September 09, 2017

Moving Closer to Immunotherapy for Canine Cancer

Veterinary oncology could be getting a step closer to using immunotherapy, given the safety and efficacy of a newly identified canine chimeric monoclonal antibody.
By JoAnna Pendergrass, DVM
Targeting immune checkpoint molecules like programmed cell death 1 (PD-1) has recently gained traction in human oncology. PD-1 is a cell surface receptor that suppresses T-cell function after binding to its ligand, PD-L1.

Previous studies have reported that blocking this binding can restore antigen-specific T-cell effector functions and ultimately induce cancer remission. Notably, the safety and efficacy of an anti–PD-1 antibody has improved treatment options for several human cancers.

However, in veterinary oncology, such immunotherapy is not currently available, limiting systemic treatment options for control of metastatic disease.

Previous veterinary studies have tested molecular-targeted antibodies for canine cancer treatment. However, rat monoclonal antibodies (mAbs) are immunogenic in dogs, posing a therapeutic challenge. A canine-chimerized antibody, though, reduces immunogenicity while conserving binding affinity.

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In the current study, published in Nature Scientific Reports, a Japanese research team developed a canine chimeric monoclonal antibody that targeted PD-L1 and demonstrated notable antitumor activity.

Selecting the Antibody
The researchers first identified 2 rat anti–PD-L1 mAbs (6G7, 4G12) that effectively blocked PD-L1. The canine-chimerized 4G12 (c4G12) demonstrated superior blocking of PD-1/PD-L1 binding and was selected for further evaluation.

Assessing c4G12 Immunomodulatory Function
Next, the researchers obtained peripheral blood mononuclear cells (PBMCs) from 7 healthy dogs. They then stimulated the cells with a superantigen, with or without c4G12 present. Compared with the control antibody, c4G12 treatment significantly enhanced PBMC production of interleukin-2 and interferon-γ, and significantly increased helper and cytotoxic T-cell proliferation.

“c4G12 appeared to restore the effector function of dog lymphocytes” that are suppressed by PD-1/PD-L1 binding, concluded the researchers.

Evaluating Safety and Efficacy
For a pilot clinical study, the researchers selected 7 dogs with oral malignant melanoma (OMM) and 2 with undifferentiated sarcoma; all but 1 dog had received prior surgical or radiation therapy.

OMM, which is highly invasive and metastatic, was staged at baseline using the TNM staging method. The researchers noted that current systemic treatment for metastatic (stage IV) OMM is ineffective, underscoring the need for better therapeutic options.

All dogs were treated with bi-weekly intravenous c4G12. Routine blood work and body surface lesion measurement were performed every 2 weeks. Tumor burden and metastases were assessed using computed tomography at baseline and every 6 weeks. Tumor response was determined according to percent reduction in tumor diameter:
  • Complete response (CR): 100% reduction
  • Partial response (PR): ≥30% reduction
  • Stable disease (SD): <20% increase or <30% reduction
  • Progressive disease (PD): ≥20% increase
One of 7 dogs with OMM experienced tumor reduction. This dog, which had stage 2 OMM, experienced an 81% reduction in tumor size; the other 6 dogs had observable PD. The objective response rate (CR + PR) for OMM was 14%, which was consistent with a previous human study that evaluated anti–PD-L1 mAb melanoma treatment. One of 2 dogs with undifferentiated sarcoma experienced tumor reduction (34%).

c4G12 treatment was well tolerated, with no reports of allergic reactions, autoimmune disease, or systemic toxicity. Reported adverse events were considered unrelated to treatment.

Compared with the survival duration of a previous set of dogs with stage IV OMM receiving standard therapy, the pilot study’s 4 dogs with stage IV OMM had a nonsignificantly shorter median survival duration (54 vs 93.5 days).

Looking Forward
The study’s findings suggest the potential of c4G12 for treating canine cancers expressing PD-L1, yet further clinical studies will be needed to fully evaluate c4G12’s clinical benefits, the researchers noted. Antibody chimerization for the development of therapeutic mAbs for dogs will also need further study.

 
Dr. Pendergrass received her Doctor of Veterinary Medicine degree from the Virginia-Maryland College of Veterinary Medicine. Following veterinary school, she completed a postdoctoral fellowship at Emory University’s Yerkes National Primate Research Center. Dr. Pendergrass is the founder and owner of JPen Communications, a medical communications company.

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