Cytokine‐Enhanced Vaccine as Surgery Adjuvant Treatment for Spontaneous Canine Melanoma: Comparison of Two Intralesional Procedures for Local Disease Control

Abstract

We present here the feasibility, safety, and efficacy results of a 7-year study that included 337 canine melanoma patients undergoing surgery with adjuvant intralesional therapies combined with immunogenic therapy. After complete (CS) or partial (PS) surgery, the patients received post-surgical bed injections of (i) lipoplexes carrying canine interferon-β (cIFNβ) gene combined with bleomycin (CTIF/B) or (ii) 5-fluorouracil (CT5FU). This surgery adjuvant therapy (SAT) also included the periodic administration of subcutaneous genetic vaccines composed of tumour extracts and lipoplexes carrying cIFNβ, human interleukin-2, and human granulocyte-macrophage colony-stimulating factor genes. Compared at the end of their individual follow-ups with controls treated with complete surgery alone (CSo), CS-CTIF/B and CS-CT5FU treatments quadrupled the fraction of local disease-free (from 19% to 81% and 85%), and increased the percentage of metastasis-free patients (M0: from 47% to 82% and 81%). Both PS arms (PS-CTIF/B and PS-CT5FU) also significantly increased the fraction of metastatic-free disease (M0: from 48% to 75% and 73%). In addition, SAT produced a significant 11- (CS-CTIF/B: p < 0.0001, HR95% CI = 0.155 [0.109–0.222]), 9- (CS-CT5FU: p < 0.0001, HR95% CI = 0.172 [0.123–0.242]), 6- (PS-CTIF/B: p < 0.0001, HR95% CI = 0.204 [0.132–0.315]), and 7- (PS-CT5FU: p < 0.0001, HR95% CI = 0.203 [0.132–0.311]) fold increase of overall survival as compared to their respective CSo and PSo controls. The respective median follow-up days for each group were: 695.5 (28-2516), 542.5 (46-2554), 458 (29-1273), and 521 (30-1659). In general terms, this SAT transformed a lethal disease into a manageable condition where 25% (CS-CTIF/B), 24% (CS-CT5FU), 22% (PS-CTIF/B), and 22% (PS-CT5FU) of patients were still alive at the end of the study, while 53%, 60%, 16%, and 17%, respectively, died from causes unrelated to melanoma. Both surgery adjuvant treatments delayed or prevented post-surgical recurrence and metastases, improved disease-free and overall survival while maintaining quality of life. These successful outcomes encourage assaying a similar scheme for human melanoma.