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

// Abhijit Ray 1,* , Matthew A. Williams 2,* , Stephanie M. Meek 2 , Randy C. Bowen 3 , Kenneth F. Grossmann 1 , Robert H.I. Andtbacka 4 , Tawnya L. Bowles 5 , John R. Hyngstrom 4,5 , Sancy A. Leachman 6 , Douglas Grossman 1 , Glen M. Bowen 1 , Sheri L. Holmen 1 , Matthew W. VanBrocklin 1 , Gita Suneja 7 and Hung T. Khong 1 1 Division of Oncology, Huntsman Cancer Institute-University of Utah, Salt Lake City, UT, USA 2 Department of Pathology, University of Utah, Salt Lake City, UT, USA 3 School of Medicine, University of Utah, Salt Lake City, UT, USA 4 Section of Surgical Oncology, Division of General Surgery Huntsman Cancer Institute-University of Utah, Salt Lake City, UT, USA 5 Department of General Surgery, Intermountain Medical Center, Murray, UT, USA 6 Department of Dermatology, Oregon Health & Science University-Knight Cancer Institute, Portland, OR, USA 7 Department of Radiation Oncology, University of Utah, Salt Lake City, UT, USA * These authors have contributed equally to this work Correspondence to: Hung T. Khong, email: // Keywords : ipilimumab, interleukin-2, intratumoral, abscopal effect, immunotherapy Received : June 17, 2016 Accepted : June 25, 2016 Published : July 06, 2016 Abstract Purpose: 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. Results: 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. Experimental Design: 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. Conclusions: 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.