A monoclonal antibody targeting programmed cell death‐1 (PD‐1) is one of the most promising treatments for human cancers. Clinical studies in humans demonstrated that the anti‐PD‐1 antibody provides a long‐lasting tumour response. Previously, we established an anti‐canine PD‐1 therapeutic antibody (ca‐4F12‐E6), and the pilot clinical study demonstrated that the antibody was effective in dogs with oral malignant melanoma (OMM). However, two OMM cases were still undergoing treatment when the pilot study was published. Here, we describe the long‐term follow‐up of those two cases. Although both cases showed long‐term survival with complete response (CR), the tumour response differed; the effect onset was slow in one case and a durable response was observed in the second case even after treatment discontinuation. Secondary malignant tumours occurred during treatment in both cases. This follow‐up study revealed that ca‐4F12‐E6 maintains CR in dogs for more than 1 year. In addition, the pattern of tumour response was unique compared to conventional therapy. These results indicate that new evaluation criteria for tumour response may be necessary for immunotherapy in veterinary medicine. Long‐term follow‐up is necessary regardless of the short‐term treatment responsiveness.
The DNA mismatch repair (MMR) system preserves genomic stability by identifying and repairing mismatched nucleotides in the DNA replication process. The dysfunction of the MMR system, also known as mismatch repair deficiency (dMMR), is implicated as a predictive biomarker for the efficacy of immune checkpoint blockade therapy regardless of the tumor type in humans. This study aimed to evaluate the immunolabeling of MMR proteins in canine tumors and to identify the types of tumors having dMMR. First, we performed immunohistochemistry in 8 different canine tumors (oral malignant melanoma, high-to-intermediate grade lymphoma, mast cell tumor, malignant mammary gland tumor, urothelial carcinoma, hepatocellular carcinoma, osteosarcoma, and hemangiosarcoma) with 15 samples each to analyze the immunolabeling of canine mismatch repair proteins (MSH2, MSH6, and MLH1) using anti-human monoclonal antibodies. We found that more than half of canine oral malignant melanoma (60%) and hepatocellular carcinoma (53%) samples and fewer of the other canine tumors had loss of immunolabeling in ≥1 MMR protein (ie, evidence of defective MMR proteins, based on the definition of dMMR in the humans). Antibodies against human MSH2, MSH6, and MLH1 were cross-reactive with the corresponding canine protein as confirmed using MMR gene knockout canine cell lines. Further studies are required to investigate the clinical outcomes in canine spontaneous tumors with dMMR to determine the potential for immune checkpoint blockade therapy for these tumor types.
Background: Microsatellite instability (MSI) is a type of genomic instability caused by mismatch repair deficiency (dMMR) in tumors. Studies on dMMR/MSI are limited, and the relationship between dMMR and MSI is unknown in tumors of dogs.Objectives: We aimed to identify the frequency of dMMR/MSI by tumor type and evaluate the relationship between dMMR and MSI in tumors of dogs.Animals: In total, 101 dogs with 11 types of malignant tumors were included.Methods: We extracted DNA from fresh normal and tumor tissues. Twelve microsatellite loci from both normal and tumor DNA were amplified by PCR and detected by capillary electrophoresis. Each microsatellite (MS) was defined as MSI if a difference in product size between the tumor and normal DNA was detected. The dMMR was evaluated by immunohistochemistry with formalin-fixed paraffin-embedded tumor tissues. Next, we confirmed whether dMMR induces MSI by serial passaging of MMR gene knockout cell lines for 3 months.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.