TY - JOUR A1 - Koch, Elias A. T. A1 - Petzold, Anne A1 - Wessely, Anja A1 - Dippel, Edgar A1 - Gesierich, Anja A1 - Gutzmer, Ralf A1 - Hassel, Jessica C. A1 - Haferkamp, Sebastian A1 - Hohberger, Bettina A1 - Kähler, Katharina C. A1 - Knorr, Harald A1 - Kreuzberg, Nicole A1 - Leiter, Ulrike A1 - Loquai, Carmen A1 - Meier, Friedegund A1 - Meissner, Markus A1 - Mohr, Peter A1 - Pföhler, Claudia A1 - Rahimi, Farnaz A1 - Schadendorf, Dirk A1 - Schell, Beatrice A1 - Schlaak, Max A1 - Terheyden, Patrick A1 - Thoms, Kai-Martin A1 - Schuler-Thurner, Beatrice A1 - Ugurel, Selma A1 - Ulrich, Jens A1 - Utikal, Jochen A1 - Weichenthal, Michael A1 - Ziller, Fabian A1 - Berking, Carola A1 - Heppt, Markus T1 - Immune checkpoint blockade for metastatic uveal melanoma: patterns of response and survival according to the presence of hepatic and extrahepatic metastasis JF - Cancers N2 - Background: Since there is no standardized and effective treatment for advanced uveal melanoma (UM), the prognosis is dismal once metastases develop. Due to the availability of immune checkpoint blockade (ICB) in the real-world setting, the prognosis of metastatic UM has improved. However, it is unclear how the presence of hepatic and extrahepatic metastasis impacts the response and survival after ICB. Methods: A total of 178 patients with metastatic UM treated with ICB were included in this analysis. Patients were recruited from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of hepatic metastasis, two cohorts were compared: patients with liver metastasis only (cohort A, n = 55) versus those with both liver and extra-hepatic metastasis (cohort B, n = 123). Data were analyzed in both cohorts for response to treatment, progression-free survival (PFS), and overall survival (OS). The survival and progression probabilities were calculated with the Kaplan–Meier method. Log-rank tests, χ\(^2\) tests, and t-tests were performed to detect significant differences between both cohorts. Results: The median OS of the overall population was 16 months (95% CI 13.4–23.7) and the median PFS, 2.8 months (95% CI 2.5–3.0). The median OS was longer in cohort B than in cohort A (18.2 vs. 6.1 months; p = 0.071). The best objective response rate to dual ICB was 13.8% and to anti-PD-1 monotherapy 8.9% in the entire population. Patients with liver metastases only had a lower response to dual ICB, yet without significance (cohort A 8.7% vs. cohort B 16.7%; p = 0.45). Adverse events (AE) occurred in 41.6%. Severe AE were observed in 26.3% and evenly distributed between both cohorts. Conclusion: The survival of this large cohort of patients with advanced UM was more favorable than reported in previous benchmark studies. Patients with both hepatic and extrahepatic metastasis showed more favorable survival and higher response to dual ICB than those with hepatic metastasis only. KW - uveal melanoma KW - immune checkpoint blockade KW - PD-1 KW - CTLA-4 KW - liver metastasis KW - treatment resistance Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-242603 SN - 2072-6694 VL - 13 IS - 13 ER - TY - JOUR A1 - Koch, Elias A. T. A1 - Petzold, Anne A1 - Wessely, Anja A1 - Dippel, Edgar A1 - Gesierich, Anja A1 - Gutzmer, Ralf A1 - Hassel, Jessica C. A1 - Haferkamp, Sebastian A1 - Kähler, Katharina C. A1 - Knorr, Harald A1 - Kreuzberg, Nicole A1 - Leiter, Ulrike A1 - Loquai, Carmen A1 - Meier, Friedegund A1 - Meissner, Markus A1 - Mohr, Peter A1 - Pföhler, Claudia A1 - Rahimi, Farnaz A1 - Schadendorf, Dirk A1 - Schell, Beatrice A1 - Schlaak, Max A1 - Terheyden, Patrick A1 - Thoms, Kai-Martin A1 - Schuler-Thurner, Beatrice A1 - Ugurel, Selma A1 - Ulrich, Jens A1 - Utikal, Jochen A1 - Weichenthal, Michael A1 - Ziller, Fabian A1 - Berking, Carola A1 - Heppt, Markus V. T1 - Immune checkpoint blockade for metastatic uveal melanoma: re-induction following resistance or toxicity JF - Cancers N2 - Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1–23.8) versus 9.4 months (cohort B, 95% CI: 6.1–14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities. KW - uveal melanoma KW - immune checkpoint blockade KW - PD-1 KW - CTLA-4 KW - re-induction KW - treatment resistance KW - toxicity Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-254814 SN - 2072-6694 VL - 14 IS - 3 ER - TY - JOUR A1 - Haist, Maximilian A1 - Stege, Henner A1 - Lang, Berenice Mareen A1 - Tsochataridou, Aikaterini A1 - Salzmann, Martin A1 - Mohr, Peter A1 - Schadendorf, Dirk A1 - Ugurel, Selma A1 - Placke, Jan-Malte A1 - Weichenthal, Michael A1 - Gutzmer, Ralf A1 - Leiter, Ulrike A1 - Kaatz, Martin A1 - Haferkamp, Sebastian A1 - Berking, Carola A1 - Heppt, Markus A1 - Tschechne, Barbara A1 - Schummer, Patrick A1 - Gebhardt, Christoffer A1 - Grabbe, Stephan A1 - Loquai, Carmen T1 - Response to first-line treatment with immune-checkpoint inhibitors in patients with advanced cutaneous squamous cell carcinoma: a multicenter, retrospective analysis from the German ADOReg registry JF - Cancers N2 - Cutaneous squamous cell carcinoma (cSCC) is a common malignancy of the skin and has an overall favorable outcome, except for patients with an advanced stage of the disease. The efficacy of checkpoint inhibitors (CPI) for advanced cSCC has been demonstrated in recent clinical studies, but data from real-world cohorts and trial-ineligible cSCC patients are limited. We retrospectively investigated patients with advanced cSCC who have been treated with CPI in a first-line setting at eight German skin cancer centers registered within the multicenter registry ADOReg. Clinical outcome parameters including response, progression-free (PFS) and overall survival (OS), time-to-next-treatment (TTNT), and toxicity were analyzed and have been stratified by the individual immune status. Among 39 evaluable patients, the tumor response rate (rwTRR) was 48.6%, the median PFS was 29.0 months, and the median OS was not reached. In addition, 9 patients showed an impaired immune status due to immunosuppressive medication or hematological diseases. Our data demonstrated that CPI also evoked tumor responses among immunocompromised patients (rwTRR: 48.1 vs. 50.0%), although these responses less often resulted in durable remissions. In line with this, the median PFS (11 vs. 40 months, p = 0.059), TTNT (12 months vs. NR, p = 0.016), and OS (29 months vs. NR, p < 0.001) were significantly shorter for this patient cohort. CPI therapy was well tolerated in both subcohorts with 15% discontinuing therapy due to toxicity. Our real-world data show that first-line CPI therapy produced strong and durable responses among patients with advanced cSCC. Immunocompromised patients were less likely to achieve long-term benefit from anti-PD1 treatment, despite similar tumor response rates. KW - advanced cutaneous squamous cell carcinoma KW - checkpoint inhibitor therapy KW - cemiplimab KW - immunosuppression KW - response durability KW - real-world data Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297506 SN - 2072-6694 VL - 14 IS - 22 ER - TY - JOUR A1 - Wendlinger, Simone A1 - Wohlfarth, Jonas A1 - Kreft, Sophia A1 - Siedel, Claudia A1 - Kilian, Teresa A1 - Dischinger, Ulrich A1 - Heppt, Markus V. A1 - Wistuba-Hamprecht, Kilian A1 - Meier, Friedegund A1 - Goebeler, Matthias A1 - Schadendorf, Dirk A1 - Gesierich, Anja A1 - Kosnopfel, Corinna A1 - Schilling, Bastian T1 - Blood eosinophils are associated with efficacy of targeted therapy in patients with advanced melanoma JF - Cancers N2 - Background: Eosinophils appear to contribute to the efficacy of immunotherapy and their frequency was suggested as a predictive biomarker. Whether this observation could be transferred to patients treated with targeted therapy remains unknown. Methods: Blood and serum samples of healthy controls and 216 patients with advanced melanoma were prospectively and retrospectively collected. Freshly isolated eosinophils were phenotypically characterized by flow cytometry and co-cultured in vitro with melanoma cells to assess cytotoxicity. Soluble serum markers and peripheral blood counts were used for correlative studies. Results: Eosinophil-mediated cytotoxicity towards melanoma cells, as well as phenotypic characteristics, were similar when comparing healthy donors and patients. However, high relative pre-treatment eosinophil counts were significantly associated with response to MAPKi (p = 0.013). Eosinophil-mediated cytotoxicity towards melanoma cells is dose-dependent and requires proximity of eosinophils and their target in vitro. Treatment with targeted therapy in the presence of eosinophils results in an additive tumoricidal effect. Additionally, melanoma cells affected eosinophil phenotype upon co-culture. Conclusion: High pre-treatment eosinophil counts in advanced melanoma patients were associated with a significantly improved response to MAPKi. Functionally, eosinophils show potent cytotoxicity towards melanoma cells, which can be reinforced by MAPKi. Further studies are needed to unravel the molecular mechanisms of our observations. KW - melanoma KW - eosinophils KW - biomarker Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-275137 SN - 2072-6694 VL - 14 IS - 9 ER - TY - JOUR A1 - Thiem, Alexander A1 - Hesbacher, Sonja A1 - Kneitz, Hermann A1 - di Primio, Teresa A1 - Heppt, Markus V. A1 - Hermanns, Heike M. A1 - Goebeler, Matthias A1 - Meierjohann, Svenja A1 - Houben, Roland A1 - Schrama, David T1 - IFN-gamma-induced PD-L1 expression in melanoma depends on p53 expression JF - Journal of Experimental & Clinical Cancer Research N2 - Background Immune checkpoint inhibition and in particular anti-PD-1 immunotherapy have revolutionized the treatment of advanced melanoma. In this regard, higher tumoral PD-L1 protein (gene name: CD274) expression is associated with better clinical response and increased survival to anti-PD-1 therapy. Moreover, there is increasing evidence that tumor suppressor proteins are involved in immune regulation and are capable of modulating the expression of immune checkpoint proteins. Here, we determined the role of p53 protein (gene name: TP53) in the regulation of PD-L1 expression in melanoma. Methods We analyzed publicly available mRNA and protein expression data from the cancer genome/proteome atlas and performed immunohistochemistry on tumors with known TP53 status. Constitutive and IFN-ɣ-induced PD-L1 expression upon p53 knockdown in wildtype, TP53-mutated or JAK2-overexpressing melanoma cells or in cells, in which p53 was rendered transcriptionally inactive by CRISPR/Cas9, was determined by immunoblot or flow cytometry. Similarly, PD-L1 expression was investigated after overexpression of a transcriptionally-impaired p53 (L22Q, W23S) in TP53-wt or a TP53-knockout melanoma cell line. Immunoblot was applied to analyze the IFN-ɣ signaling pathway. Results For TP53-mutated tumors, an increased CD274 mRNA expression and a higher frequency of PD-L1 positivity was observed. Interestingly, positive correlations of IFNG mRNA and PD-L1 protein in both TP53-wt and -mutated samples and of p53 and PD-L1 protein suggest a non-transcriptional mode of action of p53. Indeed, cell line experiments revealed a diminished IFN-ɣ-induced PD-L1 expression upon p53 knockdown in both wildtype and TP53-mutated melanoma cells, which was not the case when p53 wildtype protein was rendered transcriptionally inactive or by ectopic expression of p53\(^{L22Q,W23S}\), a transcriptionally-impaired variant, in TP53-wt cells. Accordingly, expression of p53\(^{L22Q,W23S}\) in a TP53-knockout melanoma cell line boosted IFN-ɣ-induced PD-L1 expression. The impaired PD-L1-inducibility after p53 knockdown was associated with a reduced JAK2 expression in the cells and was almost abrogated by JAK2 overexpression. Conclusions While having only a small impact on basal PD-L1 expression, both wildtype and mutated p53 play an important positive role for IFN-ɣ-induced PD-L1 expression in melanoma cells by supporting JAK2 expression. Future studies should address, whether p53 expression levels might influence response to anti-PD-1 immunotherapy. KW - Melanoma KW - PD-L1 KW - CD274 KW - p53 KW - TP53 KW - JAK2 Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-201016 VL - 38 ER -