Concurrent OX40 and CD30 Ligand Blockade Abrogates the CD4-Driven Autoimmunity Associated with CTLA4 and PD1 Blockade while Preserving Excellent Anti-CD8 Tumor Immunity.

Maher G Nawaf,James P Allison,David R Withers,Fabrina M Gaspal,Peter J L Lane,Hideo Yagita,Maria H Ulvmar,Fiona M Mcconnell,Gwilym J Webb,Nick D Jones

doi:10.4049/jimmunol.1700088

Abstract

Although strategies that block FOXP3-dependent regulatory T cell function (CTLA4 blockade) and the inhibitory receptor PD1 have shown great promise in promoting antitumor immune responses in humans, their widespread implementation for cancer immunotherapy has been hampered by significant off-target autoimmune side effects that can be lethal. Our work has shown that absence of OX40 and CD30 costimulatory signals prevents CD4 T cell–driven autoimmunity in Foxp3-deficient mice, suggesting a novel way to block these side effects. In this study, we show that excellent antitumor CD8 T cell responses can be achieved in Foxp3KO mice deficient in OX40 and CD30 signals, particularly in the presence of concurrent PD1 blockade. Furthermore, excellent antitumor immune responses can also be achieved using combinations of Abs that block CTLA4, PD1, OX40, and CD30 ligands, without CD4 T cell–driven autoimmunity. By dissociating autoimmune side effects from anticancer immune responses, this potentially shifts this antitumor approach to patients with far less advanced disease.

Highlights

The normal CD4/CD8 T cell ratio seen in WT tumors was inverted in triple knockout (tKO) and double knockout (dKO) mice (Fig. 1A), supporting the role for OX40 and CD30 signals in CD4 effector function and in agreement with the abrogation of CD4 but not CD8 IFN-g expression reported previously for CD30KOOX40KO mice [23]
The inhibition of tumor growth in tKO mice was substantially dependent on CD8 T cells, as CD8 depletion in tKO mice 12 d after injection with B16 melanoma cells led to rapid growth of B16 melanoma compared with controlinjected mice (Fig. 2), as has been found by others [27, 28]
The above data suggest that a highly effective way to ameliorate the CD4-driven toxicity associated with CTLA4 and PD1 blockade in cancer treatment [8] would be to combine this therapy with blockade of OX40 and CD30 signals, for cancers where CD8 T cells were the main effectors of the anticancer response

Summary

Introduction

PD1 blockade acts synergistically in Foxp3KO dKO (tKO) mice, and with WT mice injected with blocking mAbs to CTLA4, and OX40L and CD30L, to prevent tumor growth Treatment with combined CTLA4 and PD1 Abs in dKO mice virtually abrogated tumor growth and increased infiltrates of CD8 T cells as well as its effector functions compared with dKO mice treated with control mAbs (p , 0.004)

Results

Conclusion