BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)
Considerable effort has focused on identifying patients who respond to immunotherapy in the hope or restricting such treatment to those most likely to benefit. IL-2 response has been shown to be more likely in patients with normal serum LDH, or low plasma VEGF and fibronectin levels . In addition, response appears to be more frequent in patients whose tumors contain mutations in BRAF or NRAS, or possess an inflammatory gene expression signature . More recent studies have suggested that response to IL-2 is associated with enhancement of a pre-existing gene expression pattern within the tumor associated with immune-mediated tissue-specific destruction under the control of IFNγ . Benefit from vaccination has also been linked to tumors expressing an IFN driven chemokine signature (107). Preliminary results suggest that both PD1 antibody responsiveness and IL-2 responsive in patients with RCC may be correlated with tumor cell surface expression of PDL1 (102, 108). Furthermore, research suggests that tumor PDL1 expression is not constitutive, but is related to the secretion of IFNγ by of tumor reactive CD8 T cells in the microenvironment. Thus, effective immunotherapy may require pre-existence of tumor specific immunity within the microenvironment and the use of agents that can either drive T cell function (HD IL-2 or vaccines) or block inherent immunoregulatory signals (ipilimumab, or anti-PD1). Several current studies are underway to validate these predictive biomarkers for specific immunotherapies as well as to determine if combinations of immunotherapy with either other immunotherapies or molecularly targeted agents could convert non-immune responsive tumors into those capable of responding.
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