Pilot trial of the hu14.18-IL2 immunocytokine in patients with completely resectable recurrent stage III or stage IV melanoma
Phase I testing of the hu14.18-IL2 immunocytokine (IC) in melanoma patients showed immune activation, reversible toxicities, and a maximal tolerated dose of 7.5 mg/m2/day. Preclinical data in IC-treated tumor-bearing mice with low tumor burden documented striking antitumor effects. Patients with completely resectable recurrent stage III or stage IV melanoma were scheduled to receive 3 courses of IC at 6 mg/m2/day i.v. on days 1, 2 and 3 of each 28-day course. Patients were randomized to complete surgical resection either following neoadjuvant (Group A) or prior to adjuvant (Group B) IC course 1. Primary objectives were to: (1) evaluate histological evidence of anti-tumor activity and (2) evaluate recurrence-free survival (RFS) and OS. Twenty melanoma patients were randomized to Group A (11 patients) or B (9 patients). Two Group B patients did not receive IC due to persistent disease following surgery. Six of 18 IC-treated patients remained free of recurrence, with a median RFS of 5.7 months (95% confidence interval (CI) 1.8-not reached). The 24-month RFS rate was 38.9% (95% CI 17.5–60.0%). The median follow-up of surviving patients was 50.0 months (range: 31.8–70.4). The 24-month OS rate was 65.0% (95% CI 40.3–81.5%). Toxicities were similar to those previously reported. Exploratory tumor-infiltrating lymphocyte (TIL) analyses suggest prognostic value of TILs from Group A patients. Prolonged tumor-free survival was seen in some melanoma patients at high risk for recurrence who were treated with IC.
KeywordsImmunotherapy Immunocytokine Melanoma Anti-ganglioside antibody Interleukin-2
American Joint Committee on Cancer
Common terminology criteria adverse events
Dose limiting toxicity
Eastern cooperative oncology group
Region of antibody
Ganglioside expressed by tumor cells
National Cancer Institute
Soluble IL-2 receptor
University of Wisconsin
UW Hospitals and Clinics
The authors thank the NCI-Biological Resources Branch for assistance in producing the clinical Grade hu14.18-IL2 needed for this trial and for provision of the monoclonal 1A7 antibody needed for its detection in serum by ELISA. The authors thank Yifan Zhou for technical assistance with the immune monitoring assays and Laddie Johnson for assistance with manuscript preparation. We also thank the nurses on the Clinical Research Unit at the University of Wisconsin Hospital and Clinics for outstanding nursing care and for clinical trial support.
MRA: study conception and design, protocol chairman, laboratory and clinical data analysis and interpretation, drafted manuscript; RKY: histology data analysis and interpretation; EAR: histology data analysis and interpretation; JAH: laboratory co-chair, immunologic monitoring data collection, analysis and interpretation; CLZ: immunologic monitoring data analysis, manuscript table and figure preparation; SW: surgical team; HN: surgical team; GH: surgical team; TW: surgical team; DM: surgical team; MBH: patient care; RQ: clinical data analysis; TMF: patient care; JG: processing of clinical samples, immunologic monitoring data collection, analysis and interpretation; LC: statistical data analysis; KK: protocol statistician, statistical design of the study, statistical data analysis; HL: laboratory and clinical data interpretation; SDG: creator of hu14.18-IL2, laboratory and clinical data interpretation; PMS: study conception and design, principal investigator for NIH grant supporting the study, laboratory and clinical data analysis and interpretation. All authors reviewed and had opportunity to edit the manuscript, and all authors approved the manuscript.
Support was provided by NIH R01 CA032685, R01 CA087025, R35 CA166105, P30 CA014520 from the National Cancer Institute, by resources at the William S. Middleton Memorial Veterans Hospital, Madison, WI, and by the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS), grant UL1TR000427. Additional support was provided by grants from the Midwest Athletes for Childhood Cancer Fund, the Crawdaddy Foundation, the Stand Up to Cancer Foundation, the St. Baldrick’s Foundation, the Hyundai Hope on Wheels Program, Ann’s Hope Foundation, the Tim Eagle Memorial, and the Jay Van Sloan Memorial from the Steve Leuthold Family.
Compliance with ethical standards
Conflict of interest
The authors have the following financial or other conflicts of interests to disclose related to this publication: Dr. Hans Loibner is CEO for Apeiron Biologics AG, and Apeiron Biologics AG has ownership of the hu18.18-IL2 immunocytokine used in this study. The remaining authors reported no financial or other conflicts of interest to disclose related to this publication.
The UW Human Subjects Committee and the FDA approved the study (ClinicalTrials.gov identifier: NCT00590824; IND 12220). All procedures performed in studies involving human participants were in accordance with ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Written informed consent was obtained from all individual participants included in the study and all individual participants registered with the Biostatistics Registration Desk prior to treatment.
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