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Rohaan, Maartje W; Borch, Troels H; van den Berg, Joost H; Met, Özcan; Kessels, Rob; Geukes Foppen, Marnix H; Stoltenborg Granhøj, Joachim; Nuijen, Bastiaan; Nijenhuis, Cynthia; Jedema, Inge; van Zon, Maaike; Scheij, Saskia; Beijnen, Jos H; Hansen, Marten; Voermans, Carlijn; Noringriis, Inge M; Monberg, Tine J; Holmstroem, Rikke B; Wever, Lidwina D V; van Dijk, Marloes; Grijpink-Ongering, Lindsay G; Valkenet, Ludy H M; Torres Acosta, Alejandro; Karger, Matthias; Borgers, Jessica S W; Ten Ham, Renske M T; Retèl, Valesca P; van Harten, Wim H; Lalezari, Ferry; van Tinteren, Harm; van der Veldt, Astrid A M; Hospers, Geke A P; Stevense-den Boer, Marion A M; Suijkerbuijk, Karijn P M; Aarts, Maureen J B; Piersma, Djura; van den Eertwegh, Alfons J M; de Groot, Jan-Willem B; Vreugdenhil, Gerard; Kapiteijn, Ellen; Boers-Sonderen, Marye J; Fiets, W Edward; van den Berkmortel, Franchette W P J; Ellebaek, Eva; Hölmich, Lisbet R; van Akkooi, Alexander C J; van Houdt, Winan J; Wouters, Michel W J M; van Thienen, Johannes V; Blank, Christian U; Meerveld-Eggink, Aafke; Klobuch, Sebastian; Wilgenhof, Sofie; Schumacher, Ton N; Donia, Marco; Svane, Inge Marie; Haanen, John B A G
New England journal of medicine/The New England journal of medicine, 12/2022, Letnik: 387, Številka: 23Journal Article
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. In 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 5×10 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. 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. In patients with advanced melanoma, progression-free survival was significantly longer among those who received TIL therapy than among those who received ipilimumab. (Funded by the Dutch Cancer Society and others; ClinicalTrials.gov number, NCT02278887.).
