@article{AlbSieAdametal.2012, author = {Alb, Miriam and Sie, Christopher and Adam, Christian and Chen, Suzie and Becker, J{\"u}rgen C. and Schrama, David}, title = {Cellular and cytokine-dependent immunosuppressive mechanisms of grm1-transgenic murine melanoma}, series = {Cancer Immunology, Immunotherapy}, volume = {61}, journal = {Cancer Immunology, Immunotherapy}, number = {12}, doi = {10.1007/s00262-012-1290-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125096}, pages = {2239-2249}, year = {2012}, abstract = {Grm1-transgenic mice spontaneously develop cutaneous melanoma. This model allowed us to scrutinize the generic immune responses over the course of melanoma development. To this end, lymphocytes obtained from spleens, unrelated lymph nodes and tumor-draining lymph nodes of mice with no evidence of disease, and low or high tumor burden were analyzed ex vivo and in vitro. Thereby, we could demonstrate an increase in the number of activated CD4\(^+\) and CD8+ lymphocytes in the respective organs with increasing tumor burden. However, mainly CD4\(^+\) T cells, which could constitute both T helper as well as immunosuppressive regulatory T cells, but not CD8\(^+\) T cells, expressed activation markers upon in vitro stimulation when obtained from tumor-bearing mice. Interestingly, these cells from tumor-burdened animals were also functionally hampered in their proliferative response even when subjected to strong in vitro stimulation. Further analyses revealed that the increased frequency of regulatory T cells in tumor-bearing mice is an early event present in all lymphoid organs. Additionally, expression of the immunosuppressive cytokines TGF-β1 and IL-10 became more evident with increased tumor burden. Notably, TGF-β1 is strongly expressed in both the tumor and the tumor-draining lymph node, whereas IL-10 expression is more pronounced in the lymph node, suggesting a more complex regulation of IL-10. Thus, similar to the situation in melanoma patients, both cytokines as well as cellular immune escape mechanisms seem to contribute to the observed immunosuppressed state of tumor-bearing grm1-transgenic mice, suggesting that this model is suitable for preclinical testing of immunomodulatory therapeutics.}, language = {en} } @article{BeckerAndersenHofmeisterMuelleretal.2012, author = {Becker, J{\"u}rgen C. and Andersen, Mads H. and Hofmeister-M{\"u}ller, Valeska and Wobser, Marion and Frey, Lidia and Sandig, Christiane and Walter, Steffen and Singh-Jasuja, Harpreet and K{\"a}mpgen, Eckhart and Opitz, Andreas and Zapatka, Marc and Br{\"o}cker, Eva-B. and thor Straten, Per and Schrama, David and Ugurel, Selma}, title = {Survivin-specific T-cell reactivity correlates with tumor response and patient survival: a phase-II peptide vaccination trial in metastatic melanoma}, series = {Cancer Immunology, Immunotherapy}, volume = {61}, journal = {Cancer Immunology, Immunotherapy}, number = {11}, doi = {10.1007/s00262-012-1266-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126215}, pages = {2091-2103}, year = {2012}, abstract = {Background Therapeutic vaccination directed to induce an anti-tumoral T-cell response is a field of extensive investigation in the treatment of melanoma. However, many vaccination trials in melanoma failed to demonstrate a correlation between the vaccine-specific immune response and therapy outcome. This has been mainly attributed to immune escape by antigen loss, rendering us in the need of new vaccination targets. Patients and methods This phase-II trial investigated a peptide vaccination against survivin, an oncogenic inhibitor-of-apoptosis protein crucial for the survival of tumor cells, in HLA-A1/-A2/-B35-positive patients with treatment-refractory stage-IV metastatic melanoma. The study endpoints were survivin-specific T-cell reactivity (SSTR), safety, response, and survival (OS). Results Sixty-one patients (ITT) received vaccination therapy using three different regimens. 55 patients (PP) were evaluable for response and survival, and 41/55 for SSTR. Patients achieving progression arrest (CR + PR + SD) more often showed SSTRs than patients with disease progression (p = 0.0008). Patients presenting SSTRs revealed a prolonged OS (median 19.6 vs. 8.6 months; p = 0.0077); multivariate analysis demonstrated SSTR as an independent predictor of survival (p = 0.013). The induction of SSTRs was associated with gender (female vs. male; p = 0.014) and disease stage (M1a/b vs. M1c; p = 0.010), but not with patient age, HLA type, performance status, or vaccination regimen. Conclusion Survivin-specific T-cell reactivities strongly correlate with tumor response and patient survival, indicating that vaccination with survivin-derived peptides is a promising treatment strategy in melanoma.}, language = {en} } @article{BeckerAndersenHofmeisterMuelleretal.2012, author = {Becker, J{\"u}rgen C. and Andersen, Mads H. and Hofmeister-M{\"u}ller, Valeska and Wobser, Marion and Frey, Lidia and Sandig, Christiane and Walter, Steffen and Singh-Jasuja, Harpreet and K{\"a}mpgen, Eckhart and Opitz, Andreas and Zapatka, Marc and Br{\"o}cker, Eva-B. and thor Straten, Per and Schrama, David and Ugurel, Selma}, title = {Survivin-specific T-cell reactivity correlates with tumor response and patient survival: a phase-II peptide vaccination trial in metastatic melanoma}, series = {Cancer Immunology, Immunotherapy}, volume = {61}, journal = {Cancer Immunology, Immunotherapy}, number = {11}, doi = {10.1007/s00262-012-1266-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-124830}, pages = {2091-2103}, year = {2012}, abstract = {Background Therapeutic vaccination directed to induce an anti-tumoral T-cell response is a field of extensive investigation in the treatment of melanoma. However, many vaccination trials in melanoma failed to demonstrate a correlation between the vaccine-specific immune response and therapy outcome. This has been mainly attributed to immune escape by antigen loss, rendering us in the need of new vaccination targets. Patients and methods This phase-II trial investigated a peptide vaccination against survivin, an oncogenic inhibitor-of-apoptosis protein crucial for the survival of tumor cells, in HLA-A1/-A2/-B35-positive patients with treatment-refractory stage-IV metastatic melanoma. The study endpoints were survivin-specific T-cell reactivity (SSTR), safety, response, and survival (OS). Results Sixty-one patients (ITT) received vaccination therapy using three different regimens. 55 patients (PP) were evaluable for response and survival, and 41/55 for SSTR. Patients achieving progression arrest (CR + PR + SD) more often showed SSTRs than patients with disease progression (p = 0.0008). Patients presenting SSTRs revealed a prolonged OS (median 19.6 vs. 8.6 months; p = 0.0077); multivariate analysis demonstrated SSTR as an independent predictor of survival (p = 0.013). The induction of SSTRs was associated with gender (female vs. male; p = 0.014) and disease stage (M1a/b vs. M1c; p = 0.010), but not with patient age, HLA type, performance status, or vaccination regimen. Conclusion Survivin-specific T-cell reactivities strongly correlate with tumor response and patient survival, indicating that vaccination with survivin-derived peptides is a promising treatment strategy in melanoma.}, language = {en} } @article{BuderLapaKreissletal.2014, author = {Buder, Kristina and Lapa, Constantin and Kreissl, Michael C. and Schirbel, Andreas and Herrmann, Ken and Schnack, Alexander and Br{\"o}cker, Eva-Bettina and Goebeler, Matthias and Buck, Andreas K. and Becker, J{\"u}rgen C.}, title = {"Somatostatin receptor expression in Merkel cell carcinoma as target for molecular imaging"}, doi = {10.1186/1471-2407-14-268}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110326}, year = {2014}, abstract = {Background Merkel cell carcinoma (MCC) is a rare cutaneous neoplasm with increasing incidence, aggressive behavior and poor prognosis. Somatostatin receptors (SSTR) are expressed in MCC and represent a potential target for both imaging and treatment. Methods To non-invasively assess SSTR expression in MCC using PET and the radiotracers [68Ga]DOTA-D-Phe1-Tyr3-octreotide (DOTATOC) or -octreotate (DOTATATE) as surrogate for tumor burden. In 24 patients with histologically proven MCC SSTR-PET was performed and compared to results of computed tomography (CT). Results SSTR-PET detected primary and metastatic MCC lesions. On a patient-based analysis, sensitivity of SSTR-PET was 73\% for nodal metastases, 100\% for bone, and 67\% for soft-tissue metastases, respectively. Notably, brain metastases were initially detected by SSTR-PET in 2 patients, whereas liver and lung metastases were diagnosed exclusively by CT. SSTR-PET showed concordance to CT results in 20 out of 24 patients. Four patients (17\%) were up-staged due to SSTR-PET and patient management was changed in 3 patients (13\%). Conclusion SSTR-PET showed high sensitivity for imaging bone, soft tissue and brain metastases, and particularly in combination with CT had a significant impact on clinical stage and patient management.}, language = {en} } @article{BuderMuellerBeekmannetal.2014, author = {Buder, Kristina and M{\"u}ller, Philip A. and Beekmann, Gabriele and Ugurel, Selma and Br{\"o}cker, Eva-Bettina and Becker, J{\"u}rgen C.}, title = {Denileukin Diftitox plus Total Skin Electron Beam Radiation in Patients with Treatment-refractory Cutaneous T-cell Lymphoma (Mycosis Fungoides): Report of Four Cases}, series = {Acta Dermato-Venereologica}, volume = {94}, journal = {Acta Dermato-Venereologica}, doi = {10.2340/00015555-1627}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-120091}, pages = {94-96}, year = {2014}, abstract = {Mycosis fungoides (MF) is the most common cutaneous T-cell lymphoma (CTCL) (1). Most patients initially respond well to standard therapy, but advanced MF is often treatment refractory. Thus, a combination of the available treatment options is an important strategy. Total skin electron beam radiation (TSEB) is effective in MF, with a complete remission rate of up to 90\% in the early stages. However, in patients with more advanced stages, remission rates are considerably lower (2, 3). Denileukin diftitox (DD) (Ontak®) is a recombinant fusion protein of the receptor-binding domain of interleukin (IL)-2 and the enzymatic and translocation domains of diphtheria toxin (4). It targets the alpha-subunit of the IL-2-receptor (CD25). There are no reports on this combination therapy in MF.}, language = {en} } @article{FanZebischHornyetal.2020, author = {Fan, Kaiji and Zebisch, Armin and Horny, Kai and Schrama, David and Becker, J{\"u}rgen C.}, title = {Highly expressed miR-375 is not an intracellular oncogene in Merkel cell polyomavirus-associated Merkel cell carcinoma}, series = {Cancers}, volume = {12}, journal = {Cancers}, number = {3}, issn = {2072-6694}, doi = {10.3390/cancers12030529}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200678}, year = {2020}, abstract = {miR-375 is a highly abundant miRNA in Merkel cell carcinoma (MCC). In other cancers, it acts as either a tumor suppressor or oncogene. While free-circulating miR-375 serves as a surrogate marker for tumor burden in patients with advanced MCC, its function within MCC cells has not been established. Nearly complete miR-375 knockdown in MCC cell lines was achieved using antagomiRs via nucleofection. The cell viability, growth characteristics, and morphology were not altered by this knockdown. miR-375 target genes and related signaling pathways were determined using Encyclopedia of RNA Interactomes (ENCORI) revealing Hippo signaling and epithelial to mesenchymal transition (EMT)-related genes likely to be regulated. Therefore, their expression was analyzed by multiplexed qRT-PCR after miR-375 knockdown, demonstrating only a limited change in expression. In summary, highly effective miR-375 knockdown in classical MCC cell lines did not significantly change the cell viability, morphology, or oncogenic signaling pathways. These observations render miR-375 an unlikely intracellular oncogene in MCC cells, thus suggesting that likely functions of miR-375 for the intercellular communication of MCC should be addressed.}, language = {en} } @article{GlutschKneitzGesierichetal.2021, author = {Glutsch, Valerie and Kneitz, Hermann and Gesierich, Anja and Goebeler, Matthias and Haferkamp, Sebastian and Becker, J{\"u}rgen C. and Ugurel, Selma and Schilling, Bastian}, title = {Activity of ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma}, series = {Cancer Immunology, Immunotherapy}, volume = {70}, journal = {Cancer Immunology, Immunotherapy}, number = {7}, issn = {14320851}, doi = {10.1007/s00262-020-02832-0}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-265635}, pages = {2087-2093}, year = {2021}, abstract = {Background Merkel cell carcinoma (MCC) is a rare and aggressive neuroendocrine cutaneous malignancy with poor prognosis. In Europe, approved systemic therapies are limited to the PD-L1 inhibitor avelumab. For avelumab-refractory patients, efficient and safe treatment options are lacking. Methods At three different sites in Germany, clinical and molecular data of patients with metastatic MCC being refractory to the PD-L1 inhibitor avelumab and who were later on treated with combined IPI/NIVO were retrospectively collected and evaluated. Results Five patients treated at three different academic sites in Germany were enrolled. Three out of five patients investigated for this report responded to combined IPI/NIVO according to RECIST 1.1. Combined immunotherapy was well tolerated without any grade II or III immune-related adverse events. Two out of three responders to IPI/NIVO received platinum-based chemotherapy in between avelumab and combined immunotherapy. Conclusion In this small retrospective study, we observed a high response rate and durable responses to subsequent combined immunotherapy with IPI/NIVO in avelumab-refractory metastatic MCC patients. In conclusion, our data suggest a promising activity of second- or third-line PD-1- plus CTLA-4-blockade in patients with anti-PD-L1-refractory MCC.}, language = {en} } @article{GlutschSchummerKneitzetal.2022, author = {Glutsch, Valerie and Schummer, Patrick and Kneitz, Hermann and Gesierich, Anja and Goebeler, Matthias and Klein, Detlef and Posch, Christian and Gebhardt, Christoffer and Haferkamp, Sebastian and Zimmer, Lisa and Becker, J{\"u}rgen C and Leiter, Ulrike and Weichenthal, Michael and Schadendorf, Dirk and Ugurel, Selma and Schilling, Bastian}, title = {Ipilimumab plus nivolumab in avelumab-refractory Merkel cell carcinoma: a multicenter study of the prospective skin cancer registry ADOREG}, series = {Journal for ImmunoTherapy of Cancer}, volume = {10}, journal = {Journal for ImmunoTherapy of Cancer}, number = {11}, issn = {2051-1426}, doi = {10.1136/jitc-2022-005930}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-304613}, year = {2022}, abstract = {Merkel cell carcinoma is a rare, highly aggressive skin cancer with neuroendocrine differentiation. Immune checkpoint inhibition has significantly improved treatment outcomes in metastatic disease with response rates to programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) inhibition of up to 62\%. However, primary and secondary resistance to PD-1/PD-L1 inhibition remains a so far unsolved clinical challenge since effective and safe treatment options for these patients are lacking.Fourteen patients with advanced (non-resectable stage III or stage IV, Union international contre le cancer 2017) Merkel cell carcinoma with primary resistance to the PD-L1 inhibitor avelumab receiving subsequent therapy (second or later line) with ipilimumab plus nivolumab (IPI/NIVO) were identified in the prospective multicenter skin cancer registry ADOREG. Five of these 14 patients were reported previously and were included in this analysis with additional follow-up. Overall response rate, progression-free survival (PFS), overall survival (OS) and adverse events were analyzed.All 14 patients received avelumab as first-line treatment. Thereof, 12 patients had shown primary resistance with progressive disease in the first tumor assessment, while two patients had initially experienced a short-lived stabilization (stable disease). Six patients had at least one systemic treatment in between avelumab and IPI/NIVO. In total, 7 patients responded to IPI/NIVO (overall response rate 50\%), and response was ongoing in 4 responders at last follow-up. After a median follow-up of 18.85 months, median PFS was 5.07 months (95\% CI 2.43—not available (NA)), and median OS was not reached. PFS rates at 12 months and 24 months were 42.9\% and 26.8 \%, respectively. The OS rate at 36 months was 64.3\%. Only 3 (21\%) patients did not receive all 4 cycles of IPI/NIVO due to immune-related adverse events.In this multicenter evaluation, we observed high response rates, a durable benefit and promising OS rates after treatment with later-line combined IPI/NIVO. In conclusion, our patient cohort supports our prior findings with an encouraging activity of second-line or later-line IPI/NIVO in patients with anti-PD-L1-refractory Merkel cell carcinoma.}, language = {en} } @article{HaferkampHesbacherWeyandtetal.2014, author = {Haferkamp, Sebastian and Hesbacher, Sonja and Weyandt, Gerhard and Vetter-Kauczok, Claudia S. and Becker, J{\"u}rgen C. and Motschenbacher, Stephanie and Wobser, Marion and Maier, Melissa and Schmid, Corinna P. and Houben, Roland}, title = {p53 regulation by TRP2 is not pervasive in melanoma}, doi = {10.1371/journal.pone.0087440}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-111396}, year = {2014}, abstract = {p53 is a central tumor suppressor protein and its inhibition is believed to be a prerequisite for cancer development. In approximately 50\% of all malignancies this is achieved by inactivating mutations in the p53 gene. However, in several cancer entities, including melanoma, p53 mutations are rare. It has been recently proposed that tyrosinase related protein 2 (TRP2), a protein involved in melanin synthesis, may act as suppressor of the p53 pathway in melanoma. To scrutinize this notion we analyzed p53 and TRP2 expression by immunohistochemistry in 172 melanoma tissues and did not find any correlation. Furthermore, we applied three different TRP2 shRNAs to five melanoma cell lines and could not observe a target specific effect of the TRP2 knockdown on either p53 expression nor p53 reporter gene activity. Likewise, ectopic expression of TRP2 in a TRP2 negative melanoma cell line had no impact on p53 expression. In conclusion our data suggest that p53 repression critically controlled by TRP2 is not a general event in melanoma.}, language = {en} } @article{HafnerHoubenBaeurleetal.2012, author = {Hafner, Christian and Houben, Roland and Baeurle, Anne and Ritter, Cathrin and Schrama, David and Landthaler, Michael and Becker, J{\"u}rgen C.}, title = {Activation of the PI3K/AKT Pathway in Merkel Cell Carcinoma}, series = {PLoS One}, volume = {7}, journal = {PLoS One}, number = {2}, doi = {10.1371/journal.pone.0031255}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-131398}, pages = {e31255}, year = {2012}, abstract = {Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88\% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV). Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4\%) MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients.}, language = {en} }