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/m/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/m/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.

The antibody‐based delivery of interleukin‐12 to solid tumors boosts NK and CD8+ T cell activity and synergizes with immune checkpoint inhibitors

“…[13][14][15] Some antibody-cytokine fusions are currently being investigated in the clinic for the treatment of different types of malignancies. [16][17][18][19][20][21][22][23][24] Interleukin-12 (IL12) is a heterodimeric cytokine consisting of the p40 and p35 subunits, linked by a disulfide bond. 25,26 The protein is predominantly produced by antigenpresenting cells (APCs) upon recognition of "danger signals" such as pathogen-associated molecular patterns (PAMPs).…”

Outcome-Related Signatures Identified by Whole Transcriptome Sequencing of Resectable Stage III/IV Melanoma Evaluated after Starting Hu14.18-IL2

“…These human investigations were performed after approval by the UW institutional review board and in accordance with an assurance filed with and approved by the U.S. Department of Health and Human Services. Details of study design, conduct, and clinical results have been reported previously (36). All patients had recurrent stage III (recurrent regional metastasis), or stage IV (any distant metastasis) melanoma with biopsy-proven (current or previous) Stage III or Stage IV disease (36).…”

“…Details of study design, conduct, and clinical results have been reported previously (36). All patients had recurrent stage III (recurrent regional metastasis), or stage IV (any distant metastasis) melanoma with biopsy-proven (current or previous) Stage III or Stage IV disease (36). Eligibility criteria required that at study entry, all patients have recurrent melanoma involving <3 sites, judged to be totally resectable, where resection would be clinically recommended.…”

“…Here we present tumor analyses from a clinical trial (CO05601), wherein 21 of 23 patients with advanced melanoma received surgical resection of all evident disease to attain a complete response (CR) together with systemic IC administration (36). Patients were randomized to have their first of 3 monthly-courses on July 5, 2020.…”

“…Our primary goal for this report is to identify differences in gene expression in these tumors prior to and after treatment with hu14.18-IL2; our secondary goal is to determine if gene expression patterns before treatment, or induced by the treatment, are associated with outcome. Published data from this trial reported prolonged tumor-free survival in some patients at high-risk for recurrence (36). In this report, we analyze whole transcriptome sequencing from these resected recurrent/refractory melanoma tumors and compare results for tumors obtained before vs. after 1 course of hu14.18-IL2.…”