Clinical Research Papers:
A phase I study of intratumoral ipilimumab and interleukin-2 in patients with advanced melanoma
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Abhijit Ray1,*, Matthew A. Williams2,*, Stephanie M. Meek2, Randy C. Bowen3, Kenneth F. Grossmann1, Robert H.I. Andtbacka4, Tawnya L. Bowles5, John R. Hyngstrom4,5, Sancy A. Leachman6, Douglas Grossman1, Glen M. Bowen1, Sheri L. Holmen1, Matthew W. VanBrocklin1, Gita Suneja7 and Hung T. Khong1
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
Hung T. Khong, email:
Keywords: ipilimumab, interleukin-2, intratumoral, abscopal effect, immunotherapy
Received: June 17, 2016 Accepted: June 25, 2016 Published: July 06, 2016
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.
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