Naturally Occurring Canine Glioma as a Model for Novel Therapeutics

Hubbard, Molly E.; Arnold, Susan A.; Zahid, Abdullah Bin; McPheeters, Matthew T.; O’Sullivan, M. Gerard; Tăbăran, Alexandra; Hunt, Matthew A.; Pluhar, G. Elizabeth

doi:10.1080/07357907.2018.1514622

Cited by 29 publications

(42 citation statements)

References 21 publications

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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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“…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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“…Other canine checkpoint targeted antibodies are also in the pipeline, including PD-L1 and OX40 antibodies. In addition, several small molecule inhibitors of checkpoint molecules are being investigated in clinical tumor vaccine trials in dogs with brain cancer (64)(65)(66).…”

Section: Checkpoint Molecule Targeted Immunotherapiesmentioning

confidence: 99%

A Role for Dogs in Advancing Cancer Immunotherapy Research

Dow

2020

Front. Immunol.

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While rodent cancer models are essential for early proof-of-concept and mechanistic studies for immune therapies, these models have limitations with regards to predicting the ultimate effectiveness of new immunotherapies in humans. As a unique spontaneous, large animal model of cancer, the value of conducting studies in pet dogs with cancer has been increasingly recognized by the research community. This review will therefore summarize key aspects of the dog cancer immunotherapy model and the role that these studies may play in the overall immunotherapy drug research effort. We will focus on cancer types and settings in which the dog model is most likely to impact clinical immuno-oncology research and drug development. Immunological reagent availability is discussed, along with some unique opportunities and challenges associated with the dog immunotherapy model. Overall it is hoped that this review will increase awareness of the dog cancer immunotherapy model and stimulate additional collaborative studies to benefit both man and man's best friend.

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Naturally Occurring Canine Glioma as a Model for Novel Therapeutics

Cited by 29 publications

References 21 publications

CD200 Checkpoint Reversal: A Novel Approach to Immunotherapy

CD200 Checkpoint Reversal: A Novel Approach to Immunotherapy

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

A Role for Dogs in Advancing Cancer Immunotherapy Research

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