Abstract

We have shown that cluster intradermal vaccination of CRT/E7DNA (with a short interval between vaccinations) more rapidly induced E7-specific immune responses and generated better therapeutic effects against E7-expresslng tumors compared to DNA vaccination with longer intervals. These findings prompted us to propose a phase I trial to investigate whether the repeated, cluster intradermal CRT/E7 DNA vaccination is safe and can generate E7-specific CD8+ T cell immune responses in patients with HPV-16 associated stage 1B1 resectable cervical cancer. We plan to vaccinate two cohorts of patients, one before and one after tumor resection. The proposed trial using cluster vaccination regimen permits us to complete the vaccination regimen before tumor resection allowing us to assess the influence of DNA vaccination on tumor microenvironment without compromising the standard care. Clinical grade pNGVL4a-CRT/E7(detox) DNA vaccine has been manufactured by NCI RAID program and formulated in the proprietary ND-10 gene gun device by PowderMed/Pfizer for intradermal vaccination. The proposed trial will be performed at the University of Alabama at Birmingham, which has one of the highest populations of stage IBl cervical cancer patients. Specifically, we plan to:
Aim 1 Evaluate the safety/toxiclty associated with repeated, cluster intradermal pNGVL4a-CRT/E7 (detox) DNA vaccination via gene gun in patients with HPV 16-associated stage IBl cervical cancer, using a dose-escalating regimen;
Aim 2. Characterize systemic HPV-16 E6 and E7-speciflc humoral and T cell-mediated immune responses in stage IBl cervical cancer patients receiving the DNA vaccination via gene gun;
Aim 3. Characterize the presence of HPV-16 E6 and E7-speclfic CD8+ T cell immune responses in the tumor and draining lymph nodes in selected stage IBl cervical cancer patients receiving the DNA vaccination via gene gun;
Aim 4. Determine the subset population of immune cells infiltrating the tumor bed, B7H-1 and STAT-3 expression in tumor microenvironment and to determine the apoptotic tumor cell death in stage IB1 cervical cancer patients receiving the DNA vaccination via gene gun. The successful implementation of the proposed study will allow us to assess the systemic and local antigen- specific immune responses following repeated cluster intradermal DNA vaccination using the ND-10 gene gun device in HPV-16 associated stage IBl cervical cancer.

Public Health Relevance

This project aims to develop a therapeutic HPV DNA vaccine formulated in a gene gun device for the treatment of patients with HPV-16 associated stage IBl cervical cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA098252-06A1
Application #
7727554
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (M1))
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2009-09-01
Budget End
2010-08-31
Support Year
6
Fiscal Year
2009
Total Cost
$304,161
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Type
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Boitano, Teresa K L; Smith, Haller J; Rushton, Tullia et al. (2018) Impact of enhanced recovery after surgery (ERAS) protocol on gastrointestinal function in gynecologic oncology patients undergoing laparotomy. Gynecol Oncol 151:282-286
Anchoori, Ravi K; Jiang, Rosie; Peng, Shiwen et al. (2018) Covalent Rpn13-Binding Inhibitors for the Treatment of Ovarian Cancer. ACS Omega 3:11917-11929
Ooki, Akira; Dinalankara, Wikum; Marchionni, Luigi et al. (2018) Epigenetically regulated PAX6 drives cancer cells toward a stem-like state via GLI-SOX2 signaling axis in lung adenocarcinoma. Oncogene 37:5967-5981
Ahn, Julie; Bishop, Justin A; Roden, Richard B S et al. (2018) The PD-1 and PD-L1 pathway in recurrent respiratory papillomatosis. Laryngoscope 128:E27-E32
Silver, Michelle I; Rositch, Anne F; Phelan-Emrick, Darcy F et al. (2018) Uptake of HPV testing and extended cervical cancer screening intervals following cytology alone and Pap/HPV cotesting in women aged 30-65 years. Cancer Causes Control 29:43-50
Yang, J-Ming; Bhattacharya, Sayak; West-Foyle, Hoku et al. (2018) Integrating chemical and mechanical signals through dynamic coupling between cellular protrusions and pulsed ERK activation. Nat Commun 9:4673
Xing, Deyin; Zheng, Gang; Schoolmeester, John Kenneth et al. (2018) Next-generation Sequencing Reveals Recurrent Somatic Mutations in Small Cell Neuroendocrine Carcinoma of the Uterine Cervix. Am J Surg Pathol 42:750-760
Qiu, Jin; Peng, Shiwen; Ma, Ying et al. (2018) Epithelial boost enhances antigen expression by vaccinia virus for the generation of potent CD8+ T cell-mediated antitumor immunity following DNA priming vaccination. Virology 525:205-215
Ooki, Akira; Begum, Asma; Marchionni, Luigi et al. (2018) Arsenic promotes the COX2/PGE2-SOX2 axis to increase the malignant stemness properties of urothelial cells. Int J Cancer 143:113-126
Leath 3rd, Charles A; Monk, Bradley J (2018) Twenty-first century cervical cancer management: A historical perspective of the gynecologic oncology group/NRG oncology over the past twenty years. Gynecol Oncol 150:391-397

Showing the most recent 10 out of 291 publications