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

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

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.

Publication types

  • Clinical Trial, Phase I
  • Randomized Controlled Trial

MeSH terms

  • Adult
  • Aged
  • Antibodies, Monoclonal / pharmacology*
  • Antibodies, Monoclonal / therapeutic use
  • Antibodies, Monoclonal, Humanized
  • Antigens, Neoplasm / immunology*
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • B7-H1 Antigen / antagonists & inhibitors
  • Bevacizumab / pharmacology*
  • Bevacizumab / therapeutic use
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • Carcinoma, Renal Cell / drug therapy*
  • Carcinoma, Renal Cell / immunology
  • Carcinoma, Renal Cell / pathology
  • Carcinoma, Renal Cell / secondary
  • Cell Movement / drug effects
  • Cell Movement / immunology
  • Drug Synergism
  • Female
  • Humans
  • Kidney / pathology
  • Kidney Neoplasms / drug therapy*
  • Kidney Neoplasms / immunology
  • Kidney Neoplasms / pathology
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Treatment Outcome
  • Vascular Endothelial Growth Factor A / antagonists & inhibitors

Substances

  • Antibodies, Monoclonal
  • Antibodies, Monoclonal, Humanized
  • Antigens, Neoplasm
  • B7-H1 Antigen
  • CD274 protein, human
  • VEGFA protein, human
  • Vascular Endothelial Growth Factor A
  • Bevacizumab
  • atezolizumab