Immunological responses and clinical outcomes in dogs with osteosarcoma receiving standard therapy and a Listeria vaccine expressing HER2 - PubMed (original) (raw)
Multicenter Study
. 2025 Apr 2;33(4):1674-1686.
doi: 10.1016/j.ymthe.2025.02.023. Epub 2025 Feb 15.
Laura Selmic 2, Audrey Ruple 3, Cheryl A London 4, Lisa Barber 4, Kristen Weishaar 5, James A Perry 6, Jennifer Mahoney 7, Brian Flesner 8, Jeffrey N Bryan 8, Jennifer L Willcox 9, Jenna H Burton 9, David M Vail 10, William C Kisseberth 2, Cheryl E Balkman 11, Angela L McCleary-Wheeler 11, Katie M Curran 12, Haley Leeper 12, John Paul Woods 13, Anthony J Mutsaers 13, Mary Lynn Higginbotham 14, Raelene M Wouda 15, Heather Wilson-Robles 16, Nicholas Dervisis 17, Corey Saba 18, Valerie S MacDonald-Dickinson 19, Paul R Hess 20, Aswini Cherukuri 21, Antonia Rotolo 22, Jessica A Beck 21, Sushant Patkar 23, Christina Mazcko 21, Amy K LeBlanc 21
Affiliations
- PMID: 39955616
- PMCID: PMC11997493
- DOI: 10.1016/j.ymthe.2025.02.023
Multicenter Study
Immunological responses and clinical outcomes in dogs with osteosarcoma receiving standard therapy and a Listeria vaccine expressing HER2
Nicola J Mason et al. Mol Ther. 2025.
Abstract
A clinical trial in dogs with spontaneous osteosarcoma was performed to assess a recombinant Listeria expressing a chimeric human HER2 (ADXS31-164c) as an adjunctive vaccine strategy to prevent metastatic disease and determine immunological correlates of clinical outcome. A total of 118 dogs with appendicular osteosarcoma were recruited into a 1-arm, multicenter, prospective trial of standard of care (SOC) therapy followed by ADXS31-164c. ADXS31-164c was well tolerated, with mostly transient, low-grade side effects. Significant differences in median disease-free interval (DFI) or median overall survival (OS) of immunized dogs compared to a historical cohort of dogs receiving SOC only were not observed. Elite survivors (DFI >490 days) showed transient increases in temperature and serum cytokines, including IL-6 and TNF-α, after the first immunization compared to short-term survivors (DFI 150-235 days). However, repeat immunizations in short-term survivors led to improved and comparable pyrexic and cytokine responses to elite survivors. PBMC transcriptomic analysis following vaccinations revealed robust cytotoxic activity in elite but not short-term survivors. Although ADXS31-164c did not significantly extend DFI or OS, immune responses to ADXS31-164c distinguished elite from short-term survivors. Improvement of immune responses over sequential ADXS31-164c administrations supports a future trial design of recurrent immunizations to improve outcomes of otherwise short-term survivors.
Keywords: HER2/neu; Listeria vector; correlative biomarkers; dog; immunotherapy; large animal model; osteosarcoma; pre-clinical study; vaccine.
Copyright © 2025. Published by Elsevier Inc.
Conflict of interest statement
Declaration of interests N.J.M. is an inventor on US Patent Nos. US20150297702A1 “Compositions and methods for prevention of escape mutation in the treatment of Her2/neu over-expressing tumors” and CA2940646A1 “Compositions and methods for the treatment of HER2 over-expressing tumors.”
Figures
Graphical abstract
Figure 1
Overview of canine patient enrollment and outcomes in COTC026 vs. COTC022 within the ITT population ITT, intent-to-treat; PD, progressive disease.
Figure 2
Comparison of clinical outcomes of ITT dogs enrolled in SOC (COTC022) vs. SOC+ADXS31-164 (COTC026) (A) Disease-free interval (DFI): SOC+ADXS31-164 = 217 days (95% CI, 180–268 days) vs. SOC only = 180 days (95% CI, 140–231 days; p = 0.33). (B) Survival: ADXS31-164 = 341 days (95% CI, 276–482 days) vs. SOC = 282 days (95% CI, 224–383 days; p = 0.1).
Figure 3
Tumor microenvironment profiling of primary tumor samples derived from COTC026 clinical trial (A) Heatmap depicting MCP-counter-derived tumor microenvironment (TME) profiles of primary tumor samples from canine osteosarcoma patients. Each sample is classified into distinct TME subtypes based on MCP-counter-estimated cellular abundances (see materials and methods). (B) Kaplan-Meier depicting DFIs of COTC026 canine patients based on their inferred primary tumor TME subtype. The statistical significance of survival differences between different survival groups was estimated using the log rank test. ID, immune desert; IE, immune enriched; IE-ECM, immune and extracellular matrix enriched. (C) Normalized expression distribution of HER2 in each TME subtype. Statistical significance between groups was estimated using the pairwise Wilcox rank-sum test.
Figure 4
Pyrexic response to sequential ADXS31-164 vaccinations in elite and short-term responders Baseline (pre) and 4-h post (post) ADXS31-164 rectal temperatures were taken at each ADXS31-164 administration. (A) Elite survivors and (B) short-term survivors. Results were analyzed using a repeated-measures one-way ANOVA. ns, not significant; ∗p < 0.05; ∗∗p < 0.01; ∗∗∗p < 0.001.
Figure 5
Change in serum cytokine levels in elite and short-term survivors after ADXS31-164 administration Baseline and 4 h post ADXS31-164 serum cytokine concentrations were measured and the delta for each cytokine was plotted for elite and short-term survivors at the first (V#1) and third (V#3) ADXS31-164 administration. Results are analyzed using a two-tailed, paired t test (Wilcoxon test). ns, not significant; ∗∗p < 0.01; ∗∗∗p < 0.001;∗∗∗∗p < 0.0001.
Figure 6
Transcriptomic data from PBMCs of elite and short-term survivors following three doses of ADXS31-164 RNA extracted from cryopreserved PBMCs (taken at week 15 prior to ADXS31–164 and week 23, 2 weeks after the last ADXS31-164 administration) of elite and short-term survivors was subject to NanoString transcriptional profiling. (A) Volcano plot of DEGs from elite survivors (n = 21). (B) Volcano plot of DEGs from short-term survivors (n = 22). DEGs are defined as those genes showing greater than or less than 2-fold change over baseline (week 15). DEGs, differentially expressed genes.
References
- Chou A.J., Geller D.S., Gorlick R. Therapy for osteosarcoma: where do we go from here? Paediatr. Drugs. 2008;10:315–327. -PubMed
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