Mouse Preclinical Cancer Immunotherapy Modeling Involving Anti-PD-1 Therapies Reveals the Need to Use Mouse Reagents to Mirror Clinical Paradigms

Abstract

Immune checkpoint inhibition (ICI) has emerged as one of the most powerful tools to reverse cancer induced immune suppression. Monoclonal antibodies (mAbs) targeting programmed cell death 1/programmed cell death ligand 1(PD-1/PD-L1) are FDA-approved and their clinical use is rapidly expanding. As opposed to the clinical paradigm, which can result in significant responses and toxicities, it has been difficult to reproduce these effects preclinically using mouse models. In large part, this is due to models, which employ rapidly growing ex vivo cultured transplantable tumor cell lines engrafted into young naïve inbred laboratory mice. However, another issue concerns the use and repeated application of xenogeneic reagents in mice (i.e., rat or hamster mAbs directed against mouse antigens at variance with clinical use of human or humanized mAbs). Building on our previous studies demonstrating that repeated administration of commonly used xenogeneic anti-PD-1 mAbs derived from both rat and hamster can induce fatal hypersensitivity in some tumor-bearing mice, we sought to compare these result with the effects of a mouse anti-mouse PD-1 mAb. Application of a murine anti-mouse PD-1 (clone: MuDX400) did not result in lethal anaphylaxis in the 4T1 tumor model. It also displayed superior antitumor effects in this and other tumor models, as it did not induce neutralizing antibody responses against the anti-PD-1 mAb, such as were observed when using xenogeneic anti-PD1 mAbs. These results demonstrate that more accurate preclinical modeling necessitates the use of mouse reagents mirroring the clinical scenario to ascertain long-term effects or toxicities, while avoiding xenogeneic responses, which do not occur clinically. Furthermore, these studies suggest a direct mechanism, whereby preclinical murine studies have often failed to recapitulate the clinical efficacy and toxicity of single agent checkpoint inhibition.

Keywords

• PD-1
• checkpoint
• immunotherapy