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BACKGROUND Immune checkpoint inhibitors and targeted therapies have dramatically improved outcomes in patients with advanced melanoma, but approximately half these patients will not have a durable benefit. Phase 1–2 trials of adoptive cell therapy with tumor-infiltrating lymphocytes (TILs) have shown promising responses, but data from phase 3 trials are lacking to determine the role of TILs in treating advanced melanoma.METHODSIn this phase 3, multicenter, open-label trial, we randomly assigned patients with unresectable stage IIIC or IV melanoma in a 1:1 ratio to receive TIL or anti–cytotoxic T-lymphocyte antigen 4 therapy (ipilimumab at 3 mg per kilogram of body weight). Infusion of at least 5×109 TILs was preceded by nonmyeloablative, lymphodepleting chemotherapy (cyclophosphamide plus fludarabine) and followed by high-dose interleukin-2. The primary end point was progression-free survival. RESULTS A total of 168 patients (86% with disease refractory to anti–programmed death 1 treatment) were assigned to receive TILs (84 patients) or ipilimumab (84 patients). In the intention-to-treat population, median progression-free survival was 7.2 months (95% confidence interval [CI], 4.2 to 13.1) in the TIL group and 3.1 months (95% CI, 3.0 to 4.3) in the ipilimumab group (hazard ratio for progression or death, 0.50; 95% CI, 0.35 to 0.72; P<0.001); 49% (95% CI, 38 to 60) and 21% (95% CI, 13 to 32) of the patients, respectively, had an objective response. Median overall survival was 25.8 months (95% CI, 18.2 to not reached) in the TIL group and 18.9 months (95% CI, 13.8 to 32.6) in the ipilimumab group. Treatment-related adverse events of grade 3 or higher occurred in all patients who received TILs and in 57% of those who received ipilimumab; in the TIL group, these events were mainly chemotherapy-related myelosuppression. CONCLUSIONSIn patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. [ABSTRACT FROM AUTHOR]

Introduction: In a multicenter, open-label randomized phase 3 clinical trial conducted in the Netherlands and Denmark, treatment with ex vivo-expanded tumor-infiltrating lymphocytes (TIL-NKI/CCIT) from autologous melanoma tumor compared with ipilimumab improved progression-free survival in patients with unresectable stage IIIC-IV melanoma after failure of first-line or second-line treatment. Based on this trial, we conducted a cost-utility analysis., Methods: A Markov decision model was constructed to estimate expected costs (expressed in 2021€) and outcomes (quality-adjusted life years (QALYs)) of TIL-NKI/CCIT versus ipilimumab in the Netherlands. The Danish setting was assessed in a scenario analysis. A modified societal perspective was applied over a lifetime horizon. TIL-NKI/CCIT production costs were estimated via activity-based costing. Through sensitivity analyses, uncertainties and their impact on the incremental cost-effectiveness ratio (ICER) were assessed., Results: Mean total undiscounted lifetime benefits were 4.47 life years (LYs) and 3.52 QALYs for TIL-NKI/CCIT and 3.33 LYs and 2.46 QALYs for ipilimumab. Total lifetime undiscounted costs in the Netherlands were €347,168 for TIL-NKI/CCIT (including €67,547 for production costs) compared with €433,634 for ipilimumab. Undiscounted lifetime cost in the Danish scenario were €337,309 and €436,135, respectively. This resulted in a dominant situation for TIL-NKI/CCIT compared with ipilimumab in both countries, meaning incremental QALYs were gained at lower costs. Survival probabilities, and utility in progressive disease affected the ICER most., Conclusion: Based on the data of a randomized phase 3 trial, treatment with TIL-NKI/CCIT in patients with unresectable stage IIIC-IV melanoma is cost-effective and cost-saving, both in the current Dutch and Danish setting. These findings led to inclusion of TIL-NKI/CCIT as insured care and treatment guidelines. Publicly funded development of the TIL-NKI/CCIT cell therapy shows realistic promise to further explore development of effective personalized treatment while warranting economic sustainability of healthcare systems., Competing Interests: Competing interests: THB: Bristol-Myers Squibb(speaker engagement). MD: Achiles Therapeutics (consulting), Astra Zeneca (teaching), Bristol-Myers Squibb (consulting and teaching), F. Hoffman-La Roche (speaker engagement), Genentech (consulting), Merck (speaker engagement), Novartis (speaker engagement). JH: Achilles Therapeutics (Scientific Advisory Board), Amgen (funding), Asher Bio (funding), Bayer (consulting), BioNtech US (Scientific Advisory Board, funding), Bristol-Myers Squibb (consulting, funding, teaching), Eisai (consulting), ESMO IOTECH (Editor-in-chief), Gadeta (Scientific Advisory Board), Immunocore (Scientific Advisory Board), Instil Bio (consulting, teaching), Iovance Biotherapeutics (consulting, teaching), Ipsen Bioscience Inc (consulting), Merck Serono (consulting, teaching), Merck Sharp & Dohme Corporation (funding, consulting, teaching), Molecular Partners (consulting), Neogene Therapeutics (Scientific Advisory Board, shareholder), Novartis (funding, consulting, teaching), Pfizer (consulting, teaching), PokeAcel (Scientific Advisory Board), Roche/Genentech (consulting, teaching), Sanofi (consulting, teaching), Scenic (Scientific Advisory Board), Seattle Genetics (consulting), T-Knife (Scientific Advisory Board), Vaximm (Scientific Advisory Board). IMS: Adaptimmune (funding), Bristol-Myers Squibb (speaking engagement), Enara Bio (funding), Evaxion (funding), IO biotech (funding, stock, consulting), Lytix Biopharma (funding), Merck (speaking engagement and funding), Novartis (consulting), Pierre Fabre Pharmaceuticals, Inc (speaking engagement and consulting), Sanofi Pasteur Inc (speaking engagement), TILT Biotherapeutics (funding). Other authors declare to have no competing interests., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

LTX-315 is an oncolytic peptide that elicits both local and systemic immune responses upon intratumoral injection. In the present pilot trial, we treated patients with metastatic soft tissue sarcoma with the combination of LTX-315 and adoptive T-cell therapy using in vitro expanded tumor-infiltrating lymphocytes. Six heavily pretreated patients were included in the trial and treated with LTX-315 of which four patients proceeded to adoptive T-cell therapy. Overall, the treatment was considered safe with only expected and manageable toxicity. The best overall clinical response was stable disease for 208 days, and in this patient, we detected tumor-reactive T cells in the blood that lasted until disease progression. In three patients T-cell reactivity against in silico predicted neoantigens was demonstrated. Additionally, de novo T-cell clones were generated and expanded in the blood following LTX-315 injections. In conclusion, this pilot study provides proof that it is feasible to combine LTX-315 and adoptive T-cell therapy, and that this treatment can induce systemic immune responses that resulted in stabilization of the disease in sarcoma patients with otherwise progressive disease. Further optimization of the treatment protocol is warranted to increase clinical activity. ClinicalTrials.gov Identifier: NCT03725605., Competing Interests: VS, KC, BS and ØR are employees of Lytix Biopharma. KC, BS, and ØR are shareholders in Lytix Biopharma AS. TC and RS are employees in NEC OncoImmunity AS. IMS has received honoraria for lectures from Novo Nordisk, MSD, Novartis, Pierre Fabre, Sanofi Aventis, BMS, and Takeda. IMS has received consultancy fees from IO Biotech, MSD, Novartis, Pierre Fabre, and TILT Biotherapeutics. IMS institution has received research grants from BMS, IO Biotech, Adaptimmune, Lytix biopharma, Evaxion Biotech, TILT Biotherapeutics, Enara Bio, and Asgard Therapeutics. IMS is shareholder and co-founder of the biotech company IO Biotech ApS. TJM has received honoraria for a lecture from BMS. MN has received travel reimbursement from Lytix Biopharma., (© 2023 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: Statins are widely used to lower cholesterol concentrations in both primary and secondary prevention of cardiovascular disease. The treatment increases the risk of muscle pain (myalgia) and of type 2 diabetes. However, the underlying mechanisms remain disputed., Methods: We investigated whether statin induced myalgia is coupled to impaired glucose homeostasis using oral glucose tolerance test (OGTT), intravenous glucose tolerance test (IVGTT), and the hyperinsulinemic euglycemic clamp. We performed a cross-sectional study of statin users without CVD (primary prevention) stratified into a statin myalgic (M; n = 25) and a non-myalgic (NM; n = 39) group as well as a control group (C; n = 20) consisting of non-statin users., Results: A reduction in the insulin secretion rate during the OGTT was observed in the myalgic group compared with the non-myalgic group (AUC ISR OGTT , C: 1032 (683 - 1500); M: 922 (678 - 1091); NM: 1089 (933 - 1391) pmol·L -1 ·min (median with 25%-75% percentiles), but no other measurements indicated impaired β-cell function. We found no other differences between the three groups for other measurements in the OGTT, IVGTT, and euglycemic clamp. Muscle protein content of GLUT4 and hexokinase II was similar between the three groups., Conclusions: We conclude that statin users in primary prevention experiencing myalgia do not have impaired glucose homeostasis compared with other statin users or non-users. We consider this an important aspect in the dialogue between physician and patient regarding statin treatment and adverse effects., (© 2018 John Wiley & Sons, Ltd.)