Validation of a PD-1/CD28 chimeric switch receptor to augment CAR-T function in dogs with spontaneous B cell lymphoma

Sho Yoshimoto; Ayano Kudo; Antonia Rotolo; Kay Foos; Lauren Olenick; Satoshi Takagi; Nicola J Mason

doi:10.1016/j.isci.2024.110863

Validation of a PD-1/CD28 chimeric switch receptor to augment CAR-T function in dogs with spontaneous B cell lymphoma

iScience. 2024 Aug 31;27(9):110863. doi: 10.1016/j.isci.2024.110863. eCollection 2024 Sep 20.

Authors

Sho Yoshimoto¹, Ayano Kudo¹, Antonia Rotolo^{2

3}, Kay Foos^{4

3}, Lauren Olenick⁴, Satoshi Takagi¹, Nicola J Mason^{2

3}

Affiliations

¹ Laboratory of Small Animal Surgery, Department of Veterinary Medicine, School of Veterinary Medicine, Azabu University, Sagamihara, Kanagawa, Japan.
² Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA.
³ Center for Cellular Immunotherapies, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
⁴ Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Abstract

Chimeric antigen receptor (CAR) T cell therapy has achieved unprecedented clinical outcomes in patients with relapsed/refractory B cell leukemias; however, response rates in patients with large B cell lymphoma (LBCL) are less impressive. Expression of PD-1 on activated T cells and PD-L1 on malignant, stromal, and immune cells within the tumor microenvironment (TME) contribute to CAR-T exhaustion, hypofunction, and treatment failures. Here, a comparative approach is taken to develop a chimeric switch receptor (CSR) with potential to augment CAR-T persistence, function, and clinical efficacy in immune competent, pet dogs with spontaneous B cell lymphoma (BCL). We show that similar to human CAR-T cells, expression of a PD-1/CD28 CSR in canine CAR-T cells results in enhanced function against PD-L1⁺ targets and preserves central memory phenotype. We also demonstrate that these effects depend upon active CSR signaling. This work paves the way for in vivo studies in canine BCL patients to inform human trial design.

Keywords: Cancer; Therapeutics; Veterinary medicine.