Poor antigenicity and immunosuppressive ability of cancers pose major hurdles to vaccine development. Also, genetic differences in immune responses to an antigen result in an antigenic profile that varies from patient to patient. Despite tremendous progress in the cancer vaccine field, an efficient and easy method for preparing and administering vaccines that are customized to each individual patient is highly desirable, but is currently lacking in clinical settings. In this grant, we propose to evaluate the efficacy of a novel membrane-based breast cancer vaccine that can be rapidly prepared in clinical settings using the patient's tumor cell membranes incorporated with glycosyl phosphatidylinositol (GPI)-anchored cytokines by protein transfer technology. To accomplish the major objectives of the current research proposal, we have generated the GPI-anchored forms of interleukins and have successfully shown that they are as functionally active as soluble forms. Murine breast cancer cells expressing membrane bound GPI-IL-12 or GPI-IL-2, are effective in inducing protective anti-tumor immunity when mice are challenged with whole cells. In this grant application, we propose to: 1) Purify and incorporate GPI-anchored cytokines by protein transfer onto isolated breast cancer membrane vesicles and test their efficacy in inducing protective antitumor immunity in mice;2) Investigate tumor-specific T cell and antibody responses, quantify antigen-specific CD8+ T cell expansion, and characterize memory T cell phenotype in mice vaccinated with GPI-cytokine incorporated breast cancer membrane vaccines;3) Identify immunological mechanisms correlating with antitumor immunity elicited by the breast cancer membranes decorated with GPI-cytokine adjuvants and 4) Study tumor regression and immune responses induced by vaccination with GPI-cytokine-membranes in mice with established tumors. The advantages of the proposed membrane vaccine strategy for breast cancers are: 1) most breast cancer associated tumor antigens identified are membrane associated antigens, 2) GPI- cytokines can be stably incorporated onto membrane fragments obtained from tumor tissue thus obviating the need for establishing cell lines from patients for vaccine development, 3) vaccine preparation can be accomplished in a day and can be applied to 100% of breast cancer patients from whom tumor tissues are available, 4) due to their membrane-bound nature, GPI-cytokines will stay in the vaccination site and are unlikely to cause systemic toxicity, and 5) these cytokine-decorated tumor membranes will have the ability to deliver tumor antigens to antigen-presenting cells, such as dendritic cells, and can simultaneously activate them to elicit an effective anti-tumor immunity that can overcome tumor-induced immunosuppressive environment. The successful demonstration of this vaccine modality has the potential for development of effective membrane vaccines that are easy to prepare, store and administer to the unique tumors of individual breast cancer patients under most of the clinical settings.
The grant proposal aims to develop an effective membrane-based vaccine for breast cancer that can be custom prepared quickly for individual patients under most clinical laboratory settings. The proposed vaccine not only uses the potent antitumor properties of cytokines but also employs the versatility of the protein transfer technique to simplify the preparation of membrane-based vaccines for breast cancer. The results from these studies will provide the foundation for designing membrane-based breast cancer vaccines that can be easily prepared and administered to humans in clinical settings.
|Bozeman, Erica N; He, Sara; Shafizadeh, Yalda et al. (2016) Therapeutic efficacy of PD-L1 blockade in a breast cancer model is enhanced by cellular vaccines expressing B7-1 and glycolipid-anchored IL-12. Hum Vaccin Immunother 12:421-30|
|Patel, Jaina M; Vartabedian, Vincent F; Bozeman, Erica N et al. (2016) Plasma membrane vesicles decorated with glycolipid-anchored antigens and adjuvants via protein transfer as an antigen delivery platform for inhibition of tumor growth. Biomaterials 74:231-44|
|Yang, Emmy; Qian, Weiping; Cao, Zehong et al. (2015) Theranostic nanoparticles carrying doxorubicin attenuate targeting ligand specific antibody responses following systemic delivery. Theranostics 5:43-61|
|Patel, Jaina M; Vartabedian, Vincent F; Kim, Min-Chul et al. (2015) Influenza virus-like particles engineered by protein transfer with tumor-associated antigens induces protective antitumor immunity. Biotechnol Bioeng 112:1102-10|
|Wieland, Andreas; Shashidharamurthy, Rangaiah; Kamphorst, Alice O et al. (2015) Antibody effector functions mediated by FcÎ³-receptors are compromised during persistent viral infection. Immunity 42:367-78|
|Patel, Jaina M; Kim, Min-Chul; Vartabedian, Vincent F et al. (2015) Protein transfer-mediated surface engineering to adjuvantate virus-like nanoparticles for enhanced anti-viral immune responses. Nanomedicine 11:1097-107|
|Patel, Jaina M; Dale, Gordon A; Vartabedian, Vincent F et al. (2014) Cancer CARtography: charting out a new approach to cancer immunotherapy. Immunotherapy 6:675-8|
|Srivatsan, Sanjay; Patel, Jaina M; Bozeman, Erica N et al. (2014) Allogeneic tumor cell vaccines: the promise and limitations in clinical trials. Hum Vaccin Immunother 10:52-63|
|Bozeman, Erica N; Cimino-Mathews, Ashley; Machiah, Deepa K et al. (2013) Expression of membrane anchored cytokines and B7-1 alters tumor microenvironment and induces protective antitumor immunity in a murine breast cancer model. Vaccine 31:2449-56|
|Bozeman, E N; Srivatsan, S; Mohammadi, H et al. (2012) Ukrain, a plant derived semi-synthetic compound, exerts antitumor effects against murine and human breast cancer and induce protective antitumor immunity in mice. Exp Oncol 34:340-7|
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