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30-08-2016 | Treatment | Article

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

Authors:
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, David F. McDermott

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.

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

Programmed death-ligand 1 (PD-L1) is expressed on T cells and antigen-presenting cells, including dendritic cells, macrophages and tumour cells1. The binding of PD-L1 to the receptor programmed death-1 (PD-1) plays a central role in T-cell tolerance by inhibiting naive and effector T-cell responses2. Clinical experience with checkpoint inhibitors has shown that tumours co-opt the PD-L1/PD-1 signalling pathway as one key mechanism to evade immune destruction. Atezolizumab is an engineered humanized monoclonal anti-PD-L1 antibody that specifically inhibits PD-L1/PD-1 signalling to restore tumour-specific T-cell immunity3,4. It also induces durable antitumour effects for some cancer patients, including those with metastatic renal cell carcinoma (mRCC)1,5.

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