Buchan et al. evaluated the synergistic effects of CD27 agonism with anti-PD-1/L1 blockade. An agonistic anti-CD27 antibody increased the proliferation and effector function of CD8+ T cells, delayed tumor growth, and enhanced survival in multiple tumor models, including in human-transgenic CD27 mice, when used in combination with anti-PD-1/L1. Combination treatment dramatically promoted levels of Myc protein, a driver of CD8+ T cell proliferation, and depended on IL-2 levels, demonstrating a potential mechanism for the synergistic effects.

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 (DCs). 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-gamma, TNF-alpha, granzyme B and T-bet. Transcriptome analysis of CD8+ T cells revealed that combination therapy triggered a convergent program largely driven by IL-2 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 anti-tumor 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 co-operate for CD8+ T-cell activation.

Author Info: (1) Cancer Sciences Unit, University of Southampton. (2) Cancer Sciences Unit, Faculty of Medicine, University of Southampton. (3) Cancer Sciences, University of Southampton. (4) School

Author Info: (1) Cancer Sciences Unit, University of Southampton. (2) Cancer Sciences Unit, Faculty of Medicine, University of Southampton. (3) Cancer Sciences, University of Southampton. (4) School of Sport, Health & Social Science, Southampton Solent University. (5) Cancer Sciences Unit, Faculty of Medicine, University of Southampton. (6) Celldex Therapeutics, Inc. (7) Cancer Sciences Unit, Faculty of Medicine, University of Southampton. (8) R & D, Celldex Therapeutics (United States). (9) Immunology Program, University of Texas Graduate School of Biomedical Sciences at Houston. (10) Celldex Therapeutics, Inc. (11) Cancer Sciences Unit, Faculty of Medicine, University of Southampton aymen@soton.ac.uk.

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