Melanoma is a progressive public health problem as its incidence continues to increase. Immunotherapy is now recognized to be an effective treatment for advanced melanoma, although it only benefits a small proportion of patients. The overall goal of this grant is to develop more effective strategies to use the immune system to recognize specific targets present on melanoma cells. We seek to build on prior accomplishments of this project in several specific ways to develop the most potent immunotherapeutic program.
The first aim of the project is focused on investigating ways to stimulate a pathway known as GITR, present on T cells, as a way to stimulate effector T cells and inhibit suppressive T cells. In the second aim, different combinations of antibodies will be explored to find the optimal way to modulate different immunologic pathways. All of the immunomodulatory antibodies have clinical grade equivalents available or in development. Therefore, the results of this aim may have immediate clinical applicability. The best combination of antibodies will be combined with optimized DNA vaccine to assess if the chosen immune modulation program enhances the effect of the vaccine.
The third aim will investigate the use of antigen specific T cells as a therapy for melanoma. It is known that infusions of both CD4+ (helper) and CD8+ (cytotoxic) T cells can have therapeutic benefit in melanoma patients. Determination of the optimal number and combination of such cells will be the goal of this part of the project. Once the details of the best combination of immunomodulating antibodies and adoptively transferred T cells are known, these will be combined in an attempt to develop a comprehensive immunotherapeutic program. This will be evaluated first in a transplanted tumor in mice.
The fourth aim represents a continuing effort to generate a realistic model of spontaneous melanoma in mice. The same genetic aberrations present in human melanoma are being introduced into mice with melanocytes in the skin. This will represent the most stringent means to test the efficacy of the comprehensive immunotherapy program.
Melanoma is a progressive public health problem as its incidence continues to increase. Immunotherapy is now recognized to be an effective treatment for advanced melanoma, although it only benefits a small proportion of patients. The overall goal of this grant is to develop more effective strategies to use the immune system to recognize specific targets present on melanoma cells.
|Oseledchyk, Anton; Ricca, Jacob M; Gigoux, Mathieu et al. (2018) Lysis-independent potentiation of immune checkpoint blockade by oncolytic virus. Oncotarget 9:28702-28716|
|Zamarin, Dmitriy; Ricca, Jacob M; Sadekova, Svetlana et al. (2018) PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy. J Clin Invest 128:1413-1428|
|Ribas, Antoni; Wolchok, Jedd D (2018) Cancer immunotherapy using checkpoint blockade. Science 359:1350-1355|
|Ricca, Jacob M; Oseledchyk, Anton; Walther, Tyler et al. (2018) Pre-existing Immunity to Oncolytic Virus Potentiates Its Immunotherapeutic Efficacy. Mol Ther 26:1008-1019|
|Zamarin, Dmitriy; Holmgaard, Rikke B; Ricca, Jacob et al. (2017) Intratumoral modulation of the inducible co-stimulator ICOS by recombinant oncolytic virus promotes systemic anti-tumour immunity. Nat Commun 8:14340|
|Dai, Peihong; Wang, Weiyi; Yang, Ning et al. (2017) Intratumoral delivery of inactivated modified vaccinia virus Ankara (iMVA) induces systemic antitumor immunity via STING and Batf3-dependent dendritic cells. Sci Immunol 2:|
|Budhu, Sadna; Schaer, David A; Li, Yongbiao et al. (2017) Blockade of surface-bound TGF-? on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment. Sci Signal 10:|
|Malandro, Nicole; Budhu, Sadna; Kuhn, Nicholas F et al. (2016) Clonal Abundance of Tumor-Specific CD4(+) T Cells Potentiates Efficacy and Alters Susceptibility to Exhaustion. Immunity 44:179-193|
|Holmgaard, Rikke B; Brachfeld, Alexandra; Gasmi, Billel et al. (2016) Timing of CSF-1/CSF-1R signaling blockade is critical to improving responses to CTLA-4 based immunotherapy. Oncoimmunology 5:e1151595|
|Holmgaard, Rikke B; Zamarin, Dmitriy; Lesokhin, Alexander et al. (2016) Targeting myeloid-derived suppressor cells with colony stimulating factor-1 receptor blockade can reverse immune resistance to immunotherapy in indoleamine 2,3-dioxygenase-expressing tumors. EBioMedicine 6:50-58|
Showing the most recent 10 out of 78 publications