to enhance mucosal delivery across the genital epithelial barrier. The immunomodulatory role of IL7 was evaluated by monitoring the kinetics of various immune cells and measuring the expression of chemokines and cytokines after intravaginal administration of Fcfused IL7 (IL7-Fc). The antitumor effects of intramuscular human papillomavirus (HPV) DNA vaccine or topical IL7-Fc alone or in a combinational regimen on mice survival were compared using a orthotopic cervical cancer model. Results:Intravaginal treatment of IL7-Fc, but not native IL7, induces upregulation of chemokines (CXCL10, CCL3, CCL4, and CCL5), cytokines (IFNg, TNFa, IL6, and IL1b), and an adhesion molecule (VCAM-1) in the genital tract, leading to the recruitment of several leukocytes, including CD4, CD8, gd T cells, and dendritic cells. Importantly, in this murine cervical cancer model, topical administration of IL7-Fc after intramuscular HPV DNA vaccination increases the number of HPV-specific CD8 T cells in the genital mucosa, but not in the spleen, leading to stronger antitumor activity than the HPV DNA vaccine alone.Conclusions: Our findings provide an important insight into the immunomodulatory role of IL7-Fc via topical application and the design of therapeutic vaccine regimen that induces effective genital-mucosal CD8 T-cell responses. Clin Cancer Res; 22(23); 5898-908. Ó2016 AACR.

A Phase II, Prospective, Randomized, Multicenter, Open-Label Study of GX-188E, an HPV DNA Vaccine, in Patients with Cervical Intraepithelial Neoplasia 3

“…A previous study suggested that local immune response along with systemic immune response result in histologic regression (22). Other studies also showed that a therapeutic HPV DNA vaccination in combination with intravaginal administration of immune modulator recruits antigen-specific CD8 þ T cells to the genital tract, leading to tumor control in a mouse cervical cancer model (23,24). Thus, further study to investigate a role of local and systemic immunity in efficacy of therapeutic vaccine in CIN3 patients may be needed.…”

Hybrid Fc‐fused interleukin‐7 induces an inflamed tumor microenvironment and improves the efficacy of cancer immunotherapy

“…Recombinant human IL-7-hyFc is an engineered protein that has long bioavailability. 21,22 To investigate the systemic pharmacodynamic effects of rhIL-7-hyFc treatment, we subcutaneously (s.c.) administered a single dose of rhIL-7-hyFc and examined the immune compartments in the peripheral blood. rhIL-7-hyFc significantly increased CD3e + T cells peaked at day 7, and the increment was remained up to day 12 ( Figure 1a).…”

“…Hence, we developed a hybrid Fc‐fused long‐acting recombinant human IL‐7 (rhIL‐7‐hyFc, efineptakin‐alfa‐7 TM ) with no cytotoxicity on target cells and a long half‐life in vivo . Single topical treatment with rhIL‐7‐hyFc after administration of a DNA vaccine, which encodes tumor antigen, elicits antitumor responses by expanding populations of vaccine‐induced tumor‐specific CD8 + T cells 21 . rhIL‐7‐hyFc is thus potentially applicable as a novel cytokine‐based drug for cancer immunotherapy; however, the mechanisms underlying rhIL‐7‐hyFc‐mediated modulation of immune cells in the TME remain undetermined.…”

<p>Cervical Cancer: Emerging Immune Landscape and Treatment</p>

“…104 Administration of Fc-fused IL7 could also play a role in modulating vaccines therapy through a CD8+ T cell response. 105 Various therapeutic vaccines are being developed, including DNA, RNA and peptide vaccines. All of these vaccines types exerted antitumor effects through activating the T cell response, especially CD8+ cells.…”