High-risk resectable melanoma patients (MPs) with clinically detectable stage III with or without in-transit metastases have high-risk relapse1. Neoadjuvant immunotherapy of melanoma with anti-PD1 monoclonal antibodies alone showed evidence of immunological, pathological and clinical responses in 25-30% MPs with minimal toxicity. Neoajduvant PD1/CTLA4 blockade further improved pathological and clinical responses while causing grade 3 adverse events in 73-90% treated melanoma patients. These observations suggest that Neoadjuvant immunotherapy represents an appealing approach for the early assessment of the efficacy and toxicity of novel combinatorial immunotherapies of melanoma. In the present application, we propose to evaluate CMP-001 (CMP), a type A CpG which has several unique properties supporting its potency in increasing antigen presentation and T cell priming. In contrast to other CpGs tested in the clinic, CMP appears to potently induce IFN? but no IL10 production by plasmacytoid dendritic cells (pDCs). It is therefore a very promising therapeutic agent to circumvent the lack of IFN? production observed in ?cold? tumors, which are poorly T cell-infiltrated and fail to response to immune checkpoint blockade. To evaluate the efficacy and toxicity of CMP in melanoma, we have implemented the first-in-human neoadjuvant clinical trial with CMP intratumoral and Nivolumab (CMP/Nivolumab) in PD1 nave high-risk resectable melanoma patients. The primary end-point of the study is the rate of major pathologic response, comprising pathological complete and near-complete as assessed using consensus criteria. In this application, we will determine the mechanisms of responses or resistance to CMP/Nivolumab. Based on our preliminary findings, we investigate whether CMP/Nivolumab :1) increases pDC activation and maturation in the tumor microenvironment to promote CD8+TIL expansion and functions; 2) induces melanoma cell death and primes potent neoepitope-specific CD8+T cells; and 3) fails to induce potent T cell responses because of melanoma cell-extrinsic or melanoma cell-intrinsic mechanisms. Collectively, the findings in this application will improve our understanding of the mechanisms of response and resistance to CMP/Nivolumab in melanoma. They will further support novel combinatorial immunotherapies to further enhance the immunogenicity and clinical activity of CMP/Nivolumab in melanoma.
In melanoma, PD-1 blockade has transformed the management of advanced and high-risk resectable disease with unprecedented improvements in progression-free and overall survival. However, non-response remains a pressing issue. Although still early in clinical development, agonists of Toll-like receptor 9 (TLR9) have demonstrated potential for the treatment of cancer. TLR9 agonists directly induce activation and maturation of plasmacytoid dendritic cells and enhance differentiation of B cells into antibody-secreting plasma cells. This project aims to investigate mechanisms of response and resistance to a novel clinical trial testing neoadjuvant immunotherapy with intra-tumoral CMP- 001 and nivolumab in high-risk resectable melanoma.
