Low-dose ipilimumab plus nivolumab combined with IL-2 and hyperthermia in cancer patients with advanced disease: explora
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ORIGINAL ARTICLE
Low‑dose ipilimumab plus nivolumab combined with IL‑2 and hyperthermia in cancer patients with advanced disease: exploratory findings of a case series of 131 stage IV cancers – a retrospective study of a single institution R. Kleef1 · R. Nagy1 · A. Baierl2 · V. Bacher1 · H. Bojar3 · D. L. McKee4 · R. Moss5 · N. H. Thoennissen6 · M. Szász7 · T. Bakacs8 Received: 8 March 2020 / Accepted: 14 October 2020 © The Author(s) 2020
Abstract The 3-year overall survival (OS) rate of patients with previously treated or untreated stage III or IV melanoma has by now reached 63% using ipilimumab and nivolumab therapy. However, immune-related adverse events (irAEs) of grade 3 or 4 occurred in 59% of patients leading to discontinuation of therapy in 24.5% of patients and one death. Therapy with checkpoint inhibitors could be safer and more effective in combination with hyperthermia and fever inducing therapies. We conducted a retrospective analysis to test the safety and efficacy of a new combination immune therapy in 131 unselected stage IV solid cancer patients with 23 different histological types of cancer who exhausted all conventional treatments. Treatment consisted of locoregional- and whole-body hyperthermia, individually dose adapted interleukin 2 (IL-2) combined with low-dose ipilimumab (0.3 mg/kg) plus nivolumab (0.5 mg/kg). The objective response rate (ORR) was 31.3%, progression-free survival (PFS) was 10 months, survival probabilities at 6 months was 86.7% (95% CI, 81.0–92.8%), at 9 months was 73.5% (95% CI, 66.2–81.7%), at 12 months was 66.5% (95% CI, 58.6–75.4%), while at 24 months survival was 36.6% (95% CI:28.2%; 47.3%). irAEs of World Health Organization (WHO) Toxicity Scale grade 1, 2, 3, and 4 were observed in 23.66%, 16.03%, 6.11%, and 2.29% of patients, respectively. Our results suggest that the irAEs profile of the combined treatment is safer than that of the established protocols without compromising efficacy. Keywords Stage IV cancer · Immunotherapy · Hyperthermia · IL-2 · Checkpoint inhibitors · irAEs Abbreviations auto-GVHD Autologous-graft-versus-host-like-disease CTLA-4 Cytotoxic T-lymphocyte-associated protein-4 GVM Graft-versus-malignancy effect ICI Immune checkpoint inhibitors irAEs Immune related adverse effects IL-2 Interleukin-2 MSIlow Low microsatellite instability NK cell Natural killer cell ORR Objective response rate Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02751-0) contains supplementary material, which is available to authorized users. * T. Bakacs [email protected] Extended author information available on the last page of the article
OR Overall response rate OS Overall survival PD-1 Programmed cell death-1 protein PFS Progression free survival RECIST Response Evaluation Criteria in Solid Tumors TMBlow Low tumor mutation burden WBH Whole-body hyperthermia
Introduction Concurrent ipilimumab and nivolumab treatment has by now achieved a 3-year overall survival (OS) rate of 63% for patie
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