Melanoma is an extremely difficult disease to treat. Chemotherapy is notoriously ineffective with a negligible long-term remission rate. Recent studies have established that inhibition of BRAF signaling induces massive melanoma cell death leading to response rates exceeding 50% in patients who test positive for the BRAFV600E mutation. Responses unfortunately are transient, lasting on average 6.8 months and eventually all patients'progress or relapse. In contrast, immunotherapy can produce long-lasting cures in a small minority of patients. Combination of these approaches is therefore extremely attractive. BRAF inhibition induces cell death and the release of melanoma antigens in patients. This is exciting for the melanoma field because chemotherapy does not reliably kill melanoma tumors in patients. Recent studies suggest that dying tumor cells can be excellent sources of antigen for immunotherapy. BRAF inhibition therefore, because it causes massive tumor cell death, represents a unique opportunity to develop novel effective immunotherapies. This proposal aims to identify immune mediated strategies able to potentiate clinical remissions induced by BRAF inhibition. The study proposed herein provides the first comprehensive assessment of the contribution of cutaneous DC and macrophages to the development, or the lack thereof, of therapeutic immunity to BRAF inhibitors using an inducible model of BRAF-driven tumors. We find this to be of great importance as endogenous vaccination due to BRAF-inhibition-induced melanoma cell death could offer a novel approach to melanoma immunotherapy. Such an approach could overcome numerous drawbacks in the vaccination strategies currently in use. In the last ten years, our group of investigators has provided evidence that the expansion of endogenous DCs followed by their activation might be a valid strategy to promote antitumor immunity in several mouse tumor models. Here, we propose advancing a step further and testing whether combining BRAF inhibitors to increase tumor antigen availability, together with vaccination strategies aimed at expanding and activating tumor-associated CD103+ DC in situ while eliminating tumor-associated immunosuppressive APC via CSF-1R Ab (already in cancer Phase I trial), could prolong response to BRAF therapy. Combination therapy with BRAF inhibitors and immunotherapy is urgently needed by melanoma patients. Results of this study are expected to provide a rationale for the design of key clinical trials to treat this devastating disease.

Public Health Relevance

Effective therapies for melanoma are a critical need as cure rates for advanced disease are less than 5%. Recent studies established that 50% melanoma lesions express Braf mutations and that BRAF inhibition induces impressive, yet brief responses whereas immunotherapy can produce long-lasting cures in a small minority of patients. The overall goal of this project is to identify immune mediated strategy that could potentiate BRAF response using a BRAF V600E inducible spontaneous tumor mouse melanoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
9R01CA173861-03A1
Application #
8439839
Study Section
Special Emphasis Panel (ZRG1-OTC-C (03))
Program Officer
Yovandich, Jason L
Project Start
2008-12-01
Project End
2018-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
3
Fiscal Year
2013
Total Cost
$423,750
Indirect Cost
$173,750
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Remark, Romain; Becker, Christian; Gomez, Jorge E et al. (2015) The non-small cell lung cancer immune contexture. A major determinant of tumor characteristics and patient outcome. Am J Respir Crit Care Med 191:377-90
Yu, Chun I; Becker, Christian; Metang, Patrick et al. (2014) Human CD141+ dendritic cells induce CD4+ T cells to produce type 2 cytokines. J Immunol 193:4335-43
Muller, Paul Andrew; Koscsó, Balázs; Rajani, Gaurav Manohar et al. (2014) Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility. Cell 158:300-13
Chakraborty, Rikhia; Hampton, Oliver A; Shen, Xiaoyun et al. (2014) Mutually exclusive recurrent somatic mutations in MAP2K1 and BRAF support a central role for ERK activation in LCH pathogenesis. Blood 124:3007-15
Mortha, Arthur; Chudnovskiy, Aleksey; Hashimoto, Daigo et al. (2014) Microbiota-dependent crosstalk between macrophages and ILC3 promotes intestinal homeostasis. Science 343:1249288
Mayer, Christian Thomas; Ghorbani, Peyman; Nandan, Amrita et al. (2014) Selective and efficient generation of functional Batf3-dependent CD103+ dendritic cells from mouse bone marrow. Blood 124:3081-91