title: Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma.
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.
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors: Jeffrey J
authors: JJ
authors: Wallin
authors: GI Oncology Research, Drug Development Unit, Sarah Cannon Research Institute, 250 25th Avenue North, Suite 100, Nashville, Tennessee, 37203, USA.
authors: Johanna C
authors: JC
authors: Bendell
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors: Roel
authors: R
authors: Funke
authors: Department of Internal Medicine and Melanoma Unit, Yale Cancer Center, New Haven, Connecticut 06511, USA.
authors: Mario
authors: M
authors: Sznol
authors: Roche Diagnostics GmbH, Nonnenwald 2, 82377 Penzberg, Germany.
authors: Konstanty
authors: K
authors: Korski
authors: GI Oncology Research, Drug Development Unit, Sarah Cannon Research Institute, 250 25th Avenue North, Suite 100, Nashville, Tennessee, 37203, USA.
authors: Suzanne
authors: S
authors: Jones
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors: Genevive
authors: G
authors: Hernandez
authors: Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusets 02215, USA.
authors: James
authors: J
authors: Mier
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors: Xian
authors: X
authors: He
authors: Dana-Farber/Brigham and Women's Cancer Center, 450 Brookline Avenue, Boston, Massachusets 02215, USA.
authors: F Stephen
authors: FS
authors: Hodi
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors: Mitchell
authors: M
authors: Denker
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors: Vincent
authors: V
authors: Leveque
authors: Roche Diagnostics GmbH, Nonnenwald 2, 82377 Penzberg, Germany.
authors: Marta
authors: M
authors: Cañamero
authors: Roche Diagnostics GmbH, Nonnenwald 2, 82377 Penzberg, Germany.
authors: Galina
authors: G
authors: Babitski
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors: Hartmut
authors: H
authors: Koeppen
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors: James
authors: J
authors: Ziai
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors: Neeraj
authors: N
authors: Sharma
authors: Roche Diagnostics GmbH, Nonnenwald 2, 82377 Penzberg, Germany.
authors: Fabien
authors: F
authors: Gaire
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors: Daniel S
authors: DS
authors: Chen
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors: Daniel
authors: D
authors: Waterkamp
authors: Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.
authors: Priti S
authors: PS
authors: Hegde
authors: Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusets 02215, USA.
authors: David F
authors: DF
authors: McDermott
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm / Q000276:immunology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D060890:B7-H1 Antigen / Q000037:antagonists & inhibitors; D000068258:Bevacizumab / Q000494:pharmacology* / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology / Q000556:secondary; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007668:Kidney / Q000473:pathology; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D016896:Treatment Outcome; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000951:Antigens, Neoplasm; D060890:B7-H1 Antigen; C423236:CD274 protein, human; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C000594389:atezolizumab