Pilot trial of the hu14.18-IL2 immunocytokine in patients with completely resectable recurrent stage III or stage IV melanoma

Abstract

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.

Keywords: Anti-ganglioside antibody; Immunocytokine; Immunotherapy; Interleukin-2; Melanoma.

Conflict of interest statement

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.

Figures

Fig. 1

Immune activation following IC administration. IC levels and sIL-2R alpha levels were measured in Group A (filled circles) and Group B (open circles) patients. a Peak serum IC levels measured pre-treatment and 4 hours post-treatment for each course. Results are shown as individual data points and mean ng/ml ± SEM. The number of patients analyzed per Group at each timepoint is presented. b sIL-2R alpha levels measured pre-treatment, day 4, day 8 and day 25 post-treatment for each course. Results are shown as individual data points and mean pg/ml ± SEM. The number of patients analyzed per Group at each timepoint is presented.

Fig. 2

Recurrence-free Survival. The estimate of the survival distribution for RFS is shown. The median RFS was 5.73 months [95% CI: 1.80-not reached (months)].

Fig. 3

Overall Survival. The estimate of the survival distribution for OS is shown. The median OS was 61.57 months [95% CI: 13.67-not reached (months)].

Fig. 4

Tumor Infiltrating Lymphocytes in hu14.18-IL2 Treated Tumors Prognosticates Improved Relapse Free Survival (RFS). a H&E section of example of melanoma with low TIL percentage (400x). Lymphocytes truly infiltrating between tumor cells are scant. b H&E section of example of melanoma with high TIL percentage (400x). Tumor infiltrating lymphocytes are located histologically between tumor cells. c Relapse free survival of patients stratified by treatment group and TIL percentage. d Overall survival of patients stratified by treatment group and TIL percentage.