{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T11:50:28Z","timestamp":1791546628121,"version":"4.3.4"},"reference-count":48,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2022,6,7]],"date-time":"2022-06-07T00:00:00Z","timestamp":1654560000000},"content-version":"unspecified","delay-in-days":6,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"UC"},{"name":"Comprehensive Cancer Center"},{"name":"Cancer Center","award":["S10 OD018223"],"award-info":[{"award-number":["S10 OD018223"]}]},{"name":"Cancer Center","award":["S10 RR 026825"],"award-info":[{"award-number":["S10 RR 026825"]}]},{"name":"National Institutes of Health\/National Cancer Institute","award":["K01OD026526"],"award-info":[{"award-number":["K01OD026526"]}]},{"name":"National Institutes of Health\/National Cancer Institute","award":["R03CA252793"],"award-info":[{"award-number":["R03CA252793"]}]},{"name":"National Institutes of Health\/National Cancer Institute","award":["T32CA251007"],"award-info":[{"award-number":["T32CA251007"]}]},{"name":"National Institutes of Health\/National Cancer Institute","award":["U01 CA224166-01"],"award-info":[{"award-number":["U01 CA224166-01"]}]},{"name":"University of California Davis Flow Cytometry Shared Resource Laboratory"},{"name":"UC Davis Center for Companion Animal Health"},{"name":"NCI","award":["P30 CA093373"],"award-info":[{"award-number":["P30 CA093373"]}]},{"name":"UC Davis Veterinary Center for Clinical Trials and the Clinical Trials Residents"}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Immunother Cancer"],"accepted":{"date-parts":[[2022,5,3]]},"published-print":{"date-parts":[[2022,6]]},"abstract":"<jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental design<\/jats:title>\n                    <jats:p>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 \u00b5g twice daily \u00d7 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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>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 \u03bcg), we observed two DLTs, thereby establishing 50 \u00b5g twice daily \u00d7 14 days as the MTD and recommended phase 2 dose. Among 18 evaluable dogs, we observed one complete response &gt;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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jitc-2022-004493","type":"journal-article","created":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T13:22:20Z","timestamp":1654780940000},"page":"e004493","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":38,"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"],"prefix":"10.1136","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8047-3494","authenticated-orcid":false,"given":"Robert B","family":"Rebhun","sequence":"first","affiliation":[{"name":"Department of Surgical and Radiological Sciences, University of California, 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