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Cancer Discov. 2017 Jul;7(7):694-703. doi: 10.1158/2159-8290.CD-16-1184. Epub 2017 Mar 13.

A Combined PD-1/C5a Blockade Synergistically Protects against Lung Cancer Growth and Metastasis.

Ajona D1,2,3,4, Ortiz-Espinosa S1,4, Moreno H1,2, Lozano T2,5, Pajares MJ1,2,3,6, Agorreta J1,2,3,6, Bértolo C1, Lasarte JJ2,5, Vicent S1,2,6, Hoehlig K7, Vater A7, Lecanda F1,2,3,6, Montuenga LM1,2,3,6, Pio R8,2,3,4.

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University of Navarra, Center for Applied Medical Research (CIMA), Program in Solid Tumors and Biomarkers, Pamplona, Spain.
Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
University of Navarra, School of Sciences, Department of Biochemistry and Genetics, Pamplona, Spain.
University of Navarra, CIMA, Program in Immunology and Immunotherapy, Pamplona, Spain.
University of Navarra, School of Medicine, Department of Histology and Pathology, Pamplona, Spain.
Aptarion Biotech, Berlin, Germany.
University of Navarra, Center for Applied Medical Research (CIMA), Program in Solid Tumors and Biomarkers, Pamplona, Spain.


Disruption of the programmed cell death protein 1 (PD-1) pathway with immune checkpoint inhibitors represents a major breakthrough in the treatment of non-small cell lung cancer. We hypothesized that combined inhibition of C5a/C5aR1 and PD-1 signaling may have a synergistic antitumor effect. The RMP1-14 antibody was used to block PD-1, and an L-aptamer was used to inhibit signaling of complement C5a with its receptors. Using syngeneic models of lung cancer, we demonstrate that the combination of C5a and PD-1 blockade markedly reduces tumor growth and metastasis and leads to prolonged survival. This effect is accompanied by a negative association between the frequency of CD8 T cells and myeloid-derived suppressor cells within tumors, which may result in a more complete reversal of CD8 T-cell exhaustion. Our study provides support for the clinical evaluation of anti-PD-1 and anti-C5a drugs as a novel combination therapeutic strategy for lung cancer.Significance: Using a variety of preclinical models of lung cancer, we demonstrate that the blockade of C5a results in a substantial improvement in the efficacy of anti-PD-1 antibodies against lung cancer growth and metastasis. This study provides the preclinical rationale for the combined blockade of PD-1/PD-L1 and C5a to restore antitumor immune responses, inhibit tumor cell growth, and improve outcomes of patients with lung cancer. Cancer Discov; 7(7); 694-703. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 653.

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