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Nat Commun. 2016 Aug 30;7:12624. doi: 10.1038/ncomms12624.

Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma.

Author information

1
Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
2
GI Oncology Research, Drug Development Unit, Sarah Cannon Research Institute, 250 25th Avenue North, Suite 100, Nashville, Tennessee, 37203, USA.
3
Department of Internal Medicine and Melanoma Unit, Yale Cancer Center, New Haven, Connecticut 06511, USA.
4
Roche Diagnostics GmbH, Nonnenwald 2, 82377 Penzberg, Germany.
5
Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusets 02215, USA.
6
Dana-Farber/Brigham and Women's Cancer Center, 450 Brookline Avenue, Boston, Massachusets 02215, USA.

Abstract

Anti-tumour immune activation by checkpoint inhibitors leads to durable responses in a variety of cancers, but combination approaches are required to extend this benefit beyond a subset of patients. In preclinical models tumour-derived VEGF limits immune cell activity while anti-VEGF augments intra-tumoral T-cell infiltration, potentially through vascular normalization and endothelial cell activation. This study investigates how VEGF blockade with bevacizumab could potentiate PD-L1 checkpoint inhibition with atezolizumab in mRCC. Tissue collections are before treatment, after bevacizumab and after the addition of atezolizumab. We discover that intra-tumoral CD8(+) T cells increase following combination treatment. A related increase is found in intra-tumoral MHC-I, Th1 and T-effector markers, and chemokines, most notably CX3CL1 (fractalkine). We also discover that the fractalkine receptor increases on peripheral CD8(+) T cells with treatment. Furthermore, trafficking lymphocyte increases are observed in tumors following bevacizumab and combination treatment. These data suggest that the anti-VEGF and anti-PD-L1 combination improves antigen-specific T-cell migration.

PMID:
27571927
PMCID:
PMC5013615
DOI:
10.1038/ncomms12624
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

This study was sponsored by Genentech, Inc., a member of the Roche Group, which provided the study drug. Some of the authors of this manuscript are employees of Genentech/Roche. The remaining authors declare no competing financial interests.

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