The goal of this proposal is to test the hypothesis that the combination of pembrolizumab (anti-PD-1 antibody) and pegylated interferon (PEG IFNα-2b) is safe, therapeutically more effective than treatment with single agent anti-PD-1 antibody alone and immunogenic for patients with advanced melanoma irrespective of BRAF or NRAS mutation status. To this end, we have proposed the dose-seeking and efficacy study of the combination pembrolizumab and PEG IFNα-2b for advanced melanoma. This proposal benefits from our well-established expertise in:
- IFN-based therapy of melanoma
- Immune monitoring of T cell responses to melanoma both in the peripheral blood and at tumor sites
- Preclinical studies of inhibitory pathways that dampen T cell responses to melanoma.
This clinical trial is partially funded by an academic-industrial award (Merck and the Melanoma Research Alliance). This project proposes to perform the immunological and biomarker studies in the context of the first-in-human trial with pembrolizumab and PEG IFNα-2b for patients with recurrent inoperable AJCC stage III and metastatic stage IV melanoma.
Specific Aim 1. Pembrolizumab and PEG IFNα-2b combination therapy promote CD8+ T cell tumor infiltration and the upregulation of PD-L1 as well as multiple co-inhibitory receptors at tumor sites. Here, we propose to test whether treatment with pembrolizumab and PEG IFNα-2b will induce and/or increase CD8+ T cell infiltrates as compared to pre-treatment biopsy evaluation. We will investigate whether CD8+ T cells upregulate co-inhibitory receptors including Tim-3, BTLA, and TIGIT. We will also investigate whether tumor cells upregulate PD-L1 in tumor biopsies pre- and post-treatment.
Specific Aim 2. Anti-PD-1 antibody and PEG IFNα-2b in combination will promote the Th-1 type gene signature in non-inflamed tumors as well as increased expression of inhibitory ligands. Here, we propose to perform transcriptome studies of tumor samples taken prospectively pre- and post-treatment (12 weeks). We will investigate whether the proposed combinatory approach is successfully able to promote a Th-1 gene signature among non-inflamed tumors. We will also evaluate pre- and post-therapy the presence of gene signatures of T cell exhaustion and T cell anergy to investigate the mechanisms driving T cell dysfunction at tumor sites. Such an approach will permit us to identify biomarkers of positive clinical outcome and will also allow us to determine what inhibitory pathways beyond PD-1 may need to be targeted to enhance further the clinical efficacy of the proposed combinatorial therapy.
Specific Aim 3. Anti-PD-1 antibody and PEG IFNα-2b in combination promote clonal expansion of CD8+ T effector cells at tumor sites. Here, we propose to investigate whether the proposed combinatorial therapy will contribute to the expansion of the repertoire of tumor antigen (TA)-specific T cells in the tumor microenvironment. Such studies are important to determine whether the gain of function within TA-specific CD8 T+ TILs is best attributed to one or the other of two non-exclusive mechanisms: 1) functional improvement of persisting clonotypes; and 2) recruitment of particular clonotypes exhibiting superior functional capabilities.
This SPORE project will determine whether PD-1 blockade and PEG-IFN-α2b can prime T cell responses in non-inflamed tumors, which are less likely to respond to anti-PD-1 therapy alone. It will also determine what other inhibitory pathways may need to be targeted in combination with PD-1 blockade and PEG-IFN-α2b to reverse melanoma-induced T cell dysfunction. Finally, it is also expected that the correlative gene signature studies at tumor sites will allow us to understand better the molecular mechanisms driving tumor-induced T cell dysfunction in the tumor microenvironment.