Genetic studies have implicated the early involvement of a gene on chromosome arm 9p in the development of cutaneous melanoma. We have performed loss-of-heterozygosity studies to confirm these original findings and identify the most frequently rearranged or deleted region of 9p. Eight markers were analyzed, including (from 9pter to proximal 9q) D9S33, the beta-interferon (IFNB1) locus, the alpha-interferon (IFNA) gene cluster, D9S126, D9S3, D9S19, the glycoprotein 4 beta-galactosyltransferase (GGTB2) gene, and the argininosuccinate synthetase pseudogene 3 (ASSP3). Two or more of these loci were found to be hemizygously reduced in 12 of 14 (86%) informative metastatic melanoma tumor and cell line DNAs, and homozygous deletions of the marker D9S126 were observed in 2 of 20 (10%) melanoma cell lines. These findings have resulted in the identification of a small critical region of 2-3 megabases on 9p21 in which a putative melanoma tumor-suppressor gene appears likely to reside. Several 9p candidate genes, including IFNB1, the IFNA gene cluster, GGTB2, and the tyrosinase-related protein (TYRP) locus, have all been eliminated as potential targets because they are located outside of the homozygously deleted regions.
Abstract Advances in immune checkpoint therapy and targeted therapy have led to improvement in overall survival for patients with advanced melanoma. Single agent checkpoint PD-1 blockade and combination with BRAF/MEK targeted therapy demonstrated benefit in overall survival (OS). Superior response rates have been demonstrated with combined PD-1/CTLA-4 blockade, with a significant OS benefit compared with single-agent PD-1 blockade. Despite the progress in diagnosis of melanocytic lesions, correct classification of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to therapy remain real challenges in melanoma. Improved understanding of the tumor microenvironment, tumor immunity and response to therapy has prompted extensive translational and clinical research in melanoma. Development of novel biomarker platforms may help to improve diagnostics and predictive accuracy for selection of patients for specific treatment. There is a growing evidence that genomic and immune features of pre-treatment tumor biopsies may correlate with response in patients with melanoma and other cancers but they have yet to be fully characterized and implemented clinically. Overall, the progress in melanoma therapeutics and translational research will help to optimize treatment regimens to overcome resistance and develop robust biomarkers to guide clinical decision-making. During the Melanoma Bridge meeting (December 3rd–5th, 2020, Italy) we reviewed the currently approved systemic and local therapies for advanced melanoma and discussed novel biomarker strategies and advances in precision medicine.
<p>Perceived Stress scores (PSS). A, Waterfall plot showing best response per immune-modified RECIST as demonstrated by percentage (%) decrease in tumor size in the nine evaluable patients on the study reporting different PSS scores at baseline. B, Change in median PSS scores with subsequent visits for patients treated at 3 different dose levels. X-axis shows clinic visits and Y-axis shows the median PSS score. Dose level 1 is propranolol 10 mg BID, dose level 2 is propranolol 20 mg BID and dose level 3 is propranolol 30 mg BID. The numbers of patients at different time points reporting the PSS scores are shown on the graphs.</p>
<div>AbstractPurpose:<p>Neoadjuvant immunotherapy may improve the clinical outcome of regionally advanced operable melanoma and allows for rapid clinical and pathologic assessment of response. We examined neoadjuvant pembrolizumab and high-dose IFNα-2b (HDI) therapy in patients with resectable advanced melanoma.</p>Patients and Methods:<p>Patients with resectable stage III/IV melanoma were treated with concurrent pembrolizumab 200 mg i.v. every 3 weeks and HDI 20 MU/m<sup>2</sup>/day i.v., 5 days per week for 4 weeks, then 10 MU/m<sup>2</sup>/day subcutaneously 3 days per week for 2 weeks. Definitive surgery followed, as did adjuvant combination immunotherapy, completing a year of treatment. Primary endpoint was safety of the combination. Secondary endpoints included overall response rate (ORR), pathologic complete response (pCR), recurrence-free survival (RFS), and overall survival (OS). Blood samples for correlative studies were collected throughout. Tumor tissue was assessed by IHC and flow cytometry at baseline and at surgery.</p>Results:<p>A total of 31 patients were enrolled, and 30 were evaluable. At data cutoff (October 2, 2019), median follow-up for OS was 37.87 months (range, 33.2–43.47). Median OS and RFS were not reached. Radiographic ORR was 73.3% [95% confidence interval (CI): 55.5–85.8], with a 43% (95% CI: 27.3–60.1) pCR rate. None of the patients with a pCR have had a recurrence. HDI and pembrolizumab were discontinued in 73% and 43% of patients, respectively. Correlative analyses suggested that intratumoral PD-1/PD-L1 interaction and HLA-DR expression are associated with pCR (<i>P</i> = 0.002 and <i>P</i> = 0.008, respectively).</p>Conclusions:<p>Neoadjuvant concurrent HDI and pembrolizumab demonstrated promising clinical activity despite high rates of treatment discontinuation. pCR is a prognostic indicator.</p><p><i>See related commentary by Menzies et al., p. 4133</i></p></div>
<p>PDF file - 126KB, mAb anti-VISTA clones GA1 and GG8 specifically bind to human VISTA. a) human PBMCs were stained with anti-CD33 and anti-VISTA clone GA1 (red and blue) or isotype control (grey). Blocking VISTA-Ig was included in one sample to show specificity (red). Representative overlays show live, large scatter, singlet, CD33 positive events from at least two separate donors. b) K562 cells transduced with human VISTA (red) or parent K562 cells (grey) were stained with anti-VISTA clone GA1. Representative overlays show live, singlet events. c) consecutive sections of human splenic tissues were stained with anti-VISTA clone GG8 and/or Blocking VISTA-Ig. A pre-incubation step with Fc Receptor Blocking Solution (Human TruStain FcX, BioLegend) was included in some tissue samples as indicated.</p>
<p>A. Absolute quantitative change in peripheral blood chemokines* from baseline to week 3 (week 3 minus baseline; change in mean value +/- standard deviation). B. Quantitative change in peripheral blood cellular fractions expressed as percentage of total CD45+ cells from baseline to 3 weeks (week 3 minus baseline).</p>
