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

Jeffrey J. Wallin (), Johanna C. Bendell, Roel Funke, Mario Sznol, Konstanty Korski, Suzanne Jones, Genevive Hernandez, James Mier, Xian He, F. Stephen Hodi, Mitchell Denker, Vincent Leveque, Marta Cañamero, Galina Babitski, Hartmut Koeppen, James Ziai, Neeraj Sharma, Fabien Gaire, Daniel S. Chen, Daniel Waterkamp, Priti S. Hegde and David F. McDermott
Additional contact information
Jeffrey J. Wallin: Genentech, Inc.
Johanna C. Bendell: GI Oncology Research, Drug Development Unit, Sarah Cannon Research Institute
Roel Funke: Genentech, Inc.
Mario Sznol: Yale Cancer Center
Konstanty Korski: Roche Diagnostics GmbH
Suzanne Jones: GI Oncology Research, Drug Development Unit, Sarah Cannon Research Institute
Genevive Hernandez: Genentech, Inc.
James Mier: Beth Israel Deaconess Medical Center
Xian He: Genentech, Inc.
F. Stephen Hodi: Dana-Farber/Brigham and Women’s Cancer Center
Mitchell Denker: Genentech, Inc.
Vincent Leveque: Genentech, Inc.
Marta Cañamero: Roche Diagnostics GmbH
Galina Babitski: Roche Diagnostics GmbH
Hartmut Koeppen: Genentech, Inc.
James Ziai: Genentech, Inc.
Neeraj Sharma: Genentech, Inc.
Fabien Gaire: Roche Diagnostics GmbH
Daniel S. Chen: Genentech, Inc.
Daniel Waterkamp: Genentech, Inc.
Priti S. Hegde: Genentech, Inc.
David F. McDermott: Beth Israel Deaconess Medical Center

Nature Communications, 2016, vol. 7, issue 1, 1-8

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12624

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