Delineating the role of the gut microbiome in response to immunotherapy. Our group has contributed significantly to studies interrogating the role of the gut microbiome in response to immunotherapy. To date, we have collected and sequenced gut and oral microbiome samples on over 500 patients with melanoma, and we identified bacterial “signatures” in the gut microbiome that are associated with response to immune checkpoint blockade. We also performed mechanistic studies in pre-clinical models (using gnotobiotic mice) and have gained initial insight into how the gut microbiome modulates host and anti-tumour immunity. We have received international recognition for this work, and published these findings in Science in 2018. We are exploring the mechanisms behind this in melanoma, with a funded R01 grant (through the Provocative Questions program – PQ10). A patent was filed surrounding the signature we identified in the gut microbiome, and we are working with the Parker Institute for Cancer Immunotherapy (PICI) to run a novel clinical trial using microbiome modulation in the setting of treatment with immune checkpoint blockade in patients with melanoma.
a. Patent Application PCT/US17/53717. Methods for enhancing immune checkpoint blockade therapy by modulating the microbiome. Inventors: Jennifer A. Wargo and Vancheswaran Gopalakrishnan.
b. Gopalakrishnan V, et al. Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients. Science. 2018 Jan 5;359(6371):97-103. PMCID: PMC5827966.
Defining the immune effects of targeted therapy. Our laboratory was the first to describe the immune effects of BRAF-targeted therapy in melanoma. In our initial studies, we first assayed BRAF-mutant and BRAF-with cell lines before and after treatment with targeted therapy, and made the novel observation that treatment with targeted therapy was associated with a significant increase in melanoma antigen expression which was associated with enhanced reactivity to antigen-specific T cells. Next, we characterized the response to BRAF inhibition in patients enrolled in clinical trials of BRAF inhibitors. BRAF inhibition was associated with a dense CD8 T cell infiltrate and increased melanoma antigen expression, which were abrogated on the emergence of resistance to therapy. Interestingly, we also saw high levels of PD-L1 and lower levels of immunosuppressive cytokines (IL-6, IL-8) in patients shortly after initiation of BRAF inhibition. We also studied specificity of the immune response to BRAF-targeted therapy via T cell receptor sequencing. Simultaneously, we characterized the response to BRAF inhibition in an immunocompetent model of BRAF-mutant melanoma, demonstrating a critical contribution of CD8 T cells to the treatment response. We observed an increase on CD4 and CD8 T cell infiltration on treatment of mice with BRAF inhibitor, which was associated with increased IFN (interferon gamma) and TNF (tumor necrosis factor alpha).
a. Boni A, et al. Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function. Cancer Res. 2010 Jul 1;70(13):5213-9. PubMed PMID: 20551059.
b. Khalili JS, et al. Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin Cancer Res. 2012 Oct 1;18(19):5329-40. PMCID: PMC3463754.
c. Liu C, et al. BRAF inhibition increases tumor infiltration by T cells and enhances the antitumor activity of adoptive immunotherapy in mice. Clin Cancer Res. 2013 Jan 15;19(2):393-403. PMCID: PMC4120472.
d. Frederick DT, et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin Cancer Res. 2013 Mar 1;19(5):1225-31. PMCID: PMC3752683.
Understanding response and resistance to targeted therapy and immune checkpoint blockade in melanoma and other cancers. In addition to understanding immune effects of targeted therapy, we have also contributed significantly to the understanding of resistance mechanisms to this form of therapy. This is critical, as resistance to therapy develops in nearly all patients with melanoma who are treated with these agents. To facilitate such studies, we collected longitudinal tumor biopsies and blood samples on patients with metastatic melanoma receiving this treatment, and performed a deep molecular analysis of resistance mechanisms in pre-treatment versus progression samples. We gained a great deal of insight through these analyses, with findings published in high impact journals such as Nature, Cancer Cell, Cancer Discovery, Cancer Research, Nature Medicine, PNAS, and Clinical Cancer Research. We have continued this translational research in other forms of targeted therapy in melanoma as well as in other cancers, with promising findings.
a. Johannessen CM, et al., COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature. 2010 Dec 16;468(7326):968-72. PMCID: PMC3058384.
b. Berger MF, et al. Melanoma genome sequencing reveals frequent PREX2 mutations. Nature. 2012 May 9;485(7399):502-6. PMCID: PMC3367798.
c. Hodis E, et al. A landscape of driver mutations in melanoma. Cell. 2012 Jul 20; 150 ( 2):251-63. PMCID: PMC3600117.
d. Wagle N et al., MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov. 2014 Jan;4(1):61-8. PMCID: PMC3947296.
Delineating the role of the gut microbiome in response to immunotherapy. Our group has contributed significantly to studies interrogating the role of the gut microbiome in response to immunotherapy.
Defining the immune effects of targeted therapy. Our laboratory was the first to describe the immune effects of BRAF-targeted therapy in melanoma.
Understanding response and resistance to targeted therapy and immune checkpoint blockade in melanoma and other cancers. In addition to understanding immune effects of targeted therapy, we have also contributed significantly to the understanding of resistance mechanisms to this form of therapy.