Our group works on different aspects of tumor immunology in malignant melanoma with a special emphasis on translational research. Melanoma is a highly mutated and immunogenic malignancy that can be treated with both immunotherapy and targeted agents. However, a substantial number of patients with metastatic disease has no, minimal or short-lived benefit from these therapeutics.
In our group, we are trying to understand which patients are most likely to benefit from immunotherapy. In this perspective, so-called neoantigens seem to play a major role. These tumor antigens are formed by somatic mutations and thereby are private. We were able to show that a high number of clonal neoantigens is associated with benefit from immunotherapy in melanoma. In current projects, we are trying to detect neoantigens directly in human tissue. Our long-term goal is to develop a neoantigen-based personalized immunotherapy.
Targeted therapy of advanced melanoma is already personalized. In patients with BRAFV600 (~50% of all melanomas), dual MAPK inhibition can prolong survival. However, the majority tumours eventually become resistant and progress. To overcome resistance, combination of targeted therapies and immunotherapy has been proposed. To this end, we are exploring the immunological aspects and consequences of targeted therapy in melanoma patients. We were able to show that different targeted drugs used against BRAFV600 mutant melanoma have a specific impact on the human immune system. Currently, we are investigating how myeloid cells influence the efficacy of MAPK inhibition in melanoma. Ultimately, we want to understand how to combine or sequence targeted therapy and immunotherapy for maximal patient benefit.
Most important publications
McGranahan N**, Furness AJS**, Rosenthal R**, Ramskov S, Lyngaa R, Kumar Saini S, Jamal-Hanjani M, Wilson GA, Birkbak NJ, Hiley CT, Watkins TBK, Shafi S, Murugaesu N, Mitter R, Akarca AU, Linares J, Marafioti T, Henry JY, Van Allen EM, Miao D, Schilling B, Schadendorf D, Garraway LA, Makarov V, Rizvi NA, Snyder A, Hellmann MD, Merghoub T, Wolchok JD, Shukla SA, Wu CJ, Peggs KS, Chan TA, Hadrup SR, Quezada SA* and Swanton C*: Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade Science 351(6280):1463-9 (2016) **equally contributing first authors, *corresponding authors
Kaur A**, Marchbank K**, Webster MR, Behera R, Ndoye A, Dang VJ, Appleton J, O’Connell MP, Cheng P, Valiga AA, Morissette RA, McDonnell NB, Ferrucci L, Kossenkov AV, Meeth K, Tang H, Yin X, Wood WH, Lehrmann E, Becker KG, Flaherty KT, Frederick DT, Wargo JA, Cooper ZA, Tetzlaff MT, Hudgens C, Aird KM, Zhang R, Xu X, Liu Q, Bartlett E, Karakousis G, Eroglu Z, Lo RS, Chan M, Menzies AM, Long GV, Johnson DB, Sosman J, Schilling B, Schadendorf D, Speicher DW, Bosenberg M, Ribas A, Weeraratna A: sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 532(7598):250-4 (2016) **equally contributing first authors
Van Allen EM**, Miao D**, Schilling B**, Shukla SA, Blank C, Zimmer L, Sucker A, Hillen U, Geukes Foppen MH, Goldinger SM, Utikal J, Hassel JC, Weide B, Kaehler KC, Loquai C, Mohr P, Gutzmer R, Dummer R, Gabriel S, Wu CJ, Schadendorf D*, Garraway LA*: Genomic correlates of response to CTLA4 blockade in metastatic melanoma. Science 350(6257):207-11 (2015). **equally contributing first authors, *corresponding authors
Schilling B**, Sondermann W, Zhao F, Griewank K, Livingstone E, Sucker A, Zelba H, Weide B, Trefzer U, Wilhelm T, Loquai C, Berking C, Hassel J, Kähler KC, Utikal J, Al Ghazal P, Gutzmer R, Goldinger SM, Zimmer L, Paschen A, Hillen U*, Schadendorf D*: Differential influence of vemurafenib and dabrafenib on patients’ lymphocytes despite similar clinical efficacy in melanoma. Ann Oncol 25(3):747-53 (2014). **corresponding author, *equally contributing senior authors
Schilling B**, Sucker A, Griewank K, Zhao F, Weide B, Görgens A, Giebel B, Schadendorf D, Paschen A: Vemurafenib reverses immunosuppression by myeloid-derived suppressor cells. Int J Cancer 133(7):1653-63, (2013). **corresponding author