@article{LoddeForschnerHasseletal.2021,
  author    = {Lodde, Georg and Forschner, Andrea and Hassel, Jessica and Wulfken, Lena M. and Meier, Friedegund and Mohr, Peter and K{\"a}hler, Katharina and Schilling, Bastian and Loquai, Carmen and Berking, Carola and H{\"u}ning, Svea and Schatton, Kerstin and Gebhardt, Christoffer and Eckardt, Julia and Gutzmer, Ralf and Reinhardt, Lydia and Glutsch, Valerie and Nikfarjam, Ulrike and Erdmann, Michael and Stang, Andreas and Kowall, Bernd and Roesch, Alexander and Ugurel, Selma and Zimmer, Lisa and Schadendorf, Dirk and Livingstone, Elisabeth},
  title     = {Factors influencing the adjuvant therapy decision: results of a real-world multicenter data analysis of 904 melanoma patients},
  series = {Cancers},
  volume    = {13},
  journal   = {Cancers},
  number    = {10},
  issn      = {2072-6694},
  doi       = {10.3390/cancers13102319},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239583},
  year      = {2021},
  abstract  = {Adjuvant treatment of melanoma patients with immune-checkpoint inhibition (ICI) and targeted therapy (TT) significantly improved recurrence-free survival. This study investigates the real-world situation of 904 patients from 13 German skin cancer centers with an indication for adjuvant treatment since the approval of adjuvant ICI and TT. From adjusted log-binomial regression models, we estimated relative risks for associations between various influence factors and treatment decisions (adjuvant therapy yes/no, TT vs. ICI in BRAF mutant patients). Of these patients, 76.9\% (95\% CI 74-80) opted for a systemic adjuvant treatment. The probability of starting an adjuvant treatment was 26\% lower in patients >65 years (RR 0.74, 95\% CI 68-80). The most common reasons against adjuvant treatment given by patients were age (29.4\%, 95\% CI 24-38), and fear of adverse events (21.1\%, 95\% CI 16-28) and impaired quality of life (11.9\%, 95\% CI 7-16). Of all BRAF-mutated patients who opted for adjuvant treatment, 52.9\% (95\% CI 47-59) decided for ICI. Treatment decision for TT or ICI was barely associated with age, gender and tumor stage, but with comorbidities and affiliated center. Shortly after their approval, adjuvant treatments have been well accepted by physicians and patients. Age plays a decisive role in the decision for adjuvant treatment, while pre-existing autoimmune disease and regional differences influence the choice between TT or ICI.},
  language  = {en}
}
@phdthesis{Koenigshausen2007,
  author    = {K{\"o}nigshausen, Matthias},
  title     = {Untersuchung der PD-1/PDL-1/PDL-2 Expression und infiltrierender T-Zellen im humanen kolorektalen Karzinom und ihre Auswirkung auf die Immunantwort},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-24844},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2007},
  abstract  = {Zusammenfassung Neueste Daten deuten daraufhin, dass maligne Tumoren der immunologischen {\"U}berwachung {\"u}ber eine Herunterregulierung der T-Zell-Aktivierung mittels eines PD-1 (programmed death 1)/ PDL-1/PDL-2 Signals ausweichen. Dies f{\"u}hrt offensichtlich zu einer herabgesetzten Immunantwort und kann somit das Tumorwachstum f{\"o}rdern. Das Oberfl{\"a}chenmolek{\"u}l PD-1, welches auf T- und B-Zellen, myeloischen Zellen und auf vielen menschlichen Karzinomen exprimiert wird, geh{\"o}rt zu der CD28 Familie, und PDL-1 (B7H1) und PDL-2 (B7DC) wurden als Liganden zu PD-1 beschrieben. Der CD28/B7 Signalweg geh{\"o}rt zu der Gruppe kostimulatorischer Signale, die beim zustande kommen einer T-Zell-gerichteten Immunantwort als zweites kostimulatorisches Signal notwendig sind. In dieser Arbeit wurde die molekulare Expression von PD-1, PDL-1 und PDL-2, von Zytokinen und T-Zell-Subpopulationen im Tumorgewebe von 81 Patienten analysiert, die sich einer kurativen oder palliativen Operation (gem{\"a}ß UICC- Stadien I-IV) eines prim{\"a}ren kolorektalen Karzinoms unterzogen hatten. Es zeigte sich auf Protein- als auch auf molekularer Ebene erstmals, dass PDL-1 und PDL-2 im Tumorgewebe fortgeschrittener Tumorstadien (UICC III/IV) signifikant {\"u}berexprimiert wurden, PD-1 dagegen erniedrigt exprimiert war. PD-1 wurde dagegen deutlich auf infiltrierenden CD4+ Zellen bei Patienten fortgeschrittener Tumorstadien (UICC III/IV) detektiert, wohingegen PDL-1 auf CD4+ Zellen in fr{\"u}hen Stadien gefunden wurde. Im Vergleich zu den fr{\"u}hen Stadien (UICC I/II) wurde eine gr{\"o}ssere Anzahl an T-Zellen mit regulatorischem Charakter in den Tumorstadien III/IV beobachtet. Letzteres w{\"u}rde dem Tumor im Bezug auf sein fortschreitendes Wachstum von Vorteil sein, da regulatorische T-Zellen T-Effektorzellen inhibieren k{\"o}nnen. Im Tumorgewebe fand sich zudem eine verminderte Expression an IFN-gamma, welches unter anderem T-Effektorzellen aktiviert und damit eine Immunantwort verst{\"a}rkt. Das Zytokin IL-10, welches mit regulatorischen T-Zellen, aber auch mit T-Helfer (Th)2-Zellen und Tumorgewebe assoziiert ist und antiinflammatorische Eigenschaften besitzt, wurde in h{\"o}heren Stadien verst{\"a}rkt nachgewiesen. Dadurch verschafft es dem Tumor einen {\"U}berlebensvorteil. Die Beobachtungen in dieser Arbeit zeigen, dass PDL-1 und PDL-2 eine Schl{\"u}sselrolle w{\"a}hrend der Tumorprogression zukommen. Regulatorische T-Zellen sind offensichtlich in den Prozeß der Immunantwort gegen den Tumor eingebunden. Die deutliche PDL-1- und PDL-2-Expression auf T-Zellen insbesondere in fr{\"u}hen Tumorstadien l{\"a}sst darauf schließen, dass die PD-1/PDL-1- bzw. PD-1/PDL-2-Interaktion inhibitorische Signale zwischen Tumorzellen und den T-Zellen vermittelt. In fortgeschrittenen Stadien (UICC III/IV) waren diese kostimulatorischen Signale auf den T-Zellen nur vermindert vorzufinden. Dies hat zur Folge, dass der Tumor sein Wachstum ungehindert fortsetzen kann, da die anti-Tumor-T-Zell-Antwort, die den Tumor normalerweise in seiner Expansion beeintr{\"a}chtigt, gest{\"o}rt ist. Es wird somit festgestellt, dass eine Blockade der untersuchten Oberfl{\"a}chenmolek{\"u}le PDL-1 oder PDL-2 auf Tumorzellen eine wertvolle Option in der Immuntherapie des humanen kolorektalen Karzinoms darstellen k{\"o}nnte. Angesichts der diskutierten Tatsachen im Hinblick auf das Verhalten der regulatorischen T-Zellen in h{\"o}heren Tumorstadien k{\"o}nnte sich eventuell eine Option damit er{\"o}ffnen, die regulatorischen T-Zellen mittels eines spezifischen Antik{\"o}rpers gegen PDL-1 und/oder PDL-2 zu beeinflussen, um somit die hemmenden Auswirkungen gegen{\"u}ber der anti-Tumor-Immunantwort zu verhindern oder zu revidieren.},
  subject      = {PD-1},
  language  = {de}
}
@phdthesis{KronerMilsch2008,
  author    = {Kroner-Milsch, Antje},
  title     = {Role of immune cells in hereditary myelinopathies},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-28976},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2008},
  abstract  = {Myelin mutations in the central and peripheral nervous system lead to severely disabling, currently untreatable diseases. In this study, we used transgenic PLP overexpressing mice (PLPtg) as a model for central inherited myelinopathies, such as leukodystrophies, and heterozygously P0 deficient (P0+/-) mice as models for peripheral hereditary polyneuropathies. Both models are characterized by low grade nervous tissue inflammation. Macrophages and CD8+ T- lymphocytes contribute to the myelin pathology as shown by crossbreeding experiments with immunodeficient mice. Having shown the relevance of CD8+ T- lymphocytes in PLPtg mice, we investigated the influence of one major cytotoxic molecule (granzyme B) on neural damage. By generation of granzyme B deficient PLPtg bone marrow chimeras, we could demonstrate a reduction of myelin pathology and oligodendrocyte death. Taken together, granzyme B is at least partly responsible for the cytotoxicity induced neural damage in PLPtg mice. To further explore the role of immune modulation, we focussed on the influence of the coinhibitory molecule PD-1, a CD28-related receptor expressed on activated T- and B-lymphocytes. By investigating myelin mutants of the CNS and PNS (PLPtg and P0+/-) with an additional PD-1 deficiency, induced by crossbreeding or bone marrow chimerization, we found a significant increase of CD8+ T- lymphocytes and massive increase of the myelin pathology in both the CNS and PNS model. In PLPtg mice, absence of PD-1 increased oligodendrocyte apoptosis, clonal expansions and a higher propensity of CNS but not peripheral CD8+ T- cells to secrete proinflammatory cytokines. In P0+/- mice, absence of PD-1 lead to moderate motor and sensory disturbances, confirming the important role of PD-1 in immune homeostasis. Taken together, we identified granzyme B as an important effector agent of cytotoxic T-lymphocytes in PLPtg mice and PD-1 as a crucial player in regulating the effector cells in our models of central and peripheral myelinopathy. Alterations of this regulatory pathway lead to overt neuroinflammation of high pathogenetic impact. These results might help to understand mechanisms responsible for high clinical variability of polygenic or even monogenic disorders of the nervous system.},
  subject      = {Myelinopathie},
  language  = {en}
}
@phdthesis{Kreft2020,
  author    = {Kreft, Sophia},
  title     = {Wirksamkeit von PD-1 basierten Immuntherapien nach radiologischem Progress unter zielgerichteter Therapie im Melanom},
  doi       = {10.25972/OPUS-21882},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-218827},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {Im metastasierten Melanom sind bei Vorhandensein einer BRAF V600 Mutation zielgerichtete Therapien mit BRAF+MEK-Inhibitoren sowie Immuntherapien (ICB), die Immuncheckpoints wie PD-1 blockieren, zugelassen. Aktuell gibt es keine evidenzbasierte Empfehlung welche Therapie in der Erstlinie im BRAF V600 mutierten Melanom eingesetzt werden sollte. Bis jetzt wurde der Stellenwert PD-1 basierter Immuncheckpoint Blockade in der Zweitlinie nach Progress unter BRAF+MEK-Inhibition nicht beschrieben. Es ist auch unklar, ob die Kombinations-ICB (PD-1 plus CTLA-4 Blockade) mit einer Verbesserung des Ansprechens und {\"U}berlebens gegen{\"u}ber einer PD-1 Monotherapie assoziiert ist, wie f{\"u}r das therapie-naive Melanom beschrieben. Wir haben eine retrospektive, multizentrische Studie durchgef{\"u}hrt um die Wirksamkeit von PD-1 basierten Immuntherapien nach Progress unter zielgerichteter Therapie zu explorieren. In unserer Untersuchung zeigten PD-1 Monotherapie und die kombinierte PD-1 plus CTLA-4 Blockade eine {\"a}hnliche Wirksamkeit in Patienten mit BRAFi+MEKi-Resistenz. Die Kombinationstherapie war dagegen mit einem deutlich h{\"o}heren Risiko f{\"u}r schwerwiegende immunvermittelte Nebenwirkungen im Vergleich zu PD-1 Monotherapie assoziiert. Unsere Daten indizieren, dass eine PD-1 Blockade einer Kombinations-ICB in der Zweitlinie nach Progress unter zielgerichteter Therapie im fortgeschrittenen BRAF V600 mutierten Melanom vorzuziehen ist.},
  subject      = {Melanom},
  language  = {de}
}
@article{KochPetzoldWesselyetal.2022,
  author    = {Koch, Elias A. T. and Petzold, Anne and Wessely, Anja and Dippel, Edgar and Gesierich, Anja and Gutzmer, Ralf and Hassel, Jessica C. and Haferkamp, Sebastian and K{\"a}hler, Katharina C. and Knorr, Harald and Kreuzberg, Nicole and Leiter, Ulrike and Loquai, Carmen and Meier, Friedegund and Meissner, Markus and Mohr, Peter and Pf{\"o}hler, Claudia and Rahimi, Farnaz and Schadendorf, Dirk and Schell, Beatrice and Schlaak, Max and Terheyden, Patrick and Thoms, Kai-Martin and Schuler-Thurner, Beatrice and Ugurel, Selma and Ulrich, Jens and Utikal, Jochen and Weichenthal, Michael and Ziller, Fabian and Berking, Carola and Heppt, Markus V.},
  title     = {Immune checkpoint blockade for metastatic uveal melanoma: re-induction following resistance or toxicity},
  series = {Cancers},
  volume    = {14},
  journal   = {Cancers},
  number    = {3},
  issn      = {2072-6694},
  doi       = {10.3390/cancers14030518},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-254814},
  year      = {2022},
  abstract  = {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.},
  language  = {en}
}
@article{KochPetzoldWesselyetal.2021,
  author    = {Koch, Elias A. T. and Petzold, Anne and Wessely, Anja and Dippel, Edgar and Gesierich, Anja and Gutzmer, Ralf and Hassel, Jessica C. and Haferkamp, Sebastian and Hohberger, Bettina and K{\"a}hler, Katharina C. and Knorr, Harald and Kreuzberg, Nicole and Leiter, Ulrike and Loquai, Carmen and Meier, Friedegund and Meissner, Markus and Mohr, Peter and Pf{\"o}hler, Claudia and Rahimi, Farnaz and Schadendorf, Dirk and Schell, Beatrice and Schlaak, Max and Terheyden, Patrick and Thoms, Kai-Martin and Schuler-Thurner, Beatrice and Ugurel, Selma and Ulrich, Jens and Utikal, Jochen and Weichenthal, Michael and Ziller, Fabian and Berking, Carola and Heppt, Markus},
  title     = {Immune checkpoint blockade for metastatic uveal melanoma: patterns of response and survival according to the presence of hepatic and extrahepatic metastasis},
  series = {Cancers},
  volume    = {13},
  journal   = {Cancers},
  number    = {13},
  issn      = {2072-6694},
  doi       = {10.3390/cancers13133359},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-242603},
  year      = {2021},
  abstract  = {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.},
  language  = {en}
}
@phdthesis{Jaklin2023,
  author    = {Jaklin, Tamara},
  title     = {Nachweis von PD-1 und PD-L1 in Plattenepithelkarzinomen des Larynx und Hypopharynx},
  doi       = {10.25972/OPUS-31301},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313019},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2023},
  abstract  = {In der modernen Tumortherapie sind Checkpoint-Inhibitoren ein fester Bestandteil. Die Oberfl{\"a}chenproteine PD-L1 und PD-1 stellen die Angriffspunkte dieser spezifischen Therapie dar. Die Datenlage hinsichtlich PD-L1 in HNSCC ist sehr heterogen. Diese Arbeit besch{\"a}ftigte sich daher mit der Expression von PD-L1 und PD-1 in einem Kollektiv von 118 Plattenepithelkarzinomen in Larynx und Hypopharynx und einer prognostischen Aussagekraft hinsichtlich mehrerer histopathologischer und epidemiologischer Faktoren. Außerdem wurde ein m{\"o}glicher Zusammenhang zwischen der Expression von PD-L1, PD-1 und CD5 als T-Zell-Marker in besagtem Kollektiv untersucht. Die IHC-F{\"a}rbungen wurden lichtmikroskopisch an tissue micro arrays untersucht. F{\"u}r die Auswertung von PD-L1 wurde der bereits etablierte Cologne-Score verwendet, welcher zum einen zun{\"a}chst erweitert und anschließend zwecks einer fundierten statistischen Auswertung erg{\"a}nzend modifiziert wurde. F{\"u}r CD5 und PD-1 wurden eigene Cut-Off-Werte generiert. 48 \% der F{\"a}lle waren PD-L1+, die Spannweite im Literaturvergleich schwankt zwischen 30 - 90 \%. PD-1+ waren insgesamt 31\% der F{\"a}lle, auch hier zeigen sich deutliche Abweichungen zu den vorliegenden Publikationen. Hinsichtlich der prognostischen Aussagekraft konnte ein signifikanter Zusammenhang zwischen dem T-Stadium und der PD-L1-Expression aufgezeigt werden. Ob dies Einfluss auf m{\"o}gliche Behandlungsstrategien hat, bleibt Gegenstand weiterer Forschung. Auch im Literaturvergleich finden sich wiederholt signifikante prognostische Zusammenh{\"a}nge, jedoch beziehen sich diese auf differente Faktoren. Urs{\"a}chlich daf{\"u}r sind aller Wahrscheinlichkeit nach Diskrepanzen in der PD-L1-Expression sowie deren Schwankungen durch {\"a}ußere Einfl{\"u}sse und nicht standardisierte Testverfahren. Es zeigten sich weiterhin Korrelationen zwischen den Markern, welche sich abschließend nicht alle g{\"a}nzlich herleiten lassen. Zusammenfassend k{\"o}nnten einheitliche Testverfahren die Datenlage zu PD-L1 und PD-1 homogenisieren, auch m{\"o}gliche Vortherapien sollten dementsprechend ber{\"u}cksichtigt werden. Allerdings erscheint die prognostische Aussagekraft von PD-L1 und auch von PD-1 insgesamt aufgrund der inkonstanten Expression hochgradig eingeschr{\"a}nkt, sodass sich in Zukunft vermehrt auf andere Marker konzentriert werden sollte.},
  subject      = {Plattenepithelkarzinom},
  language  = {de}
}
@article{HarterBernatzScholzetal.2015,
  author    = {Harter, Patrick N. and Bernatz, Simon and Scholz, Alexander and Zeiner, Pia S. and Zinke, Jenny and Kiyose, Makoto and Blasel, Stella and Beschorner, Rudi and Senft, Christian and Bender, Benjamin and Ronellenfitsch, Michael W. and Wikman, Harriet and Glatzel, Markus and Meinhardt, Matthias and Juratli, Tareq A. and Steinbach, Joachim P. and Plate, Karl H. and Wischhusen, J{\"o}rg and Weide, Benjamin and Mittelbronn, Michel},
  title     = {Distribution and prognostic relevance of tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune checkpoints in human brain metastases},
  series = {Oncotarget},
  volume    = {6},
  journal   = {Oncotarget},
  number    = {38},
  doi       = {10.18632/oncotarget.5696},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-137107},
  pages     = {40836 -- 40849},
  year      = {2015},
  abstract  = {The activation of immune cells by targeting checkpoint inhibitors showed promising results with increased patient survival in distinct primary cancers. Since only limited data exist for human brain metastases, we aimed at characterizing tumor infiltrating lymphocytes (TILs) and expression of immune checkpoints in the respective tumors. Two brain metastases cohorts, a mixed entity cohort (n = 252) and a breast carcinoma validation cohort (n = 96) were analyzed for CD3+, CD8+, FOXP3+, PD-1+ lymphocytes and PD-L1+ tumor cells by immunohistochemistry. Analyses for association with clinico-epidemiological and neuroradiological parameters such as patient survival or tumor size were performed. TILs infiltrated brain metastases in three different patterns (stromal, peritumoral, diffuse). While carcinomas often show a strong stromal infiltration, TILs in melanomas often diffusely infiltrate the tumors. Highest levels of CD3+ and CD8+ lymphocytes were seen in renal cell carcinomas (RCC) and strongest PD-1 levels on RCCs and melanomas. High amounts of TILs, high ratios of PD-1+/CD8+ cells and high levels of PD-L1 were negatively correlated with brain metastases size, indicating that in smaller brain metastases CD8+ immune response might get blocked. PD-L1 expression strongly correlated with TILs and FOXP3 expression. No significant association of patient survival with TILs was observed, while high levels of PD-L1 showed a strong trend towards better survival in melanoma brain metastases (Log-Rank p = 0.0537). In summary, melanomas and RCCs seem to be the most immunogenic entities. Differences in immunotherapeutic response between tumor entities regarding brain metastases might be attributable to this finding and need further investigation in larger patient cohorts.},
  language  = {en}
}
@article{GlutschGraenWeberetal.2019,
  author    = {Glutsch, Valerie and Gr{\"a}n, Franziska and Weber, Judith and Gesierich, Anja and Goebeler, Matthias and Schilling, Bastian},
  title     = {Response to combined ipilimumab and nivolumab after development of a nephrotic syndrome related to PD-1 monotherapy},
  series = {Journal for ImmunoTherapy of Cancer},
  volume    = {7},
  journal   = {Journal for ImmunoTherapy of Cancer},
  doi       = {10.1186/s40425-019-0655-4},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-201214},
  pages     = {181},
  year      = {2019},
  abstract  = {Background High response rates of metastatic melanoma have been reported upon immune checkpoint inhibition by PD-1 blockade alone or in combination with CTLA-4 inhibitors. However, the majority of patients with a primary resistance to anti-PD-1 monotherapy is also refractory to a subsequent combined checkpoint inhibition. In BRAF wildtype patients with a primary resistance to PD-1 inhibitors, therapeutic options are therefore limited and immune-related adverse events (irAE) have to be taken into consideration when discussing a subsequent immunotherapy. Case presentation We report the case of a 68-year-old male patient with metastatic melanoma who experienced an acute renal failure with nephrotic syndrome due to a minimal change disease developing after a single dose of the anti-PD-1 antibody pembrolizumab. A kidney biopsy revealed a podocytopathy without signs of interstitial nephritis. Renal function recovered to almost normal creatinine and total urine protein levels upon treatment with oral steroids and diuretics. Unfortunately, a disease progression (PD, RECIST 1.1) was observed in a CT scan after resolution of the irAE. In a grand round, re-exposure to a PD-1-containing regime was recommended. Consensually, a combined immunotherapy with ipilimumab and nivolumab was initiated. Nephrotoxicity was tolerable during combined immunotherapy and a CT scan of chest and abdomen showed a deep partial remission (RECIST 1.1) after three doses of ipilimumab (3 mg/kg) and nivolumab (1 mg/kg). Conclusion This case illustrates that a fulminant response to combined checkpoint inhibition is possible after progression after anti-PD-1 monotherapy and a severe irAE.},
  language  = {en}
}