Establishing a model system for evaluating CAR T cell therapy using dogs with spontaneous diffuse large B cell...

Area of Science:

• Immunology
• Oncology
• Comparative Medicine

Background:

• Preclinical models like rodents and primates have limitations in predicting CAR T-cell therapy outcomes in human cancer patients.
• Developing effective CAR T-cell therapies requires models that accurately reflect clinical challenges for durable tumor elimination.

Purpose of the Study:

• To establish a novel system for evaluating next-generation CAR T-cells in pet dogs with spontaneous cancer.
• To assess the feasibility and efficacy of CD20-targeting CAR T-cells in a pilot trial for canine diffuse large B-cell lymphoma (DLBCL).

Main Methods:

• Designed and manufactured second-generation canine CAR T-cells using lentivectors, mirroring human CAR T-cell production protocols.
• Conducted a first-in-species trial treating five dogs with DLBCL.
• Performed in vitro and in vivo functional assessments of canine CAR T-cells.

Main Results:

• Canine CAR T-cells demonstrated antigen-specific killing of CD20+ targets and were detectable post-infusion.
• Development of canine anti-mouse antibodies (CAMA) correlated with CAR T-cell loss and tumor antigen escape (loss of CD20 expression).
• Patient survival was linked to ex vivo product expansion, and manufacturing improvements enhanced CAR T-cell phenotype.

Conclusions:

• Manufacturing functional canine CAR T-cells using lentivectors is achievable.
• The canine model recapitulates key challenges in human CAR T-cell therapy, including immune responses and antigen escape.
• This model provides valuable insights for refining future human clinical trial designs for CAR T-cell therapies.