Journal of Veterinary Science

The Korean Society of Veterinary Science (대한수의학회)
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Proof-of-concept study of the caninized anti-canine programmed death 1 antibody in dogs with advanced non-oral malignant melanoma solid tumors

  • Masaya Igase (Laboratory of Molecular Diagnostics and Therapeutics, The United Graduate School of Veterinary Medicine, Yamaguchi University) ;
  • Sakuya Inanaga (Laboratory of Molecular Diagnostics and Therapeutics, The United Graduate School of Veterinary Medicine, Yamaguchi University) ;
  • Shoma Nishibori (Laboratory of Molecular Diagnostics and Therapeutics, The United Graduate School of Veterinary Medicine, Yamaguchi University) ;
  • Kazuhito Itamoto (Laboratory of Veterinary Small Animal Clinical Science, Joint Faculty of Veterinary Medicine, Yamaguchi University) ;
  • Hiroshi Sunahara (Laboratory of Veterinary Surgery, Joint Faculty of Veterinary Medicine, Yamaguchi University) ;
  • Yuki Nemoto (Laboratory of Veterinary Surgery, Joint Faculty of Veterinary Medicine, Yamaguchi University) ;
  • Kenji Tani (Laboratory of Veterinary Surgery, Joint Faculty of Veterinary Medicine, Yamaguchi University) ;
  • Hiro Horikirizono (Laboratory of Veterinary Radiology, Joint Faculty of Veterinary Medicine, Yamaguchi University) ;
  • Munekazu Nakaichi (Laboratory of Veterinary Radiology, Joint Faculty of Veterinary Medicine, Yamaguchi University) ;
  • Kenji Baba (Laboratory of Veterinary Internal Medicine, Joint Faculty of Veterinary Medicine, Yamaguchi University) ;
  • Satoshi Kambayashi (Laboratory of Veterinary Internal Medicine, Joint Faculty of Veterinary Medicine, Yamaguchi University) ;
  • Masaru Okuda (Laboratory of Veterinary Internal Medicine, Joint Faculty of Veterinary Medicine, Yamaguchi University) ;
  • Yusuke Sakai (Laboratory of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Yamaguchi University) ;
  • Masashi Sakurai (Laboratory of Veterinary Pathology, Joint Faculty of Veterinary Medicine, Yamaguchi University) ;
  • Masahiro Kato (Nippon Zenyaku Kogyo Co., Ltd.) ;
  • Toshihiro Tsukui (Nippon Zenyaku Kogyo Co., Ltd.) ;
  • Takuya Mizuno (Laboratory of Molecular Diagnostics and Therapeutics, The United Graduate School of Veterinary Medicine, Yamaguchi University)
  • Received : 2023.06.05
  • Accepted : 2023.12.17
  • Published : 2024.01.31
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Abstract

Background: The anti-programmed death 1 (PD-1) antibody has led to durable clinical responses in a wide variety of human tumors. We have previously developed the caninized anti-canine PD-1 antibody (ca-4F12-E6) and evaluated its therapeutic properties in dogs with advance-staged oral malignant melanoma (OMM), however, their therapeutic effects on other types of canine tumors remain unclear. Objective: The present clinical study was carried out to evaluate the safety profile and clinical efficacy of ca-4F12-E6 in dogs with advanced solid tumors except for OMM. Methods: Thirty-eight dogs with non-OMM solid tumors were enrolled prospectively and treated with ca-4F12-E6 at 3 mg/kg every 2 weeks of each 10-week treatment cycle. Adverse events (AEs) and treatment efficacy were graded based on the criteria established by the Veterinary Cooperative Oncology Group. Results: One dog was withdrawn, and thirty-seven dogs were evaluated for the safety and efficacy of ca-4F12-E6. Treatment-related AEs of any grade occurred in 13 out of 37 cases (35.1%). Two dogs with sterile nodular panniculitis and one with myasthenia gravis and hypothyroidism were suspected of immune-related AEs. In 30 out of 37 dogs that had target tumor lesions, the overall response and clinical benefit rates were 6.9% and 27.6%, respectively. The median progression-free survival and overall survival time were 70 days and 215 days, respectively. Conclusions: The present study demonstrated that ca-4F12-E6 was well-tolerated in non-OMM dogs, with a small number of cases showing objective responses. This provides evidence supporting large-scale clinical trials of anti-PD-1 antibody therapy in dogs.

Keywords

Acknowledgement

The authors would like to acknowledge the all YUAMEC clinical staff and the laboratory members for helping us succeed in the present study. Finally, we thank the dogs and their owners for making this study possible.

References

  1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252-264. https://doi.org/10.1038/nrc3239
  2. Twomey JD, Zhang B. Cancer immunotherapy update: FDA-approved checkpoint inhibitors and companion diagnostics. AAPS J. 2021;23(2):39.
  3. Marcus L, Lemery SJ, Keegan P, Pazdur R. FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin Cancer Res. 2019;25(13):3753-3758. https://doi.org/10.1158/1078-0432.CCR-18-4070
  4. Maekawa N, Konnai S, Nishimura M, Kagawa Y, Takagi S, Hosoya K, et al. PD-L1 immunohistochemistry for canine cancers and clinical benefit of anti-PD-L1 antibody in dogs with pulmonary metastatic oral malignant melanoma. NPJ Precis Oncol. 2021;5(1):10.
  5. Maekawa N, Konnai S, Okagawa T, Nishimori A, Ikebuchi R, Izumi Y, et al. Immunohistochemical analysis of PD-L1 expression in canine malignant cancers and PD-1 expression on lymphocytes in canine oral melanoma. PLoS One. 2016;11(6):e0157176.
  6. Shosu K, Sakurai M, Inoue K, Nakagawa T, Sakai H, Morimoto M, et al. Programmed cell death ligand 1 expression in canine cancer. In Vivo. 2016;30(3):195-204.
  7. Pinard CJ, Hocker SE, Poon AC, Inkol JM, Matsuyama A, Wood RD, et al. Evaluation of PD-1 and PD-L1 expression in canine urothelial carcinoma cell lines. Vet Immunol Immunopathol. 2022;243:110367.
  8. Nemoto Y, Shosu K, Okuda M, Noguchi S, Mizuno T. Development and characterization of monoclonal antibodies against canine PD-1 and PD-L1. Vet Immunol Immunopathol. 2018;198:19-25. https://doi.org/10.1016/j.vetimm.2018.02.007
  9. Choi JW, Withers SS, Chang H, Spanier JA, De La Trinidad VL, Panesar H, et al. Development of canine PD-1/PD-L1 specific monoclonal antibodies and amplification of canine T cell function. PLoS One. 2020;15(7):e0235518.
  10. Pinard CJ, Stegelmeier AA, Bridle BW, Mutsaers AJ, Wood RD, Wood GA, et al. Evaluation of lymphocyte-specific programmed cell death protein 1 receptor expression and cytokines in blood and urine in canine urothelial carcinoma patients. Vet Comp Oncol. 2022;20(2):427-436. https://doi.org/10.1111/vco.12788
  11. Igase M, Nemoto Y, Itamoto K, Tani K, Nakaichi M, Sakurai M, et al. A pilot clinical study of the therapeutic antibody against canine PD-1 for advanced spontaneous cancers in dogs. Sci Rep. 2020;10(1):18311.
  12. Maekawa N, Konnai S, Takagi S, Kagawa Y, Okagawa T, Nishimori A, et al. A canine chimeric monoclonal antibody targeting PD-L1 and its clinical efficacy in canine oral malignant melanoma or undifferentiated sarcoma. Sci Rep. 2017;7(1):8951.
  13. Igase M, Inanaga S, Tani K, Nakaichi M, Sakai Y, Sakurai M, et al. Long-term survival of dogs with stage 4 oral malignant melanoma treated with anti-canine PD-1 therapeutic antibody: a follow-up case report. Vet Comp Oncol. 2022;20(4):901-905. https://doi.org/10.1111/vco.12829
  14. LeBlanc AK, Atherton M, Bentley RT, Boudreau CE, Burton JH, Curran KM, et al. Veterinary Cooperative Oncology Group-Common Terminology Criteria for Adverse Events (VCOG-CTCAE v2) following investigational therapy in dogs and cats. Vet Comp Oncol. 2021;19(2):311-352. https://doi.org/10.1111/vco.12677
  15. Nguyen SM, Thamm DH, Vail DM, London CA. Response evaluation criteria for solid tumours in dogs (v1.0): a Veterinary Cooperative Oncology Group (VCOG) consensus document. Vet Comp Oncol. 2015;13(3):176-183. https://doi.org/10.1111/vco.12032
  16. Inanaga S, Igase M, Sakai Y, Hagimori K, Sunahara H, Horikirizono H, et al. Relationship of microsatellite instability to mismatch repair deficiency in malignant tumors of dogs. J Vet Intern Med. 2022;36(5):1760-1769. https://doi.org/10.1111/jvim.16454
  17. Sakai O, Ii T, Uchida K, Igase M, Mizuno T. Establishment and characterization of monoclonal antibody against canine CD8 alpha. Monoclon Antib Immunodiagn Immunother. 2020;39(4):129-134. https://doi.org/10.1089/mab.2020.0002
  18. Martins F, Sofiya L, Sykiotis GP, Lamine F, Maillard M, Fraga M, et al. Adverse effects of immune-checkpoint inhibitors: epidemiology, management and surveillance. Nat Rev Clin Oncol. 2019;16(9):563-580. https://doi.org/10.1038/s41571-019-0218-0
  19. Singh P, Wolfe SP, Alloo A, Gottesman SP. Interstitial granulomatous dermatitis and granulomatous arteritis in the setting of PD-1 inhibitor therapy for metastatic melanoma. J Cutan Pathol. 2020;47(1):65-69. https://doi.org/10.1111/cup.13562
  20. Trinidad C, Nelson KC, Glitza Oliva IC, Torres-Cabala CA, Nagarajan P, Tetzlaff MT, et al. Dermatologic toxicity from immune checkpoint blockade therapy with an interstitial granulomatous pattern. J Cutan Pathol. 2018;45(7):504-507. https://doi.org/10.1111/cup.13150
  21. Harper A, Blackwood L, Mason S. Investigation of thyroid function in dogs treated with the tyrosine kinase inhibitor toceranib. Vet Comp Oncol. 2020;18(3):433-437. https://doi.org/10.1111/vco.12538
  22. Figueroa-Perez N, Kashyap R, Bal D, Anjum Khan S, Pattan V. Autoimmune myasthenia, primary adrenal insufficiency, and progressive hypothyroidism due to pembrolizumab and axitinib combination regimen. Cureus. 2021;13(8):e16933.
  23. Callahan MK, Wolchok JD. Recruit or reboot? How does anti-PD-1 therapy change tumor-infiltrating lymphocytes? Cancer Cell. 2019;36(3):215-217. https://doi.org/10.1016/j.ccell.2019.08.009
  24. Havel JJ, Chowell D, Chan TA. The evolving landscape of biomarkers for checkpoint inhibitor immunotherapy. Nat Rev Cancer. 2019;19(3):133-150. https://doi.org/10.1038/s41568-019-0116-x
  25. Seymour L, Bogaerts J, Perrone A, Ford R, Schwartz LH, Mandrekar S, et al. iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol. 2017;18(3):e143-e152. https://doi.org/10.1016/S1470-2045(17)30074-8
  26. Tazdait M, Mezquita L, Lahmar J, Ferrara R, Bidault F, Ammari S, et al. Patterns of responses in metastatic NSCLC during PD-1 or PDL-1 inhibitor therapy: Comparison of RECIST 1.1, irRECIST and iRECIST criteria. Eur J Cancer. 2018;88:38-47.  https://doi.org/10.1016/j.ejca.2017.10.017