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, David F McDermott, 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.
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.
Figures
References
- Herbst R. S. et al.. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014).
- Latchman Y. E. et al.. PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc. Natl Acad. Sci. USA 101, 10691–10696 (2004).
- Akbari O. et al.. PD-L1 and PD-L2 modulate airway inflammation and iNKT-cell-dependent airway hyperreactivity in opposing directions. Mucosal Immunol. 3, 81–91 (2010).
- Matsumoto K. et al.. B7-DC induced by IL-13 works as a feedback regulator in the effector phase of allergic asthma. Biochem. Biophys. Res. Commun. 365, 170–175 (2008).
- McDermott D. F. et al.. Atezolizumab, an anti-programmed death-ligand 1 antibody, in metastatic renal cell carcinoma: long-term safety, clinical activity, and immune correlates from a phase Ia study. J. Clin. Oncol. 34, 833–842 (2016).
- Ferrara N. & Henzel W. J. Pituitary follicular cells secrete a novel heparin-binding growth factor specific for vascular endothelial cells. Biochem. Biophys. Res. Commun. 161, 851–858 (1989).
- Voron T. et al.. Control of the immune response by pro-angiogenic factors. Front. Oncol. 4, 70 (2014).
- Escudier B. et al.. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet 370, 2103–2111 (2007).
- Hodi F. S. et al.. Bevacizumab plus ipilimumab in patients with metastatic melanoma. Cancer Immunol. Res. 2, 632–642 (2014).
- Bendell J. P. et al.. in ASCO Gastrointestinal Cancers Symposium (San Francisco, CA) (2015).
- Yang J. C. et al.. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N. Engl. J. Med. 349, 427–434 (2003).
- Brauer M. J. et al.. Identification and analysis of in vivo VEGF downstream markers link VEGF pathway activity with efficacy of anti-VEGF therapies. Clin. Cancer Res. 19, 3681–3692 (2013).
- Motz G. T. et al.. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat. Med. 20, 607–615 (2014).
- Gasparini G., Longo R., Toi M. & Ferrara N. Angiogenic inhibitors: a new therapeutic strategy in oncology. Nat. Clin. Pract. Oncol. 2, 562–577 (2005).
- Lamagna C., Aurrand-Lions M. & Imhof B. A. Dual role of macrophages in tumor growth and angiogenesis. J. Leukoc. Biol. 80, 705–713 (2006).
- Ghosh S., Paul A. & Sen E. Tumor necrosis factor alpha-induced hypoxia-inducible factor 1alpha-beta-catenin axis regulates major histocompatibility complex class I gene activation through chromatin remodeling. Mol. Cell. Biol. 33, 2718–2731 (2013).
- Florcken A. et al.. Allogeneic partially HLA-matched dendritic cells pulsed with autologous tumor cell lysate as a vaccine in metastatic renal cell cancer: a clinical phase I/II study. Hum. Vaccin. Immunother. 9, 1217–1227 (2013).
- Kessler J. H. et al.. Efficient identification of novel HLA-A(*)0201-presented cytotoxic T lymphocyte epitopes in the widely expressed tumor antigen PRAME by proteasome-mediated digestion analysis. J. Exp. Med. 193, 73–88 (2001).
- Walter S. et al.. Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival. Nat. Med. 18, 1254–1261 (2012).
- Zhao X. et al.. Vaccines targeting tumor blood vessel antigens promote CD8(+) T cell-dependent tumor eradication or dormancy in HLA-A2 transgenic mice. J. Immunol. 188, 1782–1788 (2012).
- Szukiewicz D. et al.. Fractalkine (CX3CL1) and its receptor CX3CR1 may contribute to increased angiogenesis in diabetic placenta. Mediators Inflamm. 2013, 437576 (2013).
- Umehara H. et al.. Fractalkine in vascular biology: from basic research to clinical disease. Arterioscler. Thromb. Vasc. Biol. 24, 34–40 (2004).
- Nishimura M. et al.. Dual functions of fractalkine/CX3C ligand 1 in trafficking of perforin+/granzyme B+ cytotoxic effector lymphocytes that are defined by CX3CR1 expression. J. Immunol. 168, 6173–6180 (2002).
- Klinger M. et al.. Multiplex identification of antigen-specific T cell receptors using a combination of immune assays and immune receptor sequencing. PLoS ONE 10, e0141561 (2015).
- Manning E. A. et al.. A vascular endothelial growth factor receptor-2 inhibitor enhances antitumor immunity through an immune-based mechanism. Clin. Cancer Res. 13, 3951–3959 (2007).
- Shrimali R. K. et al.. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 70, 6171–6180 (2010).
- Carlson C. S. et al.. Using synthetic templates to design an unbiased multiplex PCR assay. Nat. Commun. 4, 2680 (2013).
- Robins H. S. et al.. Comprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells. Blood 114, 4099–4107 (2009).
Source: PubMed