Summary: In an adjuvant clinical trial for high-risk patients with malignant melanoma by using recombinant interleukin-2 (rIL-2) and recombinant interferon-α2b (rIFN-α2b), we monitored the development of antibodies against rIFN-α and various immunoparameters as biologic markers for IFN activity in vivo. Thirty-one patients (22 men, nine women) with high-risk malignant melanoma received eight 6-week cycles of rIL-2 and rIFN-α. Serum samples of all patients were screened for the presence of antibodies against IFN-α by a solid enzyme immunoassay (EIA). Specimens testing positive in the EIA were assessed for their ability to neutralize the antiviral effects of IFN-α in vitro in an antibody-neutralizing bioassay (ANB). Furthermore, serum levels of neopterin, β2-microglobulin, soluble IL-2 receptor (sIL-2R), anticardiolipin and antithyroglobulin were evaluated. Of 31 patients, 11 (36%) developed binding antibodies; three (27%) of them had antibodies with neutralizing capacities (range, 350-28,000 INU/ml). Of male patients, 8 (36%) of 22 versus 1 (11%) of nine female patients developed antibodies. Statistical analysis (unpaired t test) revealed that all patients with antibody titers showed significant (p<0.04) lower serum levels of β2-microglobulin and reproducible decreases in sIL-2R levels, whereby those with neutralizing antibodies showed significantly (p<0.0001) lower values than did those with binding antibodies. Elevations of anticardiolipin (17 of 31) and antithyroglobulin (one of 31) were not correlated to the presence of IFN antibodies. Our results show the in vivo significance of antibodies against rIFN-a, especially of those with neutralizing capacities. Monitoring of antibody formation as well as immunoparameters like β2- microglobulin in clinical trials can contribute to identifying patients who, if necessary, might benefit from alternative IFN treatment, for instance, by using natural IFNs.
8575 Background: The multi-tyrosine kinase inhibitor sorafenib affects the Raf/Mek/Erk and VEGF pathway. The therapy impact on in vivo metabolic activity and transcriptional profiling was investigated. Methods: Single-arm investigator-initiated pilot study enrolled 13 first-line stage IV MM patients (LDH > 1.1 ULN) with metastases accessible for repeated biopsies. Patients were treated with sorafenib (400 mg bid, day 1-56) and DTIC (1,000 mg/m2, day 14, 42). Primary endpoints were changes in glucose uptake (PERCIST 1.0), S100 and LDH serum levels. Secondary endpoints were determination of differentially expressed genes and alternative splicing events during treatment. PET/CT, serum S100, LDH and biopsies were taken on screening, day 10, 16, and 60. Transcriptional profiling was performed using Human Exon 1.0 WT microarrays (Affymetrix). Differentially expressed genes and alternative splicing events were determined by R-Bioconductor using exonmap, limma, stats and samr packages. Enrichment analysis was performed using Genego Metacore. Results: At day 60, 5 responders and 8 non-responders (clinical and metabolic) were observed. Glucose uptake was inversely associated with response (p = 0.003) with a significant decrease of S100 in responders (p = 0.01), but not of LDH (p = 0.8, 2-tailed Mann-Whitney test). Transcriptional analysis of day 10 biopsies detected PEG10, HIGD2A, TOM1L1 for responders, and GMGF, CD163, CD53 for non-responders as top differentially expressed genes. Glucose metabolism network provided the best tool for hierarchical sample classification into responders and non-responders, confirming the in vivo data. JAK, TGFbeta and PIK3 signaling pathways, xenobiotic metabolism, DNA repair and vascularization processes were upregulated in non-regressive, but stress-induced metabolism and transcriptional reorganization networks in regressive lesions. Conclusions: Reduced glucose uptake by MM metastases under sorafenib predicts tumor regression. Metabolic tumor response is associated with distinctive molecular signatures on the transcriptional level and may contribute to rational personalized treatment approaches in MM patients. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer Bayer Bayer
B-rapidly accelerated fibrosarcoma (BRAF) inhibitor encorafenib alone and in combination with MEK inhibitor binimetinib improves survival in BRAF-mutated melanoma patients. So far, the range of cutaneous adverse events has been characterized only for established BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (trametinib, cobimetinib).The aim of this study was to investigate cutaneous adverse events emerging in melanoma patients treated with encorafenib and binimetinib.Patients treated with BRAF and MEK inhibitors in clinical trials at the University Hospital of Zurich were identified. Frequency and features of cutaneous adverse events as well as their management were assessed based on the prospectively collected clinical and histopathological data. The events emerging during encorafenib and/or binimetinib therapy were compared to other BRAF and MEK inhibitors at the institution and in the literature.The most frequent cutaneous adverse events observed in patients treated with encorafenib alone (n = 24) were palmoplantar hyperkeratosis (54%), palmoplantar erythrodysesthesia (58%) and alopecia (46%). Drug-induced papulopustular eruptions prevailed in patients with binimetinib monotherapy (n = 25). The most frequent cutaneous adverse events in patients treated with encorafenib/binimetinib (n = 49) were palmoplantar hyperkeratosis (10%).Compared to data published for established BRAFi, encorafenib monotherapy showed less hyperproliferative cutaneous adverse events. In contrast, palmoplantar hyperkeratosis and palmoplantar erythrodysesthesia seem to occur more often. The combination of encorafenib and binimetinib is well tolerated and induces few cutaneous adverse events.
Cell Genesys (formerly Somatix Therapy Corp) is developing GVAX as a potential cancer vaccine for various tumor types. Clinical trials have commenced for melanoma, renal tumor, lung tumor, pancreatic tumor, prostate tumor and multiple myeloma [191143], [287470], [298308], [367408], [401114]; trials are planned for 2001 in leukemia (phase I) and pancreatic cancer (phase II) [366918], [388814]. A worldwide collaboration was signed with Japan Tobacco in December 1998, covering the application of GVAX in prostate cancer trials [312213]. This collaboration may be extended to lung cancer and melanoma, depending on the clinical trial results for prostate cancer [309873], [311835]. The Japanese clinical trials were put on hold on 21 September 2000 due to problems with the mass production of cells by Cell Genesys [384885]. Somatix was developing GVAX until its merger with Cell Genesys in June 1997 [248422]. In April 2001, Cell Genesys initiated the first in a series of trials of a high-potency version of GVAX prostate cancer vaccine following encouraging phase II data reported for its first-generation product. The high-potency form of GVAX is similar to the first-generation product except that it releases an increased quantity of immune system stimulant [405932].
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