Developing a translational murine‐to‐canine pathway for an IL‐2/agonist anti‐CD40 antibody cancer immunotherapy

Abstract

Human and canine sarcomas are difficult to treat soft tissue malignancies with an urgent need for new improved therapeutic options. Local recurrence rates for humans are between 10%–30%, and 30%–40% develop metastases. Outcomes for dogs with sarcoma vary with grade but can be similar. Pet dogs share the human environment and represent human cancer with genetic variation in hosts and tumours. We asked if our murine studies using genetically identical mice and cloned tumour cells were translatable to larger, genetically diverse domestic dogs with naturally occurring tumours, to (i) develop a canine cancer therapeutic, and (ii) to use as a translational pathway to humans. Our murine studies showed that intra‐tumoral delivery of interleukin‐2 (IL‐2) plus an agonist anti‐CD40 antibody (Ab) induces long‐term curative responses ranging from 30% to 100%, depending on tumour type. We developed an agonist anti‐canine‐CD40 Ab and conducted a phase I dose finding/toxicology 3 + 3 clinical trial in dogs (n = 27) with soft tissue sarcomas on account of suitability for intratumoral injection and straightforward monitoring. Dogs were treated with IL‐2 plus anti‐CD40 antibody for 2 weeks. Three dose levels induced tumour regression with minimal side effects, measured by monitoring, haematological and biochemical assays. Importantly, our mouse and canine studies provide encouraging fundamental proof‐of‐concept data upon which we can develop veterinary and human immunotherapeutic strategies.

Assessment of Tumor-Associated Tissue Eosinophilia (TATE) and Tumor-Associated Macrophages (TAMs) in Canine Transitional Cell Carcinoma of the Urinary Bladder

“…Similar to TATE, our results might highlight the significance of immunotherapy, especially in relation to macrophages, such as blockers of CCL2-CCR2 or CCR5-CCL5 axes, macrophage checkpoint inhibitors, among others [23,24,[26][27][28]. However, further studies are needed with a deeper characterization of the macrophage population associated with canine TCC of the bladder (M1, M2, and subpopulations) to better understand and identify effective therapeutic targets.…”

“…Additionally, other methods to re-polarize tumor-associated macrophages (TAMs) have been explored in canine studies. These include using a canine monoclonal agonist antibody against CD40, a macrophage-activating receptor [24], and treatments like paclitaxel, imatinib, BTK inhibitors, and chloroquine [25]. Also, checkpoint inhibitors are promising in veterinary oncology [26][27][28].…”

Tumor-associated macrophages: Prognostic and therapeutic targets for cancer in humans and dogs

“…A clinical benefit was observed in 13 of 19 evaluable dogs at one month, including 2 partial responses. Seven of the 11 dogs with stable disease at one month continued to have stable disease for at least 50 days ( 197 ). As mentioned above, paclitaxel, imatinib, and BTK inhibitors can repolarize TAMs, and have been used in companion dogs with cancer ( 298 – 301 ).…”