Combination CD200R/PD-1 blockade in a humanised mouse model

Abstract

There is an increasing number of immune-checkpoint inhibitors being developed and approved for cancer immunotherapy. Most of the new therapies aim to reactivate tumour-infiltrating T cells, which are responsible for the tumour killing. However, in many tumours, the most abundant infiltrating immune cells are macrophages and myeloid cells, which can be tumour-promoting as well as tumouricidal. CD200R was initially identified as a myeloid-restricted, inhibitory immune receptor, but was subsequently also found to be expressed within the lymphoid lineage. Using a mouse model humanised for CD200R and PD-1, we investigated the potential of a combination therapy comprising Nivolumab, a clinically approved PD-1 blocking antibody, and OX108, a CD200R antagonist. We produced Nivolumab as a murine IgG1 antibody and validated its binding activity in vitro as well as ex vivo. We then tested the combination therapy in the immunogenic colorectal cancer model MC38 as well as the PD-1 blockade-resistant lung cancer model LLC1, which is characterised by a large number of infiltrating myeloid cells, making it an attractive target for CD200R blockade. No significant improvement of overall survival was found in either model, compared to Nivolumab mIgG1 monotherapy. There was a trend for more complete responses in the MC38 model, but investigation of the infiltrating immune cells failed to account for this. Importantly, MC38 cells expressed low levels of CD200, whereas LLC1 cells were CD200-negative. Further investigation of CD200R blocking antibodies in tumours expressing high levels of CD200 could be warranted.

CD200/CD200R: Bidirectional Role in Cancer Progression and Immunotherapy

“…The role of CD200R in cancer remains uncertain due to conflicting findings in mouse and human studies, with some supporting a pro-tumorigenic role. The study suggests further investigation into this combination therapy, particularly in models with higher CD200 expression [118].…”

Translation of Data from Animal Models of Cancer to Immunotherapy of Breast Cancer and Chronic Lymphocytic Leukemia

“…Also highlighted were many of the ongoing unresolved controversies. It should be noted, if it is not already self-evident, that the development of cancer immunotherapy, and in particular the study of immune checkpoint inhibition in cancer therapy, has followed many of the approaches/methodologies used herein [ 10 , 11 , 98 , 99 , 100 , 101 , 102 ]. Where relevant, similar research by other groups, again using animal studies, have been cited, both in support of, and occasionally contradictory to, our own findings.…”