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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.

Author information

1
University of Navarra, Center for Applied Medical Research (CIMA), Program in Solid Tumors and Biomarkers, Pamplona, Spain.
2
Navarra's Health Research Institute (IdiSNA), Pamplona, Spain.
3
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
4
University of Navarra, School of Sciences, Department of Biochemistry and Genetics, Pamplona, Spain.
5
University of Navarra, CIMA, Program in Immunology and Immunotherapy, Pamplona, Spain.
6
University of Navarra, School of Medicine, Department of Histology and Pathology, Pamplona, Spain.
7
Aptarion Biotech, Berlin, Germany.
8
University of Navarra, Center for Applied Medical Research (CIMA), Program in Solid Tumors and Biomarkers, Pamplona, Spain. rpio@unav.es.

Abstract

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.

PMID:
28288993
DOI:
10.1158/2159-8290.CD-16-1184
[Indexed for MEDLINE]
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