Our long-term goal is to generate cell-based cancer vaccines for the treatment of established metastatic cancer, particularly metastatic breast cancer. Because CD4+ T lymphocytes are critical cells for optimal cell-mediated immunity, we have focused on making vaccines that activate tumor-specific CD4+ T cells. The vaccines are based on two hypotheses: 1) Tumor cells genetically modified to express syngeneic MHC class II, co-stimulatory, and T cell activation molecules directly present tumor-encoded antigens to CD4+ T cells; 2) Activation of tumor-specific CD4+ T cells facilitates activation of tumor-specific CD8+ T cells and results in potent anti-tumor immunity and long-term memory. Mechanistic and therapeutic studies support both hypotheses, and in a separate project we are translating this approach to the clinic. Although the vaccines have significant therapeutic efficacy against large burdens of widely disseminated, spontaneous metastatic cancer, some mice are non-responders and although survival time for others is significantly extended, most mice still die. As we adapt the vaccines to the clinic, it is highly desirable to continue developing new approaches in innovative animal models, so that we can constantly input improved strategies to the translational studies. Further development is dependent on understanding the underlying mechanisms by which the vaccines stimulate immunity. Studies, therefore, have also focused on examining basic aspects of antigen presentation by the vaccines. To further improve and test the vaccines in mice, the following therapeutic and mechanistic questions will be addressed: 1) Do the MHC class Il-based vaccines protect very high risk mice from developing mammary cancer? 2) Can expression of transcriptional regulatory elements down-regulate Invariant chain and convert MHC class II+Ii+DM+ tumor cells to vaccines? 3) How do the cell-based vaccines present MHC class 11-restricted, endogenously synthesized tumor antigens? 4) What is the role of the vaccine cells in induction of anti-tumor immunity? Which effector cells, cytokines, and chemokines are induced during therapy? 5) Does tumor burden correlate with tumor-induced immuno-suppression? Does surgical removal of primary tumor reverse mmuno-suppression?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA052527-14
Application #
6724891
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Yovandich, Jason L
Project Start
1990-07-01
Project End
2007-03-31
Budget Start
2004-04-01
Budget End
2007-03-31
Support Year
14
Fiscal Year
2004
Total Cost
$266,468
Indirect Cost
Name
University of Maryland Balt CO Campus
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
061364808
City
Baltimore
State
MD
Country
United States
Zip Code
21250
Ostrand-Rosenberg, Suzanne (2018) Myeloid derived-suppressor cells: their role in cancer and obesity. Curr Opin Immunol 51:68-75
Ostrand-Rosenberg, Suzanne (2013) Looking to the future of cancer immunotherapy: many questions to answer and many therapeutic opportunities. Cancer Immunol Immunother 62:1-2
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Dolan, Brian P; Gibbs Jr, Kenneth D; Ostrand-Rosenberg, Suzanne (2006) Dendritic cells cross-dressed with peptide MHC class I complexes prime CD8+ T cells. J Immunol 177:6018-24
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Thompson, James A; Dissanayake, Samudra K; Ksander, Bruce R et al. (2006) Tumor cells transduced with the MHC class II Transactivator and CD80 activate tumor-specific CD4+ T cells whether or not they are silenced for invariant chain. Cancer Res 66:1147-54
Sinha, Pratima; Clements, Virginia K; Miller, Seth et al. (2005) Tumor immunity: a balancing act between T cell activation, macrophage activation and tumor-induced immune suppression. Cancer Immunol Immunother 54:1137-42

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