Abstract
Simple SummaryImmune checkpoint inhibition has revolutionized clinical cancer care. As clinical use of these inhibitors increases, the ability to study the effects of these therapies in preclinical models becomes more important. This study highlights the need for using species appropriate reagents to properly evaluate the efficacy and toxicity of cancer immunotherapy in mouse models.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.
Highlights
With a deeper understanding of tumor immunology, novel therapies have been developed that seek to counteract cancer induced immune suppression and generate T cell mediated antitumor responses
The 4T1 is a commonly used model of triplenegative human breast cancer and can spontaneously metastasizes to lungs, liver, brain, and bone [20,21,22,23]. It has previously been reported by our group that 4T1 tumor-bearing mice will succumb to anaphylaxis after the repeated administration of xenogeneic hamster or rat αPD-1 monotherapy but not with xenogeneic species-specific antibody controls or xenogeneic anti- cytotoxic T-lymphocyte-associated protein 4 (CTLA4) monoclonal antibodies (mAbs) [18]
We implanted 4T1 murine mammary carcinoma orthotopically into the breast mammary pad of female BALB/c mice to further examine the effects of xenogeneic αPD-1 in this model
Summary
With a deeper understanding of tumor immunology, novel therapies have been developed that seek to counteract cancer induced immune suppression and generate T cell mediated antitumor responses. The recent successes of immunotherapy, checkpoint blockade of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) (PD-(L)1) axis, have been tremendous breakthroughs in cancer treatment. Tumors can hijack this inhibitory checkpoint pathway to evade immune eradication [10]. PD-(L) blockade using monoclonal antibodies (mAbs) can lead to improved antitumor T cell cytotoxicity, proliferation, and proinflammatory cytokine production, which promote tumor destruction in many preclinical models and clinical responses in patients, off-target effects and toxicities still remain a significant issue [3,11,12,13,14]
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