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Background <p>Canine osteosarcoma (OSA) and melanoma are highly aggressive cancers with a high propensity for lung metastasis. A recent phase 1 trial demonstrated that inhaled recombinant human interleukin-15 (rhIL-15) immunotherapy is safe and may be effective against lung metastases in dogs with metastatic OSA or melanoma. Notably, baseline lymphopenia correlated with clinical benefit in that trial. Building on these findings, this study evaluates whether preconditioning with doxorubicin to induce transient lymphodepletion before inhaled rhIL-15 immunotherapy improves the overall response rate in dogs with metastatic melanoma or tumors of bone.</p> Methods <p>Dogs with established pulmonary metastases from melanoma or bone tumors were treated with doxorubicin (30 mg/m<sup>2</sup> or 1&#xa0;mg/kg) 7 days before starting inhaled rhIL-15 (50&#xa0;µg twice daily x 14 days). Response rate was the primary objective of this study. Secondary objectives included toxicity assessment, immune correlative analyses via hematological monitoring, and NanoString transcriptomics analysis.</p> Results <p>Ten dogs were enrolled, with eight reaching the Day 35 evaluable response assessment. One dog achieved a complete response lasting over 1 year, and two had stable disease, yielding an overall clinical benefit rate (CBR) of 30% and an overall response rate (ORR) of 10%. Doxorubicin preconditioning did not alter the toxicity of inhaled rhIL-15 therapy. While doxorubicin treatment decreased absolute lymphocyte counts (ALC), as expected, this reduction did not improve the CBR or ORR compared to the prior study evaluating inhaled rhIL-15 monotherapy. Transcriptomic analysis of peripheral blood mononuclear cells did not reveal a significant increase in natural killer or cytotoxic T-cell population frequencies following doxorubicin and inhaled rhIL-15 therapy.</p> Conclusions <p>Preconditioning with standard doses of doxorubicin does not alter the clinical response or safety profile of inhaled rhIL-15 therapy in dogs with advanced pulmonary metastatic disease. Further research is needed to evaluate combinatorial treatment strategies that enhance the efficacy of inhaled rhIL-15 in dogs with advanced metastatic disease.</p>

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Evaluating the impact of doxorubicin preconditioning on the efficacy of inhaled recombinant human IL-15 immunotherapy in dogs with pulmonary metastasis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月1日

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  • Madison E. Luker,
  • Daniel York,
  • Sami Al-Nadaf,
  • Eric G. Johnson,
  • Sita S. Withers,
  • Sylvia M. Cruz,
  • Amandine Lejeune,
  • Katherine A. Skorupski,
  • Jacque Young,
  • Tamar Cohen-Davidyan,
  • Ellen E. Sparger,
  • William TN Culp,
  • William J. Murphy,
  • Michael S. Kent,
  • Robert J. Canter,
  • Robert B. Rebhun

摘要

Background

Canine osteosarcoma (OSA) and melanoma are highly aggressive cancers with a high propensity for lung metastasis. A recent phase 1 trial demonstrated that inhaled recombinant human interleukin-15 (rhIL-15) immunotherapy is safe and may be effective against lung metastases in dogs with metastatic OSA or melanoma. Notably, baseline lymphopenia correlated with clinical benefit in that trial. Building on these findings, this study evaluates whether preconditioning with doxorubicin to induce transient lymphodepletion before inhaled rhIL-15 immunotherapy improves the overall response rate in dogs with metastatic melanoma or tumors of bone.

Methods

Dogs with established pulmonary metastases from melanoma or bone tumors were treated with doxorubicin (30 mg/m2 or 1 mg/kg) 7 days before starting inhaled rhIL-15 (50 µg twice daily x 14 days). Response rate was the primary objective of this study. Secondary objectives included toxicity assessment, immune correlative analyses via hematological monitoring, and NanoString transcriptomics analysis.

Results

Ten dogs were enrolled, with eight reaching the Day 35 evaluable response assessment. One dog achieved a complete response lasting over 1 year, and two had stable disease, yielding an overall clinical benefit rate (CBR) of 30% and an overall response rate (ORR) of 10%. Doxorubicin preconditioning did not alter the toxicity of inhaled rhIL-15 therapy. While doxorubicin treatment decreased absolute lymphocyte counts (ALC), as expected, this reduction did not improve the CBR or ORR compared to the prior study evaluating inhaled rhIL-15 monotherapy. Transcriptomic analysis of peripheral blood mononuclear cells did not reveal a significant increase in natural killer or cytotoxic T-cell population frequencies following doxorubicin and inhaled rhIL-15 therapy.

Conclusions

Preconditioning with standard doses of doxorubicin does not alter the clinical response or safety profile of inhaled rhIL-15 therapy in dogs with advanced pulmonary metastatic disease. Further research is needed to evaluate combinatorial treatment strategies that enhance the efficacy of inhaled rhIL-15 in dogs with advanced metastatic disease.