Pardoll, D.M. (Drew M.)
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- Conserved interferon-g signaling drives clinical response to immune checkpoint blockade therapy in melanoma(Elsevier, 2020) Vega-Crespo, A. (Agustin); Kalbasi, A. (Anusha); Onyshchenko, M. (Mykola); Grasso, C.S. (Catherine S.); Speiser, D.E. (Daniel E.); Wind-Rotolo, M. (Megan); Ribas, A. (Antoni); Ross-Macdonald, P. (Petra); Diab, A. (Adi); Martin-Algarra, S. (Salvador); Sanghoon-Shin, D. (Daniel); Urba, W.J. (Walter J.); Campbell, K. (Katie); Champhekar, A. (Ameya); Medina, E. (Egmidio); Hodi, F.S. (F. Stephen); Johnson, D.B. (Douglas B.); Anagnostou, V. (Valsamo); Luke, J.J. (Jason J.); Tsoi, J. (Jennifer); Haanen, J. (J.); Tran, P. (Phuong); Velculescu, V.E. (Victor E.); Bhatia, S. (Shailender); Wolchok, J.D. (Jedd D.); Abril-Rodriguez, G. (Gabriel); Topalian, S.L. (Suzanne L.); Chmielowski, B. (Bartosz); Puig-Saus, C. (Cristina); Torrejon, D.Y. (Davis Y.); Joo-Kim, Y. (Yeon); Quist, M. (Michael); Martignier, C. (Christophe); Sharfman, W. (William); Slingluff, C.L. (Craig L.); Pardoll, D.M. (Drew M.)We analyze the transcriptome of baseline and on-therapy tumor biopsies from 101 patients with advanced melanoma treated with nivolumab (anti-PD-1) alone or combined with ipilimumab (anti-CTLA-4). We find that T cell infiltration and interferon-γ (IFN-γ) signaling signatures correspond most highly with clinical response to therapy, with a reciprocal decrease in cell-cycle and WNT signaling pathways in responding biopsies. We model the interaction in 58 human cell lines, where IFN-γ in vitro exposure leads to a conserved transcriptome response unless cells have IFN-γ receptor alterations. This conserved IFN-γ transcriptome response in melanoma cells serves to amplify the antitumor immune response. Therefore, the magnitude of the antitumor T cell response and the corresponding downstream IFN-γ signaling are the main drivers of clinical response or resistance to immune checkpoint blockade therapy.
- Immunostimulatory monoclonal antibodies for cancer therapy(Nature Publishing Group, 2007) Hervas-Stubbs, S. (Sandra); Glennie, M. (Martín); Melero, I. (Ignacio); Pardoll, D.M. (Drew M.); Chen, L. (Lieping)Increasing immune responses with immunostimulatory monoclonal antibodies (mAbs) directed to immune-receptor molecules is a new and exciting strategy in cancer therapy. This expanding class of agents functions on crucial receptors, either antagonizing those that suppress immune responses or activating others that amplify immune responses. Complications such as autoimmunity and systemic inflammation are problematic side effects associated with these agents. However, promising synergy has been observed in preclinical models using combinations of immunostimulatory antibodies and other immunotherapy strategies or conventional cancer therapies. Importantly, mAbs of this type have now entered clinical trials with encouraging initial results.