Pharmacodynamic Modeling

CAR T-Cell Immunotherapy in Human and Veterinary Oncology: Changing the Odds Against Hematological Malignancies


Jonathan P Mochel1, Stephen C Ekker2, Chad M Johannes3, Albert E Jergens3, Karin Allenspach3, Agnes Bourgois-Mochel3, Michael Knouse1, Sebastien Benzekry4, Wesley Wierson5, Amy K LeBlanc6, Saad S Kenderian7,8

1Iowa State University, Department of Biomedical Sciences, Ames, IA 50011, USA.
2Mayo Clinic Cancer Center Department of Biochemistry and Molecular Biology, Rochester, MN 55905, USA.
3Iowa State University, Department of Veterinary Clinical Sciences, Ames, IA 50011, USA.
4Institut National de Recherche en Informatique et en Automatique, Team MONC, Bordeaux, France.
5Iowa State University, Department of Genetics, Development, and Cell Biology, Ames, IA 50011, USA.
6Comparative Oncology Program, Center for Cancer Research National Cancer Institute, Bethesda, MD 20892, USA.
7Mayo Clinic Division of Hematology, Department of Medicine, Rochester, MN 55905, USA.
8Department of Immunology, Mayo Clinic, Rochester, MN 55905.

The advent of the genome editing era brings forth the promise of adoptive cell transfer using engineered chimeric antigen receptor (CAR) T-cells for targeted cancer therapy. CAR T-cell immunotherapy is probably one of the most encouraging developments for the treatment of hematological malignancies. In 2017, two CAR T-cell therapies were approved by the U. S Food and Drug Administration; one for the treatment of pediatric Acute Lymphoblastic Leukemia (ALL), the other for adult patients with advanced lymphomas. However, despite significant progress in the area, CAR T-cell therapy is still in its early days and faces significant challenges, including the complexity and costs associated with the technology. B-cell lymphoma is the most common hematopoietic cancer in dogs, with an incidence approaching 0.1% and a total of 20-100 cases per 100,000 individuals. It is a widely accepted naturally occurring model for human non-Hodgkin’s lymphoma. Current treatment is with combination chemotherapy protocols, which prolong life for less than a year in canines and are associated with severe dose-limiting side effects, such as gastrointestinal and bone marrow toxicity. To date, one canine study generated CAR T-cells by transfection of mRNA for CAR domain expression. While this was shown to provide a transient anti-tumor activity, results were modest, indicating that stable, genomic integration of CAR modules is required in order to achieve lasting therapeutic benefit. This Commentary summarizes the current state of knowledge on CAR T-cell immunotherapy in human medicine and its potential applications in animal health, while discussing the potential of the canine model as a translational system for immuno-oncology research.