Class of 2016 Abstract / Objectives: To test whether ipilimumab therapy affects the endocrine system in patients with Metastatic Melanoma. Methods: A retrospective chart review was performed that included patients with Metastatic Melanoma that had at least one dose of ipilimumab. Results: The primary finding of this study is that 38% of patients used at least 20 mg of prednisone daily or more while on Ipilimumab therapy. Only 33% of patients had endocrine lab values reported. Conclusions: There was not enough data collected to adequately show that Ipilimumab affects the endocrine system. There was also insufficient reporting of appropriate serum levels. More research on the importance of reporting lab values while on ipilimumab therapy needs to be conducted.

Malignant melanoma is a growing problem with more and more people in Sweden and the world suffering from this cancer. Malignant melanoma is a disease that when discovered in time can be treated successfully with surgical methods, but the real challenge lies in treating the disease after its spread. Treatment in the past for advanced malignant melanoma has been unsuccessful with no positive effect on overall survival. However, in the last couple of years, new treatment has arrived with focus on priming the immune system to eradicate the tumors. One new drug is the CTLA-4 inhibitor ipilimumab that is given as intravenous infusion. CTLA-4 is a protein located on regulatory T-cells and that is upregulated on activated cytotoxic T-cells. This protein mediates an inhibitory signal that attenuates T-cell-activation.  Treatment with the CTLA-4 inhibitor has been shown to increase overall survival. However, not much is known about how well ipilimumab synergizes with other drugs used for treatment of malignant melanoma.   This is a literature study with the aim to evaluate if ipilimumab is used best as monotherapy or if it is of better use as part of a combination therapy. Search was made in PubMed with the key-words "Ipilimumab", "Ipilimumab treatment", CTLA-4 inhibitor" and "treatment malignant melanoma”. Six articles were chosen and each of these analyzed the effect of ipilimumab alone or combined with other agents against malignant melanoma.   The combination of ipilimumab and the alkylating agent dacarbazine was shown to have a better impact on overall survival compared with monotherapy with dacarbazine, but this combination also showed an increase in serious adverse events. Ipilimumab also showed to work in synergy with both the PD-1-inhibitor nivolumab and the granulocyte macrophage colony-stimulating factor (GM-CSF) sargramostim. Combination with sargramostim was also shown to decrease the amount of serious adverse events. Combination with a gp100 peptide vaccine failed to show any positive effects on overall survival. Also prophylactic treatment with budesonide showed no further gain in overall survival. The effect of ipilimumab was found to have a dose-ranging effect, with higher dose treatment having a better effect but also with more serious adverse events.   The results of this literature study showed that ipilimumab has a better effect with higher dose and that it can work in synergy with other agents such as nivolumab and sargramostim. Results also showed that occurring adverse effects during treatment with ipilimumab may be treated with systemic glucocorticoids that did not affect the tumor-killing ability of ipilimumab. These results should be evaluated in bigger studies and with longer follow up time.

Malignt melanom är den allvarligaste formen av hudcancer och orsakas av att friska melanocyter börjar dela sig okontrollerat, vilket resulterar i en tumör. Det finns flera riskfaktorer för melanom men en av de främsta är exponering av UV-strålning. En ytterligare riskfaktor för malignt melanom är olika genmutationer varav av en vanligt förekommande genmutation är BRAF-mutation. Det finns flera behandlingsmetoder men en nyare behandling som används vid de senare stadierna av melanom är immunterapi. Programmed cell death 1 (PD-1)-hämmaren nivolumab och cytotoxic T-lymphocyte antigen 4 (CTLA-4)-hämmaren ipilimumab är två checkpointhämmare som på olika sätt hämmar tumörtillväxten.  Syftet med denna litteraturstudie var att undersöka nivolumab och ipilimumabs effekt samt säkerhet både som monoterapi och kombinationsterapi. Databasen PubMed användes för att välja ut fem RCT-studier. Vid sökningen användes sökord som ”melanoma”, ”nivolumab” och ”ipilimumab”. Några av inklusionskriterierna var att patienterna hade melanom i stadie III och IV, och både patienter med BRAF V600-mutation och med BRAF wild-type inkluderades. Ett av exklusionskriterierna var artiklar som var inriktade på melanom i hjärna, lunga eller ögon. Resultatet visade att nivolumab och ipilimumab som kombinationsterapi var mer effektiv avseende både total överlevnad och progressionsfri överlevnad jämfört med nivolumab och ipilimumab som monoterapi. Nivolumab som monoterapi var mer effektiv än vad ipilimumab som monoterapi var avseende total överlevnad och progressionsfri överlevnad. Behandlingen med nivolumab och ipilimumab som kombinationsterapi resulterade däremot i fler biverkningar jämfört med nivolumab och ipilimumab som monoterapi. Patienter som behandlades med nivolumab som monoterapi upplevde färre biverkningar än vad patienterna som behandlades med ipilimumab som monoterapi upplevde. Utifrån resultaten i de studier som granskats så är slutsatsen att kombinationsbehandlingen var den mest effektiva, men om även säkerhet inkluderas är nivolumab som monoterapi det bättre alternativet då det hade både god effekt och en lägre biverkningsprofil jämfört med de andra behandlingsalternativen. För ett mer tillförlitligt resultat bör ytterligare studier genomföras under längre tid och i en större skala.

Le CTLA4 permet de maintenir la tolérance du soi et prévient le développement d’auto-immunités. Contenu au sein de vésicules intra-cytoplasmiques des lymphocytes T au repos, le CTLA4 est exprimé à la membrane plasmique suite à l’activation du TCR, on le qualifie de rétrocontrôle inhibiteur du système immunitaire (ICB). L’anticorps bloquant le CTLA4, l’ipilimumab induit un contrôle immunitaire à long terme chez une fraction de patients atteints de mélanomes métastatiques. Deux études cliniques de phase III ont conduit à son autorisation de mise sur le marché dans le traitement du mélanome métastatique par la FDA et l’EMA en 2011. Cependant le blocage du CTLA4 est souvent associé au développement d’effets indésirables liés à l’immunité, irAEs, majoritairement au niveau de la peau et de l’intestin, deux sites colonisés par la flore microbienne. Afin de continuer le développement des ICB et des combinaisons de traitements, de nombreux efforts visent à découpler l’efficacité anti-tumorale de la toxicité associée à l’anti-CTLA4. Bien que la stimulation du système immunitaire soit responsable des effets thérapeutiques de l’anti-CTLA4, aucun biomarqueur immunologique d’efficacité n’a été décrit. Dans notre première étude nous avons étudié le mécanisme d’action de l’anti-CTLA4 et nous avons décrit un rôle de l’IL-2 et de ses récepteurs dans l’activité anti-tumorale de l’anticorps. Nous avons également décrit la fraction soluble du récepteur à l’IL-2, le sCD25 comme un biomarqueur potentiel de résistance au traitement. Une concentration élevée de sCD25 dans le sérum des patients atteints de mélanome prédit la résistance à l’ipilimumab. Dans notre second projet, nous avons révélé le rôle du microbiote intestinale et particulièrement de bactéries Gram négatives, des Bacteroides, dans l’efficacité anti-tumorale de l’anti-CTLA4. L’absence d’efficacité du blocage du CTLA4 chez les animaux dépourvus de flore intestinale peut être rétablie par l’administration de Bacteroides fragilis, ou bien de DC, ou encore de lymphocytes T spécifiques de B. fragilis, sans déclencher de colites. Ces travaux suggèrent de nouvelles stratégies thérapeutiques pour espérer améliorer la balance bénéfice / toxicité / coût de l’ipilimumab. / CTLA4, cytotoxic T lymphocyte antigen-4, which is present in the intracytoplasmic vesicles of resting T cells, is upregulated at the surface of activated T cells where it maintains self-tolerance and prevents autoimmunity. The CTLA4-blocking antibody, ipilimumab, induces immune-mediated long term control of metastatic melanoma in a fraction of patients, leading to its approval by the US Food and Drug Administration (FDA) and the European Medical Agency (EMA) in 2011 for the treatment of advanced metastatic melanoma. However, blockade of CTLA4 by ipilimumab often results in immune-related adverse events (irAEs) at sites that are exposed to commensal flora, namely the gut and the skin. Uncoupling efficacy from toxicity is a challenge for the development of immune checkpoint blockers and therapeutic combinations. Although ipilimumab undoubtedly exerts its therapeutic effects via immunostimulation, relevant immune biomarkers that predict treatment efficiency remain elusive. Firstly, we unravel a role for IL-2 and IL-2 receptors in the anticancer activity of CTLA-4 blockade. Importantly, our study provides an immunologically relevant biomarker, elevated serum sCD25, which predicts resistance to CTLA-4 blockade in patients with melanoma. Secondly, we show that the antitumor effects of CTLA4 blockade depend upon intestinal Gram-negative bacteria, mostly Bacteroides species. These bacteria accumulate at the bottom of the intestinal crypts and elicit an IL-12-dependent Th1 immune response specific for distinct Bacteroides species, both in tumor bearing mice and in cancer patients. CTLA4 blockade lost its anticancer efficacy in antibiotic-treated or germ-free mice. This defect could be overcome by oral administration of Bacteroides fragilis (Bf), immunization with Bf polysaccharides, or adoptive transfer of Bf-specific T cells, all of which in the absence of colitis. Our study unravels the key role of Bacteroides in the immunostimulatory effects of CTLA4 blockade, suggesting novel strategies for safely broadening its clinical use