Next molecule to enter the clinic will be CDX-527, due before mid-year 2020. A bispecific CD27/PD-L1. Here is some of the project's justification........
Clin Cancer Res. 2018 May 15;24(10):2383-2394. doi: 10.1158/1078-0432.CCR-17-3057. Epub 2018 Mar 7.
PD-1 Blockade and CD27 Stimulation Activate Distinct Transcriptional Programs That Synergize for CD8+ T-Cell-Driven Antitumor Immunity.
Buchan SL#1, Fallatah M#1, Thirdborough SM2, Taraban VY1, Rogel A1, Thomas LJ3, Penfold CA1, He LZ3, Curran MA4, Keler T3, Al-Shamkhani A5.
1
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom.
2
Cancer Research UK Centre, University of Southampton, Southampton, United Kingdom.
3
Celldex Therapeutics Inc., Hampton, New Jersey.
4
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Cancer Sciences Unit, Faculty of Medicine, University of Southampton, Southampton, United Kingdom. aymen@soton.ac.uk.
Purpose: PD-1 checkpoint blockade has revolutionized the field of cancer immunotherapy, yet the frequency of responding patients is limited by inadequate T-cell priming secondary to a paucity of activatory dendritic cells (DC). DC signals can be bypassed by CD27 agonists, and we therefore investigated if the effectiveness of anti-PD-1/L1 could be improved by combining with agonist anti-CD27 monoclonal antibodies (mAb).Experimental Design: The efficacy of PD-1/L1 blockade or agonist anti-CD27 mAb was compared with a dual-therapy approach in multiple tumor models. Global transcriptional profiling and flow cytometry analysis were used to delineate mechanisms underpinning the observed synergy.Results: PD-1/PD-L1 blockade and agonist anti-CD27 mAb synergize for increased CD8+ T-cell expansion and effector function, exemplified by enhanced IFN?, TNFa, granzyme B, and T-bet. Transcriptome analysis of CD8+ T cells revealed that combination therapy triggered a convergent program largely driven by IL2 and Myc. However, division of labor was also apparent such that anti-PD-1/L1 activates a cytotoxicity-gene expression program whereas anti-CD27 preferentially augments proliferation. In tumor models, either dependent on endogenous CD8+ T cells or adoptive transfer of transgenic T cells, anti-CD27 mAb synergized with PD-1/L1 blockade for antitumor immunity. Finally, we show that a clinically relevant anti-human CD27 mAb, varlilumab, similarly synergizes with PD-L1 blockade for protection against lymphoma in human-CD27 transgenic mice.Conclusions: Our findings suggest that suboptimal T-cell invigoration in cancer patients undergoing treatment with PD-1 checkpoint blockers will be improved by dual PD-1 blockade and CD27 agonism and provide mechanistic insight into how these approaches cooperate for CD8+ T-cell activation. Clin Cancer Res; 24(10); 2383-94. ©2018 AACR. |
