No abstract

No abstract

Combined immune checkpoint blockade (ICB) provides unprecedented efficacy gains in numerous cancer indications, with PD-1 inhibitor nivolumab plus CTLA-4 inhibitor ipilimumab in advanced melanoma as first-ever approved therapies for combined ICB. However, gains in efficacy must be balanced against a higher frequency and severity of adverse drug reactions (ADR). Because delays in diagnosis and management might result in symptom worsening and further complications, clinicians shall be well trained to identify ADR promptly and monitor patients adequately. This paper reviews safety data assessed by the European Medicines Agency for the anti-PD-1/CTLA-4 combination and provides a literature overview on published case reports for rare ADR with suspected potential underreporting. Incidences and kinetics of immune-related ADR are described. Recommendations for the evaluation and management of ADR are convened by an interdisciplinary expert panel focusing on rare but clinically important side effects arising from combined ICB. Pooled safety data from 1551 patients with advanced melanoma, treated either with 3mg/kg ipilimumab plus 1mg/kg nivolumab (N=407), or nivolumab alone (N=787), or ipilimumab alone (N=357) demonstrate that immune-related ADR occur more frequently for the combination, with a shorter time-to-onset, and tend to be more severe. The majority of events is reversible after systemic use of glucocorticoids, notably methylprednisolone or equivalents; in certain cases of long-lasting and refractory immune toxicities, non-steroidal immunosuppressants may be used, once ICB is interrupted or terminated. Combined ICB has considerable toxicities, therefore close monitoring and high experience in diagnosis and treatment of ADR is necessary.

No abstract

Rosazea ist eine häufige, entzündliche, vornehmlich das Gesicht betreffende Dermatose vorzugsweise des Erwachsenenalters. Die Erkrankung zeichnet sich durch einen chronischen, schubhaften Verlauf aus, wobei klinisch-morphologisch unterschiedliche Schweregrade abgegrenzt werden können. Im Initialstadium können flüchtige Erytheme im Gesicht auftreten, welche später persistieren. Weiterhin sind Teleangiektasien -hauptsächlich an den Wangen -sehr häufig. Papeln und Papulopusteln sind für den Schweregrad II typisch. Auch an das Gesicht angrenzende Hautareale wie Hals, Brust, Rücken und Kopfhaut können betroffen sein. Andere Formen sind durch ein Lymphödem und eine diffuse Hyperplasie des Bindegewebes und der Talgdrüsen, sogenannte Phyme, gekennzeichnet. Diese können mit den anderen Hautveränderungen vergesellschaftet sein oder auch unabhängig von diesen auftreten. Die Erkrankung betrifft häufig auch die Augen. Das klinische Erscheinungsbild der Rosacea papulopustulosa kann dem der Akne ähneln, es fehlen jedoch Komedonen und die Patienten sind deutlich älter als typische Aknepatienten. Auch wird bei Rosazea noch diskutiert, ob es sich um eine primär follikuläre Erkrankung handelt.Es liegen nur wenige größere Studien zur Epidemiologie der Rosazea vor. In einer aktuellen Studie aus Großbritannien wurde eine Inzidenz von 1,65/1 000 Personenjahren (Definition der Inzidenz: X neue Fälle/100 000 Einwohner/Jahr, d. h. 165/100 000 Einwohner/Jahr) festgestellt, mit jährlich 4 000-5 000 neu diagnostizierten Fällen [1]. Die Prävalenz der Rosazea wurde in verschiedenen Studien untersucht, allerdings bestehen zwischen den Ergebnissen erhebliche Diskrepanzen. So ermittelte eine deutsche Studie in einer Kohorte mit 90 880 Personen eine Prävalenz der Rosazea von 2,3 % [2], eine in Schweden durchgeführte Studie, in der 809 Arbeiter untersucht wurden, hingegen eine Prävalenz von 10 % [3]. In einer estnischen Studie wurde bei 348 Angestellten eine Prävalenz von sogar 22 % festgestellt, allerdings war die untersuchte Zielgruppe 30 Jahre oder älter, was die Prävalenz automatisch erhöht, da die Erkrankung gewöhnlich erst im höheren Lebensalter auftritt [4]. Tatsächlich erfolgt in 80 % der Fälle die Diagnose einer Rosazea im Alter von 30 Jahren oder später [1]. Interessanterweise zeigen sich bezüglich der betroffenen

Memory T cells exhibit tremendous antigen specificity within the immune system and accumulate with age. Our studies reveal an antigen-independent expansion of memory, but not naive, CD8 ؉ T cells after several immunotherapeutic regimens for cancer resulting in a distinctive phenotype. Signaling through T-cell receptors (TCRs) or CD3 in both mouse and human memory CD8 ؉ T cells markedly up-regulated programmed death-1 (PD-1) and CD25 (IL-2 receptor ␣ chain), and led IntroductionMemory T cells represent an arm of the adaptive immune system that are long-lived, and capable of rapid antigen-specific responses. Memory T cells have been shown to have functional advantages more than naive T cells, as they develop more rapidly into cytolytic effector cells and produce greater amounts of cytokines after antigenic stimulation. 1 Although T cells classically require T-cell receptor (TCR) engagement and proper costimulation for complete activation and proliferation, memory T cells have also been observed to proliferate in response to various cytokines during viral infections. [2][3][4][5][6] These "bystander cells" proliferate and gain effector functions in response to the cytokine milieu produced during the course of viral and bacterial infections in mice and humans. [7][8][9][10] Cytokines alone can induce this as a single dose of recombinant type-I interferon (IFN) resulting in a transient increase in the proliferation of CD8 ϩ , CD62L ϩ CD44 high memory T cells, which was independent of coligation of the TCRs. 11 Such proliferation was not induced by the direct effects of type-I IFNs on CD8 ϩ T cells, but was because of type-I IFN-driven production of secondary cytokines such as 12 Effector and memory CD8 ϩ T cells express elevated levels of the receptors for IL-12 and IL-18, and secrete IFN-␥ in response to stimulation with both cytokines, 13 which suggests that other cytokine pathways can also induce their expansion. Similar to the secondary cytokine-driven proliferation observed after type-I IFN stimulation, IL-2, and toll-like receptor (TLR) agonists, that is, CpG and Poly:IC have also been described as having the capacity to induce bystander proliferation of CD8 ϩ CD44 high T cells. 12,14,15 The extent of antigen-specific proliferation versus bystander expansion has been the subject of considerable debate and may be contingent on the pathogen model and tissue examined. 9,13,16 Cancer therapies that target the stimulation of the immune system via agonist antibodies, cytokine-based modalities, or TLR agonists have been shown to result in potent CD8 ϩ T cell-mediated antitumor effects. 17,18 We have previously shown that a combination immunotherapy consisting of an agonist CD40 antibody and IL-2 results in synergistic antitumor effects. 19 Treatment of mice with other cytokine or TLR agonist combinations, such as CpGs and IL-15 or IL-2 and IL-12, also resulted in marked antitumor effects. 18 In all of these models, the antitumor effects were associated with rapid, extensive CD8 ϩ T-cell expansion. The antitumor effec...

Growing evidence suggests that concurrent loco-regional and systemic treatment modalities may lead to synergistic anti-tumor effects in advanced melanoma. In this retrospective multicenter study, we evaluate the use of electrochemotherapy (ECT) combined with ipilimumab or PD-1 inhibition. We investigated patients with unresectable or metastatic melanoma who received the combination of ECT and immune checkpoint blockade for distant or cutaneous metastases within 4 weeks. Clinical and laboratory data were collected and analyzed with respect to safety and efficacy. A total of 33 patients from 13 centers were identified with a median follow-up time of 9 months. Twenty-eight patients received ipilimumab, while five patients were treated with a PD-1 inhibitor (pembrolizumab n = 3, nivolumab n = 2). The local overall response rate (ORR) was 66.7 %. The systemic ORR was 19.2 and 40.0 % in the ipilimumab and PD-1 cohort, respectively. The median duration of response was not reached in either group. The median time to disease progression was 2.5 months for the entire population with 2 months for ipilimumab and 5 months for PD-1 blockade. The median overall survival was not reached in patients with ipilimumab and 15 months in the PD-1 group. Severe systemic adverse events were detected in 25.0 % in the ipilimumab group. No treatment-related deaths were observed. This is the first reported evaluation of ECT and simultaneous PD-1 inhibition and the largest published dataset on ECT with concurrent ipilimumab. The local response was lower than reported for ECT only. Ipilimumab combined with ECT was feasible, tolerable and showed a high systemic response rate.

We investigated a patient who developed multiple sclerosis (MS) during treatment with the CTLA4‐blocking antibody ipilimumab for metastatic melanoma. Initially he showed subclinical magnetic resonance imaging (MRI) changes (radiologically isolated syndrome). Two courses of ipilimumab were each followed by a clinical episode of MS, 1 of which was accompanied by a massive increase of MRI activity. Brain biopsy confirmed active, T‐cell type MS. Quantitative next generation sequencing of T‐cell receptor genes revealed distinct oligoclonal CD4+ and CD8+ T‐cell repertoires in the primary melanoma and cerebrospinal fluid. Our results pinpoint the coinhibitory molecule CTLA4 as an immunological checkpoint and therapeutic target in MS. Ann Neurol 2016;80:294–300