Anti-programmed death (PD)-1 (aPD1) therapy is an effective treatment for metastatic melanoma (MM); however, over 50% of patients progress due to resistance. We tested a first-in-class immune-modulatory vaccine (IO102/IO103) against indoleamine 2,3-dioxygenase (IDO) and PD ligand 1 (PD-L1), targeting immunosuppressive cells and tumor cells expressing IDO and/or PD-L1 (IDO/PD-L1), combined with nivolumab. Thirty aPD1 therapy-naive patients with MM were treated in a phase 1/2 study (https://clinicaltrials.gov/, NCT03047928). The primary endpoint was feasibility and safety; the systemic toxicity profile was comparable to that of nivolumab monotherapy. Secondary endpoints were efficacy and immunogenicity; an objective response rate (ORR) of 80% (confidence interval (CI), 62.7–90.5%) was reached, with 43% (CI, 27.4–60.8%) complete responses. After a median follow-up of 22.9 months, the median progression-free survival (PFS) was 26 months (CI, 15.4–69 months). Median overall survival (OS) was not reached. Vaccine-specific responses assessed in vitro were detected in the blood of >93% of patients during vaccination. Vaccine-reactive T cells comprised CD4+ and CD8+ T cells with activity against IDO- and PD-L1-expressing cancer and immune cells. T cell influx of peripherally expanded T cells into tumor sites was observed in responding patients, and general enrichment of IDO- and PD-L1-specific clones after treatment was documented. These clinical efficacy and favorable safety data support further validation in a larger randomized trial to confirm the clinical potential of this immunomodulating approach.

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OBJECTIVE:To investigate the in¯uence of the pancreas lipase inhibitor orlistat (OLS) on calcium metabolism, bone turnover, bone mass, bone density and body composition when given for obesity as adjuvant to an energy-and fat-restricted diet. DESIGN: Randomized controlled double-blinded trial of treatment with OLS 120 mg three times daily or placebo for 1 y. SUBJECTS: Thirty obese subjects with a mean body mass index (BMI) of 36.9 AE 3.7 kgam 2 and a mean age of 41 AE 11 y. Sixteen patients were assigned to OLS and 14 to placebo. MEASUREMENTS: Dual energy X-ray absorptiometry (DXA) measurements of bone mineral and body composition included total bone mineral content (TBMC), total bone mineral density (TBMD), lumbar spine BMC and BMD, forearm BMC and BMD, fat mass (FM), fat free-mass (FFM), percentage fat mass (FM%) as well as a DXA estimate of the body weight. Body composition (FM, FFM and FM%) was estimated by total body potassium (TBK). Indices of calcium metabolism and bone turnover included serum values of ionized calcium (Ca ), iPTH (parathyroid hormone), alkaline phosphatase, 25(OH)-vitamin D, 1,25(OH) 2 vitamin D and osteocalcin as well as fasting urinary ratios of hydroxyprolineacreatinine and Caacreatinine (fU-OHpracreat, fUCaacreat). RESULTS: There were no signi®cant differences between OLS and placebo groups as to any of the body composition variables (FFM, FM, FM%) at baseline or after 1 y treatment. Weight loss was of 11.2 AE 7.5 kg in the OLS group and 8.1 AE 7.5 kg in the placebo group (NS). The changes in FM and FM% were signi®cant in both groups determined by DXA as well as by TBK, but the group differences between these changes were not signi®cant. The composition of the weight loss was approximately 80% fat in both groups. FFM only changed signi®cantly by DXA in the OLS group (71.3 kg), but the difference from the placebo group was not signi®cant. Forearm BMD in both groups, forearm BMC in the OLS group and TBMD in the placebo group fell discretely but signi®cantly, but there were no signi®cant group differences between the OLS and the placebo-treated group. All biochemical variables except s-osteocalcin changed signi®cantly after 1 y in the OLS group, disclosing a pattern of an incipient negative vitamin D balance, a secondary increase in PTH-secretion, and an increase in bone turnover with the emphasis on an increase in resorption parameters (fU-OHpracreat, fUCaacreat). In the placebo group, only s-25(OH)vitamin D and fUOHpracreat changed signi®cantly, but the pattern was also that of a deteriorated vitamin D status and an increase in PTH levels and bone turnover. The only biochemical variable which was signi®cantly different between OLS and placebo groups after one year was the fU-OHpracreat ratio, which increased from 12.0 to 20.1 in the OLS group but only from 10.9 to 13.2 in the placebo group. CONCLUSION: One year's treatment with OLS induces a lipid malabsorption which enhances a dietary weight loss without any signi®cant deleterious effects on body composition. OLS induces a relative in...