Phase 2 Trial (COTC-030) of adjuvant inhaled recombinant human IL-15 combined with amputation and adjuvant carboplatin chemotherapy in dogs with appendicular osteosarcoma

ABSTRACT: We have previously shown that inhaled IL-15 is associated with anti-tumor responses in dogs with pulmonary metastatic osteosarcoma (OSA) and melanoma. Here, we evaluated inhaled IL-15 combined with amputation and chemotherapy for dogs with localized OSA eligible for treatment with curative intent. In a multicenter COTC phase II trial for dogs with limb OSA, we hypothesized that 2 weeks of inhaled rhIL-15 after amputation and prior to chemotherapy would reduce the risk of metastatic failure at the completion of chemotherapy from a historical rate of 40% to 20%. Using a 2-sided alpha of 0.05, we planned an accrual of 40 dogs to test this hypothesis with 80% power. We also performed immune correlative assays and sequencing of blood immune cells (PBMCs) and primary amputation specimens. Unexpectedly, disease-free and survival outcomes for dogs in the intent-to-treat population were statistically inferior to a well-validated historical control cohort (P=0.03, P=0.003), so the trial was halted for futility. Cytotoxicity assays of PBMCs showed significant decreases after both surgery and chemotherapy with an overall decrease from the start to the end of therapy (-18.2±16.1%, P<0.001). Some dogs demonstrated positive fold change in PBMC cytotoxicity, and this correlated significantly with improved dog survival (P=0.004, r=0.62). Although plasma concentrations of key cytokines varied markedly with no significant differences between disease-free and metastatic-failure patients, inflammatory cytokines such as IL-6 showed absolute increases post-amputation and post-chemotherapy correlating with decreases in cytotoxicity. Tumor sequencing data reproduced immune signatures as observed in both human and canine cohorts, and PBMC sequencing data from 4 dogs showed upregulation of IL-15 receptor alpha on myeloid derived suppressor cells post-surgery. Inhaled IL-15 as part of multimodality approach with amputation and chemotherapy appears to be associated with worse outcomes in dogs with appendicular OSA. Correlative assays suggest significant immunological effects of amputation and chemotherapy on immune responses. These data have important implications for the design and testing of novel immunotherapy strategies involving multimodality approaches including surgery and chemotherapy.

ORGANISM(S): Canis lupus familiaris

PROVIDER: GSE304066 | GEO | 2025/11/13

REPOSITORIES: GEO