Long‐term survival of dogs with stage 4 oral malignant melanoma treated with anti‐canine <scp>PD</scp>‐1 therapeutic antibody: A follow‐up case report

Igase, Masaya; Inanaga, Sakuya; Tani, Kenji; Nakaichi, Munekazu; Sakai, Yusuke; Sakurai, Masashi; Kato, Masahiro; Tsukui, Toshihiro; Mizuno, Takuya

doi:10.1111/vco.12829

Cited by 19 publications

(12 citation statements)

References 30 publications

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“…Recently, a pan-cancer, T-cell-inflamed 18-gene signature indicative of a T-cell-activated tumor microenvironment was reported to be associated with response to PD-1 immune checkpoint blockade, including patients with HNSCC ( 70 , 71 ). A canine anti-PD-1 therapeutic antibody has been developed and a pilot study investigating its safety and efficacy in treating dogs with a variety of spontaneous cancers demonstrated encouraging results, supporting further comparative investigation of this immunotherapy ( 72 , 73 ). Moving forward, investigation of this human T-cell-inflamed gene expression profile in dogs with T cell targeted immunotherapies may also be useful.…”

Section: Discussionmentioning

confidence: 91%

Canine oral squamous cell carcinoma as a spontaneous, translational model for radiation and immunology research

et al. 2023

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IntroductionImproving outcomes for oral squamous cell carcinoma (OSCC) patients has been hindered by a lack of effective predictive animal models. Spontaneously occurring canine OSCC could help fill this gap. The objective of this study was to characterize the immune landscape of canine OSCC to advance understanding of how dogs could serve as a surrogate for human OSCC.Methods/ResultsCanine OSCC contains a heterogenous tumor immune microenvironment. CD3+ T cells were the predominant tumor infiltrating immune cell population; however, there was a wide range CD3+ T cell density across samples. The most common CD3+ T cell micro-anatomical distribution was defined as “pre-existing immunity”, but the remaining 20% of tumors were characterized as “immunologically ignorant” or “excluded infiltrates” patterns. When compared to normal oral mucosa, the tumor gene expression pattern suggests that canine OSCC microenvironment is highly inflamed and characterized by the presence of an anti-tumor immune response dominated by cytotoxic\effector T cells and NK cells (CD8a, GZMA, OX40, and HLA-A); however, overexpression of genes associated with effector T cell exhaustion and microenvironmental immunosuppression was also identified (PD-1, LAG3, CXCL2). Correlations between CD3+ T cell density and immune gene expression revealed key genes associated with cytotoxic anti-tumor T cell responses (GZMA, GZMB, PRF1), co-stimulation of T cells (CD27, CD28, ICOS), and other immune processes, including Type I IFN response (TNF, TNFSF10), and T cell exhaustion (CTLA4, PD-1). CD3+ T cell density in canine OSCC was significantly correlated with a cytolytic activity score (mean PRF1 and GZMA expression), suggestive of active effector CD8 T cell function. CD204+ macrophages were the second most abundant tumor infiltrating immune cell, and when comparing to normal oral mucosa, two differently expressed genes linked to tumor associated macrophages and myeloid derived suppressor cells (MDSC) were identified: CXCL2, CD70. Overexpression of CXCL2 was also identified in canine OSCC “T cell-high” tumors compared to “T cell-low” tumors.DiscussionThis study identified actionable immunotherapy targets which could inform future comparative oncology trials in canine OSCC: CTLA-4, PD-1, CXCL2. These data provide a good first step towards utilizing spontaneous canine OSCC as a comparative model for human OSCC radiation and immuno-oncology research.

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Section: Discussionmentioning

confidence: 91%

Canine oral squamous cell carcinoma as a spontaneous, translational model for radiation and immunology research

et al. 2023

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“…Clinical pilot studies used chimeric or caninized anti-canine PD-1 antibodies and the chimeric anti-canine PD-L1 antibody in dogs with advanced tumors [ 4 11 12 ]; most of those were OMM cases. Our previous studies produced rat-canine chimeric anti-canine PD-1 antibody (ch-4F12-E6) and caninized anti-canine PD-1 therapeutic antibody (ca-4F12-E6) and confirmed that these antibodies can block the binding between canine PD-1 and canine PD-L1 molecules followed by T cell re-activation [ 11 13 ]. We investigated the safety profile and efficacy in 30 dogs with advanced tumors, including OMM (21 cases), mammary gland tumor (MGT, 1 case), SCC (2 cases), renal cell carcinoma (1 case), lymphoma (1 case), sebaceous carcinoma (1 case), lung adenocarcinoma (1 case), and skin melanoma (2 cases), after the safety examination of those antibodies against healthy beagles.…”

Section: Introductionmentioning

confidence: 92%

Proof-of-concept study of the caninized anti-canine programmed death 1 antibody in dogs with advanced non-oral malignant melanoma solid tumors

Igase,

Inanaga,

Nishibori

et al. 2024

J Vet Sci

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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.

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“…More recently, veterinary medicine has been focusing in the expression and functional analysis of these immune checkpoint molecules and their usefulness as therapeutic targets in animals 22 . In dogs, mAbs against PD-1/PD-L1 have been developed 23 – 25 , some of which have shown therapeutic efficacy in clinical trials 26 – 29 .…”

Section: Introductionmentioning

confidence: 99%

Development of anti-feline PD-1 antibody and its functional analysis

NISHIBORI

Kaneko

Nakagawa

et al. 2023

Sci Rep

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Antibodies against immune checkpoint molecules restore T-cell function by inhibiting the binding of PD-1 and PD-L1 and have been shown to exert therapeutic effects in various human cancers. However, to date, no monoclonal antibody that recognizes feline PD-1 or PD-L1 has been reported, and there are many unknowns regarding the expression of immune checkpoint molecules and their potential as therapeutic targets in cats. Here we developed anti-feline PD-1 monoclonal antibody (1A1-2), and found that the monoclonal antibody against anti-canine PD-L1 (G11-6), which was previously developed in our laboratory, cross-reacted with feline PD-L1. Both antibodies inhibited the interaction of feline PD-1 and feline PD-L1 in vitro. These inhibitory monoclonal antibodies augmented the interferon-gamma (IFN-γ) production in activated feline peripheral blood lymphocytes (PBLs). Furthermore, for clinical application in cats, we generated a mouse-feline chimeric mAb by fusing the variable region of clone 1A1-2 with the constant region of feline IgG1 (ch-1A1-2). Ch-1A1-2 also augmented the IFN-γ production in activated feline PBLs. From this study, 1A1-2 is first anti-feline PD-1 monoclonal antibody with the ability to inhibit the interaction of feline PD-1 and PD-L1, and the chimeric antibody, ch-1A1-2 will be a beneficial therapeutic antibody for feline tumors.

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Long‐term survival of dogs with stage 4 oral malignant melanoma treated with anti‐canine PD‐1 therapeutic antibody: A follow‐up case report

Cited by 19 publications

References 30 publications

Canine oral squamous cell carcinoma as a spontaneous, translational model for radiation and immunology research

Canine oral squamous cell carcinoma as a spontaneous, translational model for radiation and immunology research

Proof-of-concept study of the caninized anti-canine programmed death 1 antibody in dogs with advanced non-oral malignant melanoma solid tumors

Development of anti-feline PD-1 antibody and its functional analysis

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