Chien-Fu Hung, PhD
Johns Hopkins University
Innovative Hsp70-secreting tumor cell-based vaccines.
Immunotherapy using gene-transduced tumor cells has emerged as a potentially plausible approach for the control of advanced stage ovarian cancer. We have recently demonstrated that vaccination with irradiated murine allogeneic ovarian cancer cells secreting heat shock protein 70 (Hsp70) were capable of generating potent tumor antigen-specific immune responses and strong anti-tumor effects against ovarian cancers (Chang et al. Cancer Research 2007; 67, 10047-10057).
Hsp70 has been shown to bind antigenic peptides from tumors. The secretion of Hsp70 from the ovarian cancer cells will allow the Hsp70-associated antigenic peptide to be concentrated and targeted to dendritic cells (DCs) with subsequent DC activation. Based on the encouraging preclinical data, we propose to generate a clinical grade tumor cell-based vaccine engineered to secrete high levels of Hsp70. We have access to several high grade serous carcinoma cell lines, that express several known tumor antigens, such as CA-125 and mesothelin.
The generation of the cGMP clinical lots of a tumor cell-based vaccine using high grade serous carcinoma cell lines that secrete high levels of Hsp70 represents an innovative approach that may create an opportunity for the therapy of these devastating ovarian cancers. This product will form the basis for the development of a pipeline of immunotherapeutic approaches at Johns Hopkins University. Thus, in the current proposal, we propose the following.
- Specific Aim 1: To generate and characterize a high grade serous carcinoma cell line that stably secretes high levels of Hsp70.
- Specific Aim 2: To cGMP manufacture and release Master Cell Banks and a clinical lot, per FDA CBER guidelines, of the Hsp70-secreting ovarian cancer cell-based vaccines.
- Specific Aim 3: To perform phase I clinical studies using clinical grade Hsp70-secreting ovarian cancer cell-based vaccines in patients with high grade serous carcinoma.
- Specific Aim 4: To characterize tumor antigen-specific CD8+ T cell immune responses in vaccinated individuals.
Successful implementation of the current proposal may lead to the development of an innovative therapeutic vaccine against high grade ovarian serous carcinoma. We are currently testing two distinct types of cancer vaccines developed at Johns Hopkins, including a mesothelin-expressing Listeria-based vaccine, which is being developed by Anza Therapeutics and the GM-CSF secreting K562 cell line, which is being developed by Cell Genesys.
The mesothelin-expressing Listeria-based vaccine is currently being tested in patients with pancreatic cancer and mesothelioma, while the GM-CSF secreting K562 cell line is being tested in chronic myeloid leukemia patients. Given the suitable safety of the proposed Hsp70-secreting ovarian cancer cell-based vaccine, we will also examine its application in combination with mesothelin- expressing Listeria and/or GM-CSF secreting K562 cell lines to further enhance the tumor specific immune responses.
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Chien-Fu Hung, PhD
The Johns Hopkins Medical Institutions
CRB 2, Room 307
1550 Orleans Street
Baltimore, MD 21231