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Clinical Trial
. 2018 Oct;67(10):1647-1658.
doi: 10.1007/s00262-018-2223-z. Epub 2018 Aug 3.

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

Mark R Albertini  1   2   3   4 , Richard K Yang  5 , Erik A Ranheim  6   5 , Jacquelyn A Hank  6   7 , Cindy L Zuleger  6   8 , Sharon Weber  6   9 , Heather Neuman  6   9 , Greg Hartig  6   9 , Tracey Weigel  10 , David Mahvi  11 , Mary Beth Henry  7 , Renae Quale  6 , Thomas McFarland  6   8 , Jacek Gan  6 , Lakeesha Carmichael  12 , KyungMann Kim  6   12 , Hans Loibner  13 , Stephen D Gillies  14 , Paul M Sondel  6   7   15
Affiliations
Clinical Trial

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

Mark R Albertini et al. Cancer Immunol Immunother. 2018 Oct.

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.

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Conflict of interest statement

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
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 h 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
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
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
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 (×400). Lymphocytes truly infiltrating between tumor cells are scant. b H&E section of example of melanoma with high TIL percentage (×400). 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
See this image and copyright information in PMC

References

    1. Albertini MR, Ranheim EA, Hank JA, Zuleger CL, McFarland T, Collins J et al (2014) A pilot trial of hu14.18-IL2 in patients with completely resectable recurrent stage III or stage IV melanoma. Annual Meeting of the American Society of Clinical Oncology (ASCO 2014), Chicago, IL, USA, May 30-June 3, 2014. J Clin Oncol 32 (5 s): (Abstract 9044, Poster)
    1. Albertini MR, Ranheim EA, Hank JA, Zuleger CL, McFarland T, Collins J et al (2016) Final statistical analysis of a pilot trial of hu14.18-IL2 in patients with completely resectable recurrent stage III or stage IV melanoma. 31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016), National Harbor, MD, USA, November 9–13, 2016. J Immunother Cancer 4 (Suppl 1): (Abstract 163, Poster).10.1186/s40425-016-0172-7
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