Canine brain tumours: a model for the human disease?

Hicks, Jill; Platt, Simon R.; Kent, Marc; Haley, Allison

doi:10.1111/vco.12152

Cited by 65 publications

(52 citation statements)

References 152 publications

(252 reference statements)

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“…Strong similarities have been shown between the canine and human genome, especially with respect to gene families associated with cancer. These combined factors suggest cancer in companion dogs as a viable model for preclinical human cancer research including brain tumors (38)(39)(40)). Because of our success in the canine CD200 trial (41), the human CD200AR-L, P4A10, most analogous to the canine CD200AR-L, was initially selected for a human phase I trial.…”

Section: Discussionmentioning

confidence: 99%

CD200 Checkpoint Reversal: A Novel Approach to Immunotherapy

Xiong

Mesias

Pluhar

et al. 2020

Clinical Cancer Research

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◥ Purpose: Advances in immunotherapy have revolutionized care for some patients with cancer. However, current checkpoint inhibitors are associated with significant toxicity and yield poor responses for patients with central nervous system tumors, calling into question whether cancer immunotherapy can be applied to glioblastoma multiforme. We determined that targeting the CD200 activation receptors (CD200AR) of the CD200 checkpoint with a peptide inhibitor (CD200AR-L) overcomes tumor-induced immunosuppression. We have shown the clinical efficacy of the CD200AR-L in a trial in companion dogs with spontaneous high-grade glioma. Addition of the peptide to autologous tumor lysate vaccines significantly increased the median overall survival to 12.7 months relative to tumor lysate vaccines alone, 6.36 months.Experimental Design: This study was developed to elucidate the mechanism of the CD200ARs and develop a humanized peptide inhibitor. We developed macrophage cell lines with each of four CD200ARs knocked out to determine their binding specificity and functional response. Using proteomics, we developed humanized CD200AR-L to explore their effects on cytokine/chemokine response, dendritic cell maturation and CMV pp65 antigen response in human CD14 þ cells. GMP-grade peptide was further validated for activity.Results: We demonstrated that the CD200AR-L specifically targets a CD200AR complex. Moreover, we developed and validated a humanized CD200AR-L for inducing chemokine response, stimulating immature dendritic cell differentiation and significantly enhanced an antigen-specific response, and determined that the use of the CD200AR-L downregulated the expression of CD200 inhibitory and PD-1 receptors.Conclusions: These results support consideration of a CD200AR-L as a novel platform for immunotherapy against multiple cancers including glioblastoma multiforme.

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Section: Discussionmentioning

confidence: 99%

CD200 Checkpoint Reversal: A Novel Approach to Immunotherapy

Xiong

Mesias

Pluhar

et al. 2020

Clinical Cancer Research

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“…Radiotherapy (RT) with curative or post‐surgical adjuvant intent began to play a fundamental role in human medicine glioma treatment, with accompanying improvements in survival time and quality of life . Despite the similarities between human and canine gliomas, and the fact that translational clinical canine studies are likely to provide a valuable additional perspective to human and murine studies, few veterinary studies have investigated the subject to date …”

Section: Introductionmentioning

confidence: 99%

Frameless stereotactic radiotherapy alone and combined with temozolomide for presumed canine gliomas

Dolera

Malfassi

Bianchi

et al. 2017

Vet Comparative Oncology

115

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We evaluated stereotactic volume modulated arc radiotherapy (VMAT) for canine gliomas, alone (radiotherapy [RT]) and in combination with temozolomide (RT + TMZ), compared with palliation. Overall and disease-specific survival times were estimated. Thirty dogs were palliated, 22 dogs were treated with RT and 20 with RT + TMZ. Complete and partial responses were observed in 63.2% and 90.9% of patients in the RT and RT + TMZ arms, respectively, that were alive at 1 year. Median survival in the palliation arm was 94 days (95% conformity index [CI] 87÷101). Median survivals of the RT arm (383 days, 95% CI 276÷490) and RT+TMZ arm (420 days, 95% CI 280÷560) were not significantly different (P = .61). Positive correlation with survival was found both for the ratio between target and brain (relative) volume of the tumour of <5% (P = .013) and for a clinical presentation with normal mentation (P = .032). VMAT is feasible and effective for canine brain gliomas. Combining this therapy with TMZ did not elicit any additional improvement in survival time.

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“…These combined factors suggest cancer in companion dogs as a viable model for pre-clinical human cancer research including brain tumors. [37][38][39] Due to the success in the canine CD200 trial, 40 the human CD200AR-L, P4A10, analogous to the canine CD200AR-L, was selected for use in a human phase I trial. However, the charges within this peptide made it difficult to scale up for GMP production.…”

Section: Discussionmentioning

confidence: 99%

CD200 immune checkpoint reversal at the site of tumor vaccine inoculation: A novel approach to glioblastoma immunotherapy

Xiong

Ampudia-Mesias

Pluhar

et al. 2019

Preprint

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Purpose: Advances in immunotherapy have revolutionized care for some cancer patients. However, current checkpoint inhibitors are associated with significant toxicity and yield poor responses for patients with central nervous system tumors, calling into question whether cancer immunotherapy can be applied to glioblastoma multiforme. We determined that targeting the CD200 activation receptors (CD200AR) of the CD200 checkpoint with a peptide inhibitor overcomes tumor-induced immunosuppression. We have shown the clinical efficacy of the peptide inhibitor in a trial in companion dogs with spontaneous high-grade glioma; adding the peptide to autologous tumor lysate vaccines significantly increased overall survival relative to tumor lysate alone (median survival of 12.7 and 6.36 months, respectively).Experimental design: This study was developed to elucidate the mechanism of the CD200ARs and develop a humanized peptide inhibitor. We developed macrophage cell lines with each of four CD200ARs knocked out to determine their binding specificity and functional responses. Using proteomics, we developed humanized peptide inhibitors to explore their effects on cytokine/chemokine response, dendritic cell maturation and CMV pp65 antigen response in CD14 + cells. GMP-grade peptide was further validated for activity. Results:We demonstrated that the peptide specifically targets the CD200AR complex to induce an immune response. Moreover, we developed and validated our humanized peptides for inducing chemokine response, stimulating immature dendritic cell differentiation and significantly enhancing an antigen-specific response. We also determined that the use of the peptide downregulated the expression of CD200 inhibitory and PD-1 receptors. Conclusion:These results support consideration of a CD200 peptide ligand as a novel platform for immunotherapy against multiple cancers including glioblastoma multiforme.Translational relevance. This report evaluates the ability to modulate the CD200 immune checkpoint by employing synthetic peptides directed as ligands to its paired immune activation receptor. We previously reported the presence of CD200 in the sera and tumor vasculature of patients with glioblastoma multiforme (GBM). We have also shown that a canine CD200 activation receptor ligand extends the lives of companion dogs with high grade glioma. The data we present here show that the human peptide ligand (hCD200ARL) directed to the CD200 activation receptor on CD14+ cells activates immune upregulation through induction of a cytokine response and dendritic cell differentiation. In addition, hCD200ARL downregulates the inhibitory CD200 and PD-1 receptors. These findings provide a basis to evaluate hCD200ARL as a novel immune therapy for patients with GBM. Downregulation of PD-1 suggests that hCD200ARL may also obviate the need for PD1 and PD-L1 directed therapies for GBM and other malignancies.

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Canine brain tumours: a model for the human disease?

Cited by 65 publications

References 152 publications

CD200 Checkpoint Reversal: A Novel Approach to Immunotherapy

CD200 Checkpoint Reversal: A Novel Approach to Immunotherapy

Frameless stereotactic radiotherapy alone and combined with temozolomide for presumed canine gliomas

CD200 immune checkpoint reversal at the site of tumor vaccine inoculation: A novel approach to glioblastoma immunotherapy

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