Phase I trial of combined treatment with ch14.18 and R24 monoclonal antibodies and interleukin-2 for patients with melanoma or sarcoma |
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| Authors: | Brian S Choi Paul M Sondel Jacquelyn A Hank Heidi Schalch Jacek Gan David M King Kari Kendra David Mahvi Li-Yin Lee KyungMann Kim Mark R Albertini |
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| Institution: | (1) Department of Medicine, University of Wisconsin, Madison, WI, USA;(2) Department of Human Oncology, University of Wisconsin, Madison, WI, USA;(3) Department of Pediatrics, University of Wisconsin, Madison, WI, USA;(4) Department of Genetics, University of Wisconsin, Madison, WI, USA;(5) Department of Hematology and Oncology, Ohio State University, Columbus, OH, USA;(6) Department of Surgery, University of Wisconsin, Madison, WI, USA;(7) Department of Biostatistics, University of Wisconsin, Madison, WI, USA;(8) K4/414 Clinical Science Center, University of Wisconsin, 600 Highland Avenue, Madison, WI 53792, USA |
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| Abstract: | Purpose: We conducted a phase I trial of interleukin 2 (IL-2) in combination with chimeric 14.18 (ch14.18) and murine R24 antibodies
to determine the maximal tolerated dose (MTD), immunological effects, and toxicity of this treatment combination. Experimental Design: Twenty-seven patients with either melanoma (23 patients) or sarcoma (4 patients) were enrolled to receive a combination
therapy with ch14.18 and R24 antibodies together with continuous infusion of Roche IL-2 (1.5×106 U/m2/day, 26 patients) or Chiron IL-2 (4.5×106 U/m2/day, 1 patient) given 4 days/week for 3 weeks. The antibodies ch14.18 (2–7.5 mg/m2/day) and R24 (1–10 mg/m2/day) were scheduled to be administered for 5 days during the second week of IL-2 therapy. Results: When given in combination in this study, the MTD for ch14.18 was 5 mg/m2/day and the MTD for R24 was 5 mg/m2/day. Dose-limiting toxicities were severe allergic reactions to both ch14.18 and R24 as well as pain related to ch14.18.
This ch14.18 MTD was lower than the 7.5 mg/m2/day MTD previously determined for ch14.18 given alone with the same dose and schedule of IL-2. Immunological effects included
the induction of lymphokine-activated killer (LAK) activity and antibody-dependent cell-mediated cytoxicity (ADCC). Anti-idiotype
response to ch14.18 was seen in six patients, including two melanoma patients who had a partial response to treatment. In
addition to two partial responses, four patients had a stable disease and one patient remained without any evidence of disease.
Conclusions: Immunotherapy with IL-2 in combination with ch14.18 and R24 antibodies augments LAK function and ADCC measured in vitro
in all patients. While there exist theoretical advantages of combining these two antibodies, the MTD of ch14.18 and of R24
were lower than the MTD of each antibody in prior studies evaluating single antibody therapy with IL-2. As such, the combination
of these two antibodies together with IL-2 therapy appeared to influence the MTD and toxicity of each of the administered
antibodies.
This work is supported by NIH grants M01-RR03186, R01-CA32685, and P30-CA14520 |
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| Keywords: | Melanoma Immunotherapy Ganglioside GD2 Ganglioside GD3 Antibody-dependent cell cytotoxicity |
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