Interdisciplinary Melanoma Cooperative Group (IMCG): Major Accomplishments
Our researchers spearheaded the construction of the NYU Cancer Institute Vaccine Center and established an Immunotherapy Program in Melanoma. They have modified and developed standard operating procedures to prepare human dendritic cells for immunotherapeutic purposes. Our scientists have overseen the production of more than 500 vaccines in this facility, including cell-based vaccines. The immune monitoring laboratory uses state-of-the-art techniques to analyze blood samples from patients enrolled in immunotherapy trials, and thus far has validated and executed more than 400 assays.
Scientists have found that dendritic cells can be manipulated in vitro to express a variety of antigens through RNA transfection (Minkis et al., Cancer Research 2008).
We showed that TLR7 (Imiquimod) or TLR9 (GpG) agonists induce T-cell immunity to melanoma-associated antigens (NY-ESO-1) in patients with melanoma (Adams et al., Journal of Immunology 2008; Ayyoub et al., Proc Natl Acad Sci 2010).
Researchers found that patients with immune cell infiltration and reduced cell proliferation in lymph node tumors had improved survival (Bogunovic et al., Proc Natl Acad Sci, 2009).
We found that miR-182 is upregulated in human melanoma cell lines and tissue samples, and that this upregulation correlates with gene copy number in a subset of melanoma cell lines. Moreover, miR-182 ectopic expression stimulates migration of melanoma cells in vitro and their metastatic potential in vivo, whereas miR-182 downregulation impedes invasion and triggers apoptosis. This miR-182 overexpression promotes migration and survival by directly repressing microphthalmia-associated transcription factor-M and FOXO3, whereas enhanced expression of either microphthalmia-associated transcription factor-M or FOXO3 blocks miR-182's proinvasive effects. (Segura et al., PNAS, 2009)
IMCG researchers found a six-miRNA signature that was able to significantly stratify stage III patients into "better" and "worse" prognostic categories (Segura et al., Clin Cancer Res, 2010).
IMCG investigators Drs. Iman Osman and Eva Hernando were awarded the Department of Defense-sponsored Multi-PIs Translational Science Award for their proposal "Altered microRNAs in melanoma brain metastasis." The primary aims of this study are to evaluate the ability of miRNAs to predict spread of melanoma to the brain at the time of diagnosis and to investigate the role of specific miRNAs in modulating the spread of melanoma to the brain in a clinical setting.
Brain metastases have been an important area of study for IMCG researchers. Upon examining clinical variables and primary tumor characteristics predictive of the development of melanoma brain metastases and post-brain metastases survival, tumor ulceration was found to be the strongest predictor of brain metastases development and poor survival (Zakrzewski et al., Cancer, 2010).
We provided proof that miRNA targeting against metastatic tumors is safe and efficacious by using anti-miR-182 oligonucleotides in a mouse model of melanoma liver metastasis (Huynh et al., Oncogene, 2010).
Through collaboration with the Mount Sinai School of Medicine, we found that the histone variant macroH2A (mH2A) suppresses tumor progression of malignant melanoma (Kapoor et al., Nature, 2010).
IMCG investigators Drs. Nina Bhardwaj, Anna Pavlick, and Iman Osman received a $1 million grant from the Melanoma Research Foundation for developing innovative vaccine approaches to treat melanoma. They will be evaluating improved methods of generating dendritic cells using Toll-like receptor agonists such as poly I:V, alongside montanide.
IMCG investigators found that the immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival. Any of the four parameters (prevalidated gene expression signature, TILs, CD3, and in particular MI) improved the ability of current Tumor, Node, Metastasis (TNM) staging to predict post-recurrence survival (Bogunovic et al., Proc Natl Acad Sci, 2010).
IMCG investigator Dr. Nina Bhardwaj reported that matrix metalloproteinase 2 (MMP-2) a product of tumor cells, adversely affects the immune response to tumors by negatively modulating the activity of dendritic cells, the body's most potent antigen-presenting cells (Godefroy et al., Cancer Cell, 2011).