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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.
Rebhun, Robert B; York, Daniel; Cruz, Sylvia Margret; Judge, Sean J; Razmara, Aryana M; Farley, Lauren E; Brady, Rachel V; Johnson, Eric G; Burton, Jenna H; Willcox, Jennifer; Wittenburg, Luke A; Woolard, Kevin; Dunai, Cordelia; Stewart, Susan L; Sparger, Ellen E; Withers, Sita S; Gingrich, Alicia A; Skorupski, Katherine A; Al-Nadaf, Sami; LeJeune, Amandine T; Culp, William Tn; Murphy, William J; Kent, Michael S; Canter, Robert J.
Afiliação
  • Rebhun RB; Department of Surgical and Radiological Sciences, University of California, Davis, California, USA rbrebhun@ucdavis.edu rjcanter@ucdavis.edu.
  • York D; Department of Surgical and Radiological Sciences, University of California, Davis, California, USA.
  • Cruz SM; Division of Surgical Oncology, Department of Surgery, University of California Davis Medical Center, Sacramento, California, USA.
  • Judge SJ; Division of Surgical Oncology, Department of Surgery, University of California Davis Medical Center, Sacramento, California, USA.
  • Razmara AM; Division of Surgical Oncology, Department of Surgery, University of California Davis Medical Center, Sacramento, California, USA.
  • Farley LE; Division of Surgical Oncology, Department of Surgery, University of California Davis Medical Center, Sacramento, California, USA.
  • Brady RV; College of Veterinary Medicine, Colorado State University, Fort Collins, Colorado, USA.
  • Johnson EG; Department of Surgical and Radiological Sciences, University of California, Davis, California, USA.
  • Burton JH; Department of Clinical Sciences, Colorado State University College of Veterinary Medicine, Fort Collins, Colorado, USA.
  • Willcox J; Department of Surgical and Radiological Sciences, University of California, Davis, California, USA.
  • Wittenburg LA; Department of Surgical and Radiological Sciences, University of California, Davis, California, USA.
  • Woolard K; Department of Pathology, University of California, Davis, California, USA.
  • Dunai C; Department of Dermatology, University of California, Davis, California, USA.
  • Stewart SL; Department of Public Health Sciences, University of California, Davis, California, USA.
  • Sparger EE; Department of Medicine and Epidemiology, University of California, Davis, California, USA.
  • Withers SS; Department of Veterinary Clinical Sciences, Louisiana State University, Baton Rouge, Louisiana, USA.
  • Gingrich AA; Division of Surgical Oncology, Department of Surgery, University of California Davis Medical Center, Sacramento, California, USA.
  • Skorupski KA; Department of Surgical and Radiological Sciences, University of California, Davis, California, USA.
  • Al-Nadaf S; Department of Surgical and Radiological Sciences, University of California, Davis, California, USA.
  • LeJeune AT; Department of Surgical and Radiological Sciences, University of California, Davis, California, USA.
  • Culp WT; Department of Surgical and Radiological Sciences, University of California, Davis, California, USA.
  • Murphy WJ; Department of Dermatology, University of California Davis Medical Center, Sacramento, California, USA.
  • Kent MS; Division of Hematology and Oncology, Department of Medicine, University of California Davis Medical Center, Sacramento, California, USA.
  • Canter RJ; Department of Surgical and Radiological Sciences, University of California, Davis, California, USA.
J Immunother Cancer ; 10(6)2022 06.
Article em En | MEDLINE | ID: mdl-35680383
PURPOSE: 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. EXPERIMENTAL DESIGN: 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. RESULTS: 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. CONCLUSIONS: 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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Ósseas / Osteossarcoma / Neoplasias Pulmonares / Melanoma Limite: Animals / Humans Idioma: En Revista: J Immunother Cancer Ano de publicação: 2022 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Neoplasias Ósseas / Osteossarcoma / Neoplasias Pulmonares / Melanoma Limite: Animals / Humans Idioma: En Revista: J Immunother Cancer Ano de publicação: 2022 Tipo de documento: Article