We have found that chemotherapy and radiation converts the tumor site into an antigen-presenting cell-rich environment, rendering it ideal for the direct injection of a peptide or protein vaccine into the tumor to elicit potent antigen-specific T cell-mediated immune responses. Here, we propose the use of a therapeutic HPV protein vaccine, administered intratumorally, during chemoradiation in patients with inoperable HPV16+ cervical cancer. We have secured the therapeutic HPV protein vaccine TA-CIN from Cancer Research Technology, Ltd. and the adjuvant GPI-0100 from Hawaii Biotech. We have also secured support from the NCI NExT program to formulate and vial clinical grade TA-CIN with GPI-0100. The proposed trial will be performed at the University of Alabama at Birmingham. Specifically we plan to: 1) evaluate the safety and toxicity of TA-CIN with GPI-0100 administered intratumorally in inoperable HPV16+ cervical cancer patients;2) characterize the HPV-16 E6 and E7 cell-mediated immune responses and L2-specific antibody titers in advanced cervical cancer patients intratumorally vaccinated with TA-CIN/GPI-0100;3) determine the subset population of immune cells infiltrating the lesion bed, the expression of PD-L1 in the tumor microenvironment and the apoptotic tumor cell death in HPV 16+ advanced cervical cancer patients receiving intratumoral TA-CIN/ GPI-0100 vaccination;and 4) characterize the HPV-16 antigen-specific CD8+ T cell-mediated immune responses and therapeutic antitumor effects against E6/E7-expressing tumors in tumor-bearing mice treated with intratumoral vaccination with TA-CIN/GPI-0100, TA-HPV vaccinia or pNGVL4a-hCRTE6E7L2 DNA vaccine in conjunction with cisplatin and/or radiation treatment. The successful implementation of the proposed project will not only improve the treatment of HPV-associated advanced cervical cancer but may also serve as a platform technology for the development of effective therapeutic vaccines for other HPV associated malignancies including vaginal, vulva, anal, penile and HPV positive oropharyngeal squamous cell carcinoma.
This project aims to take advantage of the temporally permissive tumor microenvironment induced by chemoradiation and the availability of clinical grade HPV protein-based vaccine to potentially enhance E6/E7 antigen-specific immune responses and antitumor effects in TA-CIN/GPI-0100 vaccinated inoperable HPV- 16+ cervical cancer patients, a population needing new therapeutic paradigms to improve clinical outcomes.
|Wang, Joshua W; Hung, Chein-Fu; Huh, Warner K et al. (2015) Immunoprevention of human papillomavirus-associated malignancies. Cancer Prev Res (Phila) 8:95-104|
|Banet, Natalie; Gown, Allen M; Shih, Ie-Ming et al. (2015) GATA-3 expression in trophoblastic tissues: an immunohistochemical study of 445 cases, including diagnostic utility. Am J Surg Pathol 39:101-8|
|Wu, Chao-Yi; Yang, Li-Hua; Yang, Huang-Yu et al. (2014) Enhanced cancer radiotherapy through immunosuppressive stromal cell destruction in tumors. Clin Cancer Res 20:644-57|
|Zhao, Rui-Xun; Xu, Zhi-Xiang (2014) Targeting the LKB1 tumor suppressor. Curr Drug Targets 15:32-52|
|Kwak, Kihyuck; Jiang, Rosie; Wang, Joshua W et al. (2014) Impact of inhibitors and L2 antibodies upon the infectivity of diverse alpha and beta human papillomavirus types. PLoS One 9:e97232|
|Coughlin, Kathleen; Anchoori, Ravi; Iizuka, Yoshie et al. (2014) Small-molecule RA-9 inhibits proteasome-associated DUBs and ovarian cancer in vitro and in vivo via exacerbating unfolded protein responses. Clin Cancer Res 20:3174-86|
|Wang, Joshua W; Jagu, Subhashini; Wang, Chenguang et al. (2014) Measurement of neutralizing serum antibodies of patients vaccinated with human papillomavirus L1 or L2-based immunogens using furin-cleaved HPV Pseudovirions. PLoS One 9:e101576|
|Paul, Proma; Tanner, Amanda E; Gravitt, Patti E et al. (2014) Acceptability of HPV vaccine implementation among parents in India. Health Care Women Int 35:1148-61|
|Soong, Ruey-Shyang; Song, Liwen; Trieu, Janson et al. (2014) Direct T cell activation via CD40 ligand generates high avidity CD8+ T cells capable of breaking immunological tolerance for the control of tumors. PLoS One 9:e93162|
|Zhang, Huang-Ge; Grizzle, William E (2014) Exosomes: a novel pathway of local and distant intercellular communication that facilitates the growth and metastasis of neoplastic lesions. Am J Pathol 184:28-41|
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