# Development of Novel Spontaneous HPV Cervicovaginal Carcinoma Models for Cancer Immunotherapy

> **NIH NIH R01** · JOHNS HOPKINS UNIVERSITY · 2020 · $583,657

## Abstract

PROJECT SUMMARY / ABSTRACT
The identification of human papillomavirus (HPV) as a causative agent for a host of conditions, particularly
cervical cancer, has led to the development of HPV-targeting therapeutics, including therapeutic HPV
vaccines, for the treatment of HPV-associated malignancies. However, the potent efficacies demonstrated by
the therapeutic HPV vaccine candidates in preclinical studies are often not reflected in clinical settings. This
discrepancy is potentially due to the inability of existing preclinical HPV tumor models to fully replicate the
biology of clinical HPV-associated cancers. We hypothesize that an ideal preclinical HPV tumor model should
possess the following characteristics: 1) forms spontaneous, localized, HPV oncogenic proteins-expressing
tumors; 2) displays carcinoma morphology; 3) possesses a locally immunosuppressive tumor
microenvironment (TME) resembling that of clinical HPV+ tumors; 4) tumor formation should follow clinical
progression starting from a precancerous to an invasive and metastatic state; 5) be applicable to different MHC
class I backgrounds; and 6) the tumor-bearing mice should respond appropriately to immunotherapeutic
strategies and generate anti-tumor immunity. Preliminary data: We developed a strategy for the generation of
preclinical spontaneous HPV cervicovaginal carcinoma based on orthotopic injection of oncogenic plasmids
encoding HPV16-E6, HPV16-E7, constitutively active Akt, luciferase reporter gene, and Sleeping Beauty
Transposase (SB) into the cervicovaginal tract of mice with electroporation to enhance transfection efficiency.
Subsequent expression of SB induces the integration of plasmid DNA into the genome of transfected cells,
resulting in persistent oncogenes expression and spontaneous transformation of transfected cells. In a
systemic immunosuppressed setting induced by short-term anti-CD3 administration, intracervicovaginal
oncogenic plasmid transfection led to the spontaneous formation of HPV+ tumors with carcinoma
characteristics. We propose to further optimize our model by incorporating immunosuppressive molecules that
are often overexpressed in clinical cervical cancers into our spontaneous HPV cervicovaginal tumor model and
eliminate the need of short-term CD3 depletion. Also, we will further utilize genetic outbred mice and HPV16
pseudovirion delivery of oncogenes for the generation of spontaneous tumors, thereby recapitulating the
genetic diverse patient population and HPV16 infection-induced oncogene introduction. Furthermore, we will
examine various treatment strategies, such as the combination of therapeutic HPV vaccination with inhibitors
of immunosuppressive molecules, in overcoming the immunosuppressive TME for the generation of improved
therapeutic antitumor responses. Impact: A novel preclinical HPV cervicovaginal cancer model that faithfully
recapitulates the clinical situation would potentiate crucial immunotherapeutic and biological research for HPV-
associa...

## Key facts

- **NIH application ID:** 9851859
- **Project number:** 5R01CA237067-02
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** TZYY-CHOOU WU
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $583,657
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851859

## Citation

> US National Institutes of Health, RePORTER application 9851859, Development of Novel Spontaneous HPV Cervicovaginal Carcinoma Models for Cancer Immunotherapy (5R01CA237067-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9851859. Licensed CC0.

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