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

Abstract

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 US Food and Drug Administration: one for the treatment of pediatric acute lymphoblastic leukemia (ALL) and 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.

Effective Combinations of Immunotherapy and Radiotherapy for Cancer Treatment

“…CAR-T enables the patient's T cells to express the chimeric antigen receptor (CAR) through gene transduction. The modified T cells are returned to the patient's body to generate many CAR-T cells that specifically recognize tumors and kill tumor cells (91)(92)(93). CAR-T cells have a particular effect in treating solid tumors such as renal cell carcinoma, HER2 positive sarcoma, ovarian cancer (94), and colorectal cancer (95).…”

Time to evolve: predicting engineered T cell-associated toxicity with next-generation models

“…In return, information from human clinical trials can guide the development of cell-based therapies in veterinary oncology, under the so-called One Health initiative. 37…”

Spontaneously occurring canine cancer as a relevant animal model for developing novel treatments for human cancers

“…Although several types of CAR-T cell therapies have already been approved in humans [104], there are still no approved CAR-T cell therapies for dogs. However, several groups, including our own, have already reported on how to create canine CAR-T cells with some efficacy in vitro [105] and in vivo [106][107][108]. To maximize the effect of CAR-T cell therapy in patients, CAR-T cells must be administered after myelosuppression using strong anticancer drugs and radiation to eliminate the immune cells.…”