Canine cancer immunotherapy studies: linking mouse and human

Abstract

Despite recent major clinical breakthroughs in human cancer immunotherapy including the use of checkpoint inhibitors and engineered T cells, important challenges remain, including determining the sub-populations of patients who will respond and who will experience at times significant toxicities. Although advances in cancer immunotherapy depend on preclinical testing, the majority of in-vivo testing currently relies on genetically identical inbred mouse models which, while offering critical insights regarding efficacy and mechanism of action, also vastly underrepresent the heterogeneity and complex interplay of human immune cells and cancers. Additionally, laboratory mice uncommonly develop spontaneous tumors, are housed under specific-pathogen free conditions which markedly impacts immune development, and incompletely model key aspects of the tumor/immune microenvironment. The canine model represents a powerful tool in cancer immunotherapy research as an important link between murine models and human clinical studies. Dogs represent an attractive outbred combination of companion animals that experience spontaneous cancer development in the setting of an intact immune system. This allows for study of complex immune interactions during the course of treatment while also directly addressing long-term efficacy and toxicity of cancer immunotherapies. However, immune dissection requires access to robust and validated immune assays and reagents as well as appropriate numbers for statistical evaluation. Canine studies will need further optimization of these important mechanistic tools for this model to fulfill its promise as a model for immunotherapy. This review aims to discuss the canine model in the context of existing preclinical cancer immunotherapy models to evaluate both its advantages and limitations, as well as highlighting its growth as a powerful tool in the burgeoning field of both human and veterinary immunotherapy.

Obesity as an immune-modifying factor in cancer immunotherapy

“…For over 100 years, mouse models have been the foundation for basic discoveries in immunology and immunotherapy, and there is no question that mouse models remain fundamentally important today. 32 A fundamental advance in the study of obesity was the discovery/development of mice on the C57BL/6 background lacking the leptin gene (ob/ob mice). 33,34 Without leptin, ob/ob mice eat excessively and become profoundly obese routinely achieving weights of 50-60 grams due to excessive eating and lack of appetite regulation.…”

“…In fact, the parallel evolutionary history of humans and dogs, and the shared exposure of environmental risk factors have led to many similarities in disease prevalence and incidence between humans and dogs. 32,56 In the United States, it is estimated that approximately 25% of dogs are obese. 57 In dogs, obesity is categorized using a body condition score (BCS).…”

From Famine to Feast: Developing Early-Phase Combination Immunotherapy Trials Wisely

“…Another example is the use of companion canines that develop spontaneous tumors in the setting of an intact immune system (27). The advantages of canine models include large population size and tumor and immune system characteristics that are more akin to that of humans compared with rodent models (80). …”

Barking up the right tree: advancing our understanding and treatment of lymphoma with a spontaneous canine model

“…Following the success of anti-CD20 therapeutic antibodies in treating diffuse large B-cell lymphoma in humans, numerous canine specific anti-CD20 monoclonal antibodies are currently in development [40]. Blocking the immune checkpoint CD47/SIRPa together with anti-CD20 immunotherapy elicited an augmented response in xenograft mouse models bearing canine lymphoma [41*].…”