Aryl hydrocarbon receptor (AHR) activation by tryptophan (Trp) catabolites enhances tumor malignancy and suppresses anti-tumor immunity. The context specificity of AHR target genes has so far impeded ...systematic investigation of AHR activity and its upstream enzymes across human cancers. A pan-tissue AHR signature, derived by natural language processing, revealed that across 32 tumor entities, interleukin-4-induced-1 (IL4I1) associates more frequently with AHR activity than IDO1 or TDO2, hitherto recognized as the main Trp-catabolic enzymes. IL4I1 activates the AHR through the generation of indole metabolites and kynurenic acid. It associates with reduced survival in glioma patients, promotes cancer cell motility, and suppresses adaptive immunity, thereby enhancing the progression of chronic lymphocytic leukemia (CLL) in mice. Immune checkpoint blockade (ICB) induces IDO1 and IL4I1. As IDO1 inhibitors do not block IL4I1, IL4I1 may explain the failure of clinical studies combining ICB with IDO1 inhibition. Taken together, IL4I1 blockade opens new avenues for cancer therapy.
Display omitted
•A pan-tissue AHR signature identifies IL4I1 as a major AHR-activating enzyme•IL4I1-mediated Trp catabolism yields indoles and kynurenic acid that activate the AHR•IL4I1 promotes AHR-driven cancer cell motility and suppresses adaptive immunity•IL4I1 enhances CLL progression and is induced by immune checkpoint blockade
Immune checkpoint blockade therapy induces the AHR-activating enzyme IL4I1, which promotes tumor progression, through its effects on tumor cell motility and adaptive immunity.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Purpose Mucosal melanoma is an aggressive malignancy with a poor response to conventional therapies. The efficacy and safety of nivolumab (a programmed death-1 checkpoint inhibitor), alone or ...combined with ipilimumab (a cytotoxic T-lymphocyte antigen-4 checkpoint inhibitor), have not been reported in this rare melanoma subtype. Patients and Methods Data were pooled from 889 patients who received nivolumab monotherapy in clinical studies, including phase III trials; 86 (10%) had mucosal melanoma and 665 (75%) had cutaneous melanoma. Data were also pooled for patients who received nivolumab combined with ipilimumab (n = 35, mucosal melanoma; n = 326, cutaneous melanoma). Results Among patients who received nivolumab monotherapy, median progression-free survival was 3.0 months (95% CI, 2.2 to 5.4 months) and 6.2 months (95% CI, 5.1 to 7.5 months) for mucosal and cutaneous melanoma, with objective response rates of 23.3% (95% CI, 14.8% to 33.6%) and 40.9% (95% CI, 37.1% to 44.7%), respectively. Median progression-free survival in patients treated with nivolumab combined with ipilimumab was 5.9 months (95% CI, 2.8 months to not reached) and 11.7 months (95% CI, 8.9 to 16.7 months) for mucosal and cutaneous melanoma, with objective response rates of 37.1% (95% CI, 21.5% to 55.1%) and 60.4% (95% CI, 54.9% to 65.8%), respectively. For mucosal and cutaneous melanoma, respectively, the incidence of grade 3 or 4 treatment-related adverse events was 8.1% and 12.5% for nivolumab monotherapy and 40.0% and 54.9% for combination therapy. Conclusion To our knowledge, this is the largest analysis of data for anti-programmed death-1 therapy in mucosal melanoma to date. Nivolumab combined with ipilimumab seemed to have greater efficacy than either agent alone, and although the activity was lower in mucosal melanoma, the safety profile was similar between subtypes.
Indolent cutaneous B-cell lymphomas (CBCL) are a rare disease for which the therapeutic recommendations are based on clinical reports. Recommendations for solitary lesions include surgery or ...irradiation. However, the high relapse rates may require less invasive repeatable therapy. This study seeks to retrospectively assess the efficacy of intralesional rituximab (ILR) for indolent CBCL when compared with intravenous rituximab (IVR). Patients treated for indolent CBCL with ILR or IVR at the Division of DermatoOncology of the University Hospital Heidelberg were eligible for this study. Characteristics of lymphoma, treatment response, and adverse events were assessed. Twenty-one patients, 67% male at a median age of 52 (range 17–80), were included. Nineteen (90%) had only localized lymphoma (stage T1 and T2). Complete response was achieved in 92% (11/12) of ILR after a median of one cycle (three injections) and 78% (7/8) of IVR patients after a median of six cycles. Half of ILR patients and 78% of IVR patients showed relapse after a median of 15 and 23 months, respectively. Adverse reactions were usually mild and were limited to the first injection of ILR. One patient with IVR contracted a pulmonary infection. ILR may be an alternative to the intravenous administration of rituximab for localized indolent CBCL.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
36.
Neues vom ASCO 2022 für die Dermato Onkologie Gutzmer, Ralf; Hassel, Jessica C.
Journal der Deutschen Dermatologischen Gesellschaft,
August 2022, 20220801, Volume:
20, Issue:
8
Journal Article
Peer reviewed
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Immune checkpoint inhibitors (ICIs) have shown promising anti-tumor activities and are widely used for the treatment of advanced cancers. However, they may lead to immune-related adverse events ...(irAEs) and some of them, such as hypophysitis, can be life-threatening. Here, early diagnosis is critical.
We retrospectively analyzed 40 melanoma patients who developed hypophysitis during ICI treatment with either ipilimumab and/or anti-PD1 therapy and compared them to 40 control patients who did not develop hypophysitis during the ICI treatment, matched for age, gender, type of immunotherapy, and stage. Clinical data and blood values such as LDH, CRP, TSH, T3, T4, and absolute immune cell counts were retrieved from the medical records. Patient characteristics, laboratory values, progression-free survival, and overall survival were compared between the two groups.
Patients with ir-hypophysitis had a median age of 59 years, and most of them were male. Clinically, frequent symptoms were fatigue, headache, dizziness, and gastrointestinal symptoms such as nausea or abdominal pain. The onset of ir-hypophysitis differed much between ipilimumab- (median 8 weeks) and anti-PD1 (median 40 weeks)-induced hypophysitis (
< 0.001). At baseline, besides a slightly increased CRP level (
= 0.06), no differences were observed in patients who later developed hypophysitis compared to the control. After treatment started, hypophysitis patients showed a constant and significant decline in T4 levels from the start of therapy until diagnosis (
< 0.05), independent of the ICI treatment regime. However, a decline in T3 and TSH was only noted in patients with ipilimumab-induced ir-hypophysitis. Furthermore, serum sodium levels declined rapidly at the diagnosis of hypophysitis (
< 0.001). In addition, there was a constant increase in the absolute counts of eosinophils and lymphocytes from baseline in hypophysitis patients (
< 0.05).
Ir-hypophysitis reveals different clinical pictures and onset times depending on the ICI regime used. Whereas a drop in T4 levels was indicative of developing hypophysitis independent of the ICI regime, TSH levels only declined in patients under ipilimumab-based ICI regimes. To best monitor our patients, it is important to recognize these differences.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
The CheckMate 066 trial investigated nivolumab monotherapy as first-line treatment for patients with previously untreated
wild-type advanced melanoma. Five-year results are presented herein.
In this ...multicenter, double-blind, phase III study, 418 patients with previously untreated, unresectable, stage III/IV, wild-type
melanoma were randomly assigned 1:1 to receive nivolumab 3 mg/kg every 2 weeks or dacarbazine 1,000 mg/m
every 3 weeks. The primary end point was overall survival (OS), and secondary end points included progression-free survival (PFS), objective response rate (ORR), and safety.
Patients were followed for a minimum of 60 months from the last patient randomly assigned (median follow-up, 32.0 months for nivolumab and 10.9 months for dacarbazine). Five-year OS rates were 39% with nivolumab and 17% with dacarbazine; PFS rates were 28% and 3%, respectively. Five-year OS was 38% in patients randomly assigned to dacarbazine who had subsequent therapy, including nivolumab (n = 37). ORR was 42% with nivolumab and 14% with dacarbazine; among patients alive at 5 years, ORR was 81% and 39%, respectively. Of 42 patients treated with nivolumab who had a complete response (20%), 88% (37 of 42) were alive as of the 5-year analysis. Among 75 nivolumab-treated patients alive and evaluable at the 5-year analysis, 83% had not received subsequent therapy; 23% were still on study treatment, and 60% were treatment free. Safety analyses were similar to the 3-year report.
Results from this 5-year analysis confirm the significant benefit of nivolumab over dacarbazine for all end points and add to the growing body of evidence supporting long-term survival with nivolumab mono-therapy. Survival is strongly associated with achieving a durable response, which can be maintained after treatment discontinuation, even without subsequent systemic therapies.
Treatment with trametinib, a MEK inhibitor, resulted in significantly improved progression-free and overall survival, as compared with chemotherapy, in patients with advanced melanoma and activating ...BRAF mutations.
About 160,000 new cases of melanoma are diagnosed and 48,000 melanoma-related deaths occur worldwide each year.
1
Among cancers in patients under 40 years of age, the incidence of melanoma is second only to that of breast cancer for women and leukemia for men.
2
Before 2010, no systemic therapy had been shown to improve overall survival among patients with metastatic melanoma, and only modest improvements were observed with interferon as an adjuvant drug.
3
Ipilimumab, a monoclonal antibody targeting cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), and vemurafenib, a selective BRAF inhibitor, have both been shown to improve survival among patients with metastatic melanoma . . .
Immune checkpoint inhibitors (ICIs) are widely used and may induce long-term survival in various types of cancer. Yet, there is scarce evidence on potential effects on patient fertility and the ...necessity of cryopreservation before treatment onset. The aim of our study was to assess the prevalence of male infertility after initiation of ICI treatment.
This is a monocenter, cross-sectional pilot study. Fertility was investigated by spermiogram, analysis of sexual hormones and questionnaires on sexual function and sexual activity. Male patients under the age of 60 years previously or currently treated with ICI for cutaneous malignancies or uveal melanoma were included.
Twenty-five patients were included, with a median age of 49 years. Eighteen of 22 (82%) available spermiograms showed no pathologies, all patients reported a normal sexual function and sexual activity. Of four patients with pathological spermiogram, three patients were diagnosed with azoospermia and one with oligoasthenoteratozoospermia. Three patients had significant confounding factors (previous inguinal radiotherapy, chemotherapy and chronic alcohol abuse, and bacterial orchitis). One patient with normal spermiogram before ICI treatment presented 1 year after initiation with azoospermia, showing an asymptomatic, inflammatory infiltrate with predominantly neutrophil granulocytes, macrophages and T-lymphocytes in the ejaculate. Infectious causes were ruled out; andrological examination was unremarkable. A second case with reduced sperm counts during treatment may be ICI-induced also.
Most patients had no restrictions in fertility, yet an inflammatory loss of spermatogenesis seems possible. Cryopreservation should be discussed with all patients with potential future desire for children before treatment.
•This cross-sectional study included 25 male patients; 22 spermiograms were available.•Most patients (18/22, 82%) remained fertile, with no restrictions of spermatogenesis.•Of four patients with pathological spermiograms, three had confounding influences.•One case of new-onset, inflammatory azoospermia is presumably of autoimmune origin.•A second case of reduced sperm counts may also be treatment related.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
PDF
