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Intratumoral treatment of smaller mouse neuroblastoma tumors with a recombinant protein consisting of IL-2 linked to the Hu14.18 antibody increases intratumoral CD8+ T and NK cells and improves survival |
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| Authors: | Richard K Yang Nicholas A Kalogriopoulos Alexander L Rakhmilevich Erik A Ranheim Songwon Seo KyungMann Kim Kory L Alderson Jacek Gan Ralph A Reisfeld Stephen D Gillies Jacquelyn A Hank Paul M Sondel |
| Institution: | 1. The Department of Human Oncology, University of Wisconsin, 4159 WIMR Bldg., 1111 Highland Ave, Madison, WI, 53705, USA 5. The Department of Carbone Cancer Center, University of Wisconsin, Madison, WI, USA 2. The Departments of Pathology and Laboratory Medicine, University of Wisconsin, Madison, WI, USA 3. The Departments of Biostatistics and Medical Informatics, University of Wisconsin, Madison, WI, USA 6. The Department of Immunology, The Scripps Research Institute, La Jolla, CA, USA 7. Provenance Biopharmaceuticals Corp., Waltham, MA, USA 4. The Department of Pediatrics, University of Wisconsin, Madison, WI, USA |
| Abstract: | Hu14.18-IL2 is an immunocytokine (IC) consisting of human IL-2 linked to hu14.18 mAb, which recognizes GD2 disialoganglioside. Phase II clinical trials of intravenous-hu14.18-IL2 (IV-IC) in neuroblastoma and melanoma are underway, and have already demonstrated activity in neuroblastoma. In our Phase II trial, lower neuroblastoma burden at the time of treatment was associated with a greater likelihood of clinical response to IV-IC. We have previously shown that intratumoral-hu14.18-IL2 (IT-IC) compared to IV-IC results in enhanced local and systemic antitumor activity in tumor-bearing mice. We utilized a mouse model to investigate the impact of tumor burden on hu14.18-IL2 treatment efficacy in IV- versus IT-treated animals. Studies presented here describe the analyses of tumor burden at the initiation of treatment and its effects on treatment efficacy, survival, and tumor-infiltrating leukocytes in A/J mice bearing subcutaneous NXS2 neuroblastoma. We show that smaller tumor burden at treatment initiation is associated with increased infiltration of NK and CD8+ T cells and increased overall survival. NXS2 tumor shrinkage shortly after completion of the 3 days of hu14.18-IL2 treatment is necessary for long-term survival. This model demonstrates that tumor size is a strong predictor of hu14.18-IL2-induced lymphocyte infiltration and treatment outcome. |
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