We are developing vaccine strategies for inducing immunity to ocular melanoma, the most common malignancy of the eye. Although primary tumor can be treated, 50% of patients develop metastatic disease for which there is no successful therapy. We hypothesize that the generation of tumor-specific, long-term immunity may be a useful therapy for established primary and metastatic disease. During the past 8 years we have developed a unique immunization therapy using genetically modified tumor cell-based vaccines for enhancing antigen presentation of tumor antigens. Our strategy focuses on activating tumor-specific CD4+ T helper lymphocytes. CD4+ T cells are particularly important in anti- tumor immunity because they provide the requisite """"""""help"""""""" for optimal CD8+ activity, and because they are critical for long-term memory. We have shown in 3 mouse models that tumor cells transfected with syngeneic MHC class II, CD80 and superantigen genes are potent immunotherapeutic agents. Given the promising animal results, we would like to test our approaches in patients. The animal studies used autologous tumor cells for the """"""""base"""""""" vaccine. Autologous human tumor material, however, is not always available, and customization for individual patients is neither cost effective nor feasible. As an alternative approach we will use established human ocular melanoma tumor cell lines as the """"""""base"""""""" vaccine. We believe that optimal vaccine efficacy can be achieved if we understand the mechanism by which the vaccines stimulate anti- tumor immunity. We will, therefore, not only assess vaccine efficacy, but also test several hypothesis on which the vaccine strategy is based by performing the following Specific Aims: 1) Identify human ocular melanoma cell lines are the """"""""base"""""""" lines for the vaccine, and transfect them with CD80, HLA-DR, and superantigen genes. 2) Determine the ability of the transfectants to stimulate tumor-specific HLA-DR restricted CD4+ T cell responses. 3) Determine if the stage or extent of disease affects patients' ability to respond to the vaccine. 4) Determine if individuals with tumor are """"""""tolerant"""""""" to their tumor antigens and hence less likely to respond; and 5) Determine if the vaccines function as antigen presenting cells for tumor-encoded endogenously synthesized antigens. Completion of these studies will provide the framework for conducting a clinical trial, and will provide mechanistic information for further improvement of the vaccines.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Experimental Therapeutics Subcommittee 1 (ET)
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Yovandich, Jason L
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University of Maryland Balt CO Campus
Schools of Arts and Sciences
United States
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Ostrand-Rosenberg, Suzanne; Fenselau, Catherine (2018) Myeloid-Derived Suppressor Cells: Immune-Suppressive Cells That Impair Antitumor Immunity and Are Sculpted by Their Environment. J Immunol 200:422-431
Ostrand-Rosenberg, Suzanne (2018) Myeloid derived-suppressor cells: their role in cancer and obesity. Curr Opin Immunol 51:68-75
Horn, Lucas A; Long, Tiha M; Atkinson, Ryan et al. (2018) Soluble CD80 Protein Delays Tumor Growth and Promotes Tumor-Infiltrating Lymphocytes. Cancer Immunol Res 6:59-68
Horn, Lucas A; Ciavattone, Nicholas G; Atkinson, Ryan et al. (2017) CD3xPDL1 bi-specific T cell engager (BiTE) simultaneously activates T cells and NKT cells, kills PDL1+ tumor cells, and extends the survival of tumor-bearing humanized mice. Oncotarget 8:57964-57980
Ostrand-Rosenberg, Suzanne (2016) Tolerance and immune suppression in the tumor microenvironment. Cell Immunol 299:23-9
Parker, Katherine H; Horn, Lucas A; Ostrand-Rosenberg, Suzanne (2016) High-mobility group box protein 1 promotes the survival of myeloid-derived suppressor cells by inducing autophagy. J Leukoc Biol 100:463-70
Beury, Daniel W; Carter, Kayla A; Nelson, Cassandra et al. (2016) Myeloid-Derived Suppressor Cell Survival and Function Are Regulated by the Transcription Factor Nrf2. J Immunol 196:3470-8
Ostrand-Rosenberg, Suzanne; Horn, Lucas A; Alvarez, Juan A (2015) Novel strategies for inhibiting PD-1 pathway-mediated immune suppression while simultaneously delivering activating signals to tumor-reactive T cells. Cancer Immunol Immunother 64:1287-93
Parker, Katherine H; Beury, Daniel W; Ostrand-Rosenberg, Suzanne (2015) Myeloid-Derived Suppressor Cells: Critical Cells Driving Immune Suppression in the Tumor Microenvironment. Adv Cancer Res 128:95-139
Ostrand-Rosenberg, Suzanne; Horn, Lucas A; Haile, Samuel T (2014) The programmed death-1 immune-suppressive pathway: barrier to antitumor immunity. J Immunol 193:3835-41

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