Title |
Inhaled recombinant human IL-15 in dogs with naturally occurring pulmonary metastases from osteosarcoma or melanoma: a phase 1 study of clinical activity and correlates of response
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Published in |
Journal for Immunotherapy of Cancer, June 2022
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DOI | 10.1136/jitc-2022-004493 |
Pubmed ID | |
Authors |
Robert B Rebhun, Daniel York, Sylvia Margret Cruz, Sean J Judge, Aryana M Razmara, Lauren E Farley, Rachel V Brady, Eric G Johnson, Jenna H Burton, Jennifer Willcox, Luke A Wittenburg, Kevin Woolard, Cordelia Dunai, Susan L Stewart, Ellen E Sparger, Sita S Withers, Alicia A Gingrich, Katherine A Skorupski, Sami Al-Nadaf, Amandine T LeJeune, William TN Culp, William J Murphy, Michael S Kent, Robert J Canter |
Abstract |
Although recombinant human interleukin-15 (rhIL-15) has generated much excitement as an immunotherapeutic agent for cancer, activity in human clinical trials has been modest to date, in part due to the risks of toxicity with significant dose escalation. Since pulmonary metastases are a major site of distant failure in human and dog cancers, we sought to investigate inhaled rhIL-15 in dogs with naturally occurring lung metastases from osteosarcoma (OSA) or melanoma. We hypothesized a favorable benefit/risk profile given the concentrated delivery to the lungs with decreased systemic exposure. We performed a phase I trial of inhaled rhIL-15 in dogs with gross pulmonary metastases using a traditional 3+3 cohort design. A starting dose of 10 µg twice daily × 14 days was used based on human, non-human primate, and murine studies. Safety, dose-limiting toxicities (DLT), and maximum tolerated dose (MTD) were the primary objectives, while response rates, progression-free and overall survival (OS), and pharmacokinetic and immune correlative analyses were secondary. From October 2018 to December 2020, we enrolled 21 dogs with 18 dogs reaching the 28-day response assessment to be evaluable. At dose level 5 (70 μg), we observed two DLTs, thereby establishing 50 µg twice daily × 14 days as the MTD and recommended phase 2 dose. Among 18 evaluable dogs, we observed one complete response >1 year, one partial response with resolution of multiple target lesions, and five stable disease for an overall clinical benefit rate of 39%. Plasma rhIL-15 quantitation revealed detectable and sustained rhIL-15 concentrations between 1-hour and 6 hour postnebulization. Decreased pretreatment lymphocyte counts were significantly associated with clinical benefit. Cytotoxicity assays of banked peripheral blood mononuclear cells revealed significant increases in peak cytotoxicity against canine melanoma and OSA targets that correlated with OS. In this first-in-dog clinical trial of inhaled rhIL-15 in dogs with advanced metastatic disease, we observed promising clinical activity when administered as a monotherapy for only 14 days. These data have significant clinical and biological implications for both dogs and humans with refractory lung metastases and support exploration of combinatorial therapies using inhaled rhIL-15. |
X Demographics
Geographical breakdown
Country | Count | As % |
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United States | 7 | 32% |
United Kingdom | 1 | 5% |
Australia | 1 | 5% |
Saudi Arabia | 1 | 5% |
India | 1 | 5% |
Japan | 1 | 5% |
France | 1 | 5% |
Unknown | 9 | 41% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 19 | 86% |
Scientists | 2 | 9% |
Science communicators (journalists, bloggers, editors) | 1 | 5% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
Unknown | 17 | 100% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Other | 2 | 12% |
Lecturer | 2 | 12% |
Student > Ph. D. Student | 2 | 12% |
Student > Postgraduate | 2 | 12% |
Professor > Associate Professor | 1 | 6% |
Other | 1 | 6% |
Unknown | 7 | 41% |
Readers by discipline | Count | As % |
---|---|---|
Veterinary Science and Veterinary Medicine | 4 | 24% |
Medicine and Dentistry | 2 | 12% |
Immunology and Microbiology | 2 | 12% |
Biochemistry, Genetics and Molecular Biology | 1 | 6% |
Agricultural and Biological Sciences | 1 | 6% |
Other | 0 | 0% |
Unknown | 7 | 41% |