Anti-CTLA-4 antibody treatment effective for canine cancer

A research group led by Specially Appointed Assistant Professor Naoya Maekawa and Professor Satoru Konnai from the Graduate School of Veterinary Medicine, Hokkaido University, Associate Professor Takeshi Nakanishi and Professor Taro Tachibana from the Graduate School of Engineering, Osaka Metropolitan University, and Professor Yukinari Kato from the Graduate School of Medicine, Tohoku University has developed an antibody drug that inhibits canine immune checkpoint molecules (CTLA-4) and confirmed that it provides anti-tumor effects against advanced malignant tumors in dogs. All 12 dogs used in the experiment had previously received anti-PD-L1 antibody monotherapy and showed tumor progression. Although some adverse events were observed, they were within acceptable limits for therapeutic use. The study demonstrated that combination therapy with anti-CTLA-4 antibodies may be effective even in dogs that have developed resistance to anti-PD-L1 antibodies. The results were published in the international academic journal Frontiers in Immunology on May 20.

Recent advances in veterinary medicine have led to longer lifespans for pets, but aging has been accompanied by increased incidence of cancer (malignant tumors). Tumors cause approximately 30% of canine deaths.

Canine cancer treatment is generally performed through surgical resection, radiation therapy, and chemotherapy (anticancer drug treatment), but many cases do not achieve a complete cure. In human medicine, in addition to these treatments, immunotherapy using immune checkpoint inhibitors has been expanding.

The research group had previously developed the world's first immunotherapy for canine cancer using anti-PD-L1 antibodies and demonstrated its effectiveness through clinical trials at the Hokkaido University Veterinary Teaching Hospital and other facilities. However, while this treatment showed effects against advanced malignant tumors, tumor regression was observed in only some dogs. Further innovations including combination therapies were considered necessary.

Cancer cells are normally attacked by the immune system, but some acquire mechanisms to evade (suppress) immunity. When a protein called PD-L1 binds to cancer cells, immune cells stop attacking the cancer cells. However, by inhibiting these bindings, anti-tumor immunity can be activated (immunotherapy). Because PD-1 and PD-L1 play important roles in regulating immune responses, they are called immune checkpoint molecules, and drugs targeting them are called immune checkpoint inhibitors.

In this study, the researchers developed a new anti-CTLA-4 antibody that binds to canine CTLA-4 and inhibits its immunosuppressive action, and examined its effects in canine immune cell culture systems. The anti-CTLA-4 antibody was found to enhance cytokine production and show immune activation effects even when used alone. When combined with anti-PD-L1 antibodies, it demonstrated higher immune activation effects than either antibody alone.

In actual dogs, treatment-related adverse events were confirmed in 4 out of 12 dogs (33%) that received combination therapy, with 3 dogs (25%) classified as Grade 3 (severe). However, these were similar to reports in humans and were considered to be within acceptable limits for therapeutic use.

Of the 6 dogs whose treatment effects were evaluated, 5 showed tumor progression, but 1 showed tumor regression and was judged to have achieved a partial response.

Conscious of human drug development

Konnai commented: "Our research group has previously reported that immune checkpoint inhibitors can bring about tumor regression in dogs, but, similar to humans, the dogs that achieve responses remain limited. We are currently working on various research approaches to improve their efficacy, and this time we were able to confirm that combining them with CTLA-4 antibodies is effective. Naturally occurring tumors and infectious diseases in animals share many similarities with human diseases, and it is possible to conduct various clinical studies as therapeutic models for human diseases. The Graduate School of Veterinary Medicine at Hokkaido University plans to continue developing applied research that is conscious of bridging research for human drug development."

Journal Information
Publication: Frontiers in Immunology
Title: Development of caninized anti-CTLA-4 antibody as salvage combination therapy for anti-PD-L1 refractory tumors in dogs
DOI: 10.3389/fimmu.2025.1570717