A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma

• Published in: Oncotarget Vol. 7; no. 39; pp. 64390 - 64399
• Main Authors: Ray, Abhijit, Williams, Matthew A, Meek, Stephanie M, Bowen, Randy C, Grossmann, Kenneth F, Andtbacka, Robert H I, Bowles, Tawnya L, Hyngstrom, John R, Leachman, Sancy A, Grossman, Douglas, Bowen, Glen M, Holmen, Sheri L, VanBrocklin, Matthew W, Suneja, Gita, Khong, Hung T
• Format: Journal Article
• Language: English
• Published: United States Impact Journals LLC 27-09-2016
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Clinical Research Paper; Female; Humans; Injections, Intralesional; Interleukin-2 - administration & dosage; Interleukin-2 - adverse effects; Ipilimumab - administration & dosage; Ipilimumab - adverse effects; Lymphocytes, Tumor-Infiltrating - drug effects; Lymphocytes, Tumor-Infiltrating - immunology; Male; Melanoma - diagnostic imaging; Melanoma - drug therapy; Melanoma - immunology; Melanoma - pathology; Middle Aged; Neoplasm Staging; Skin Neoplasms - diagnostic imaging; Skin Neoplasms - drug therapy; Skin Neoplasms - immunology; Skin Neoplasms - pathology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Time Factors; Tomography, X-Ray Computed; Treatment Outcome; Utah; interleukin-2; abscopal effect; intratumoral; immunotherapy; ipilimumab
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.10453

Intratumoral interleukin-2 (IL-2) is effective but does not generate systemic immunity. Intravenous ipilimumab produces durable clinical response in a minority of patients, with potentially severe toxicities. Circulating anti-tumor T cells activated by ipilimumab may differ greatly from tumor-infiltrating lymphocytes activated by intratumoral ipilimumab in phenotypes and functionality. The objective of this study was to primarily assess the safety of intratumoral ipilimumab/IL-2 combination and to obtain data on clinical efficacy.
There was no dose limiting toxicity. While local response of injected lesions was observed in 67% patients (95% CI, 40%-93%), an abscopal response was seen in 89% (95% CI, 68%-100%). The overall response rate and clinical benefit rate by immune-related response criteria (irRC) was 40% (95% CI, 10%-70%) and 50% (95% CI, 19%-81%), respectively. Enhanced systemic immune response was observed in most patients and correlated with clinical responses.
Twelve patients with unresectable stages III/IV melanoma were enrolled. A standard 3+3 design was employed to assess highest tolerable intratumoral dose of ipilimumab and IL-2 based on toxicity during the first three weeks. Escalated doses of ipilimumab was injected into only one lesion weekly for eight weeks in cohorts of three patients. A fixed dose of IL-2 was injected three times a week into the same lesion for two weeks, followed by two times a week for six weeks.
Intratumoral injection with the combination of ipilimumab/IL-2 is well tolerated and generates responses in both injected and non-injected lesions in the majority of patients.