ABSTRACT
Chimeric antigen receptor (CAR) T-adoptive cell therapy has transformed the treatment of human hematologic malignancies. However, its application for the treatment of solid tumors remains challenging. An exciting avenue for advancing this field lies in the use of pet dogs, in which cancers that recapitulate the biology, immunological features, and clinical course of human malignancies arise spontaneously. Moreover, their large size, outbred genetic background, shared environment with humans, and immunocompetency make dogs ideal for investigating and optimizing CAR therapies before human trials. Here, we will outline how challenges in early clinical trials in patients with canine lymphoma, including issues related to autologous CAR T-cell manufacturing, limited CAR T-cell persistence, and tumor antigen escape, mirrored challenges observed in human CAR T trials. We will then highlight emerging adoptive cell therapy strategies currently under investigation in dogs with hematological and solid cancers, which will provide crucial safety and efficacy data on novel CAR T regimens that can be used to support clinical trials. By drawing from ongoing studies, we will illustrate how canine patients with spontaneous cancer may serve as compelling screening platforms to establish innovative CAR therapy approaches and identify predictive biomarkers of response, with a specific emphasis on solid tumors. With increased funding for canine immunotherapy studies, multi-institutional investigations are poised to generate highly impactful clinical data that should translate into more effective human trials, ultimately benefiting both human and canine cancer patients.
Subject(s)
Immunotherapy, Adoptive , Neoplasms , Receptors, Chimeric Antigen , Animals , Dogs , Humans , Dog Diseases/therapy , Dog Diseases/immunology , Immunotherapy, Adoptive/methods , Neoplasms/therapy , Neoplasms/immunology , Neoplasms/genetics , Receptors, Antigen, T-Cell/genetics , Receptors, Antigen, T-Cell/immunology , Receptors, Antigen, T-Cell/metabolism , Receptors, Chimeric Antigen/immunology , Receptors, Chimeric Antigen/genetics , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Clinical Trials, Veterinary as TopicABSTRACT
Progressive carcinogenesis of a gastric polyp with transformation to gastric adenocarcinoma and subsequent development of leptomeningeal carcinomatosis is described in an adult male Scottish terrier. Presenting clinical signs consisted of vomiting with intermittent hematemesis. Surgical biopsies over the course of 14 months documented the progression from gastric polyp to minimally invasive gastric carcinoma to invasive gastric adenocarcinoma, a pathogenesis not previously documented in veterinary oncology. The patient ultimately developed neurologic pathology and was euthanized, and necropsy evaluation identified widespread carcinomatosis with accompanying leptomeningeal metastasis. As in humans, gastric polyps in dogs rarely have malignant potential.
Subject(s)
Adenocarcinoma , Dog Diseases , Meningeal Carcinomatosis , Stomach Neoplasms , Dogs , Animals , Dog Diseases/pathology , Stomach Neoplasms/veterinary , Stomach Neoplasms/pathology , Meningeal Carcinomatosis/veterinary , Meningeal Carcinomatosis/secondary , Meningeal Carcinomatosis/pathology , Male , Adenocarcinoma/veterinary , Adenocarcinoma/pathology , Adenocarcinoma/secondary , Cell Transformation, Neoplastic/pathologyABSTRACT
Tumor-infiltrating lymphocyte (TIL) density plays an important role in anti-tumor immunity and is associated with patient outcome in various human and canine malignancies. As a first assessment of the immune landscape of the tumor microenvironment in canine renal cell carcinoma (RCC), we retrospectively analyzed clinical data and quantified CD3, FoxP3, and granzyme B immunostaining in formalin-fixed paraffin-embedded tumor samples from 16 dogs diagnosed with renal cell carcinoma treated with ureteronephrectomy. Cell density was low for all markers evaluated. Increased numbers of intratumoral FoxP3 labelled (+) cells, as well as decreased granzyme B+: FoxP3+ TIL ratio, were associated with poor patient outcomes. Our initial study of canine RCC reveals that these tumors are immunologically cold and Tregs may play an important role in immune evasion.