Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy

Zuqiang Liu; Roshni Ravindranathan; Pawel Kalinski; Z. Sheng Guo; David L. Bartlett

doi:10.1038/ncomms14754

journal article Open Access Mar 27, 2017

Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy

Zuqiang Liu Roshni Ravindranathan Pawel Kalinski Z. Sheng Guo David L. Bartlett

Nature Communications Vol. 8 No. 1 · Springer Science and Business Media LLC

View at Publisher Save 10.1038/ncomms14754

Abstract

AbstractBoth anti-PD1/PD-L1 therapy and oncolytic virotherapy have demonstrated promise, yet have exhibited efficacy in only a small fraction of cancer patients. Here we hypothesized that an oncolytic poxvirus would attract T cells into the tumour, and induce PD-L1 expression in cancer and immune cells, leading to more susceptible targets for anti-PD-L1 immunotherapy. Our results demonstrate in colon and ovarian cancer models that an oncolytic vaccinia virus attracts effector T cells and induces PD-L1 expression on both cancer and immune cells in the tumour. The dual therapy reduces PD-L1+ cells and facilitates non-redundant tumour infiltration of effector CD8+, CD4+ T cells, with increased IFN-γ, ICOS, granzyme B and perforin expression. Furthermore, the treatment reduces the virus-induced PD-L1+ DC, MDSC, TAM and Treg, as well as co-inhibitory molecules-double-positive, severely exhausted PD-1+CD8+ T cells, leading to reduced tumour burden and improved survival. This combinatorial therapy may be applicable to a much wider population of cancer patients.

Topics

No keywords indexed for this article. Browse by subject →

References

48

[1]

Bartlett, D. L. et al. Oncolytic viruses as therapeutic cancer vaccines. Mol. Cancer 12, 103 (2013). 10.1186/1476-4598-12-103

[2]

Lichty, B. D., Breitbach, C. J., Stojdl, D. F. & Bell, J. C. Going viral with cancer immunotherapy. Nat. Rev. Cancer 14, 559–567 (2014). 10.1038/nrc3770

[3]

Talimogene Laherparepvec Improves Durable Response Rate in Patients With Advanced Melanoma

Robert H.I. Andtbacka, Howard L. Kaufman, Frances Collichio et al.

Journal of Clinical Oncology 2015 10.1200/jco.2014.58.3377

[4]

Mellman, I., Coukos, G. & Dranoff, G. Cancer immunotherapy comes of age. Nature 480, 480–489 (2011). 10.1038/nature10673

[5]

Schlom, J. Therapeutic cancer vaccines: current status and moving forward. J. Natl. Cancer Inst. 104, 599–613 (2012). 10.1093/jnci/djs033

[6]

Restifo, N. P., Dudley, M. E. & Rosenberg, S. A. Adoptive immunotherapy for cancer: harnessing the T cell response. Nat. rev. Immunol. 12, 269–281 (2012). 10.1038/nri3191

[7]

Barrett, D. M., Singh, N., Porter, D. L., Grupp, S. A. & June, C. H. Chimeric antigen receptor therapy for cancer. Annu. rev. med. 65, 333–347 (2014). 10.1146/annurev-med-060512-150254

[8]

Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy

Suzanne L. Topalian, Janis M. Taube, Robert A. Anders et al.

Nature Reviews Cancer 2016 10.1038/nrc.2016.36

[9]

Melero, I. et al. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat. rev. Cancer 15, 457–472 (2015). 10.1038/nrc3973

[10]

Oncolytic viruses: a new class of immunotherapy drugs

Howard L. Kaufman, Frederick J. Kohlhapp, Andrew Zloza

Nature Reviews Drug Discovery 2015 10.1038/nrd4663

[11]

Kirn, D. H. & Thorne, S. H. Targeted and armed oncolytic poxviruses: a novel multi-mechanistic therapeutic class for cancer. Nat. rev. Cancer 9, 64–71 (2009). 10.1038/nrc2545

[12]

Kaufman, H. L. et al. Targeting the local tumor microenvironment with vaccinia virus expressing B7.1 for the treatment of melanoma. J. clin. invest. 115, 1903–1912 (2005). 10.1172/jci24624

[13]

Chard, L. S., Lemoine, N. R. & Wang, Y. New role of interleukin-10 in enhancing the antitumor efficacy of oncolytic vaccinia virus for treatment of pancreatic cancer. Oncoimmunology 4, e1038689 (2015). 10.1080/2162402x.2015.1038689

[14]

Liu, Z. et al. CXCL11-armed oncolytic poxvirus elicits potent antitumor immunity and shows enhanced therapeutic efficacy. Oncoimmunology 5, e1091554 (2016). 10.1080/2162402x.2015.1091554

[15]

Heo, J. et al. Randomized dose-finding clinical trial of oncolytic immunotherapeutic vaccinia JX-594 in liver cancer. Nat. med. 19, 329–336 (2013). 10.1038/nm.3089

[16]

Zeh, H. J. et al. First-in-man study of western reserve strain oncolytic vaccinia virus: safety, systemic spread, and antitumor activity. Mol. Ther. 23, 202–214 (2015). 10.1038/mt.2014.194

[17]

Downs-Canner, S. et al. Phase 1 study of intravenous oncolytic poxvirus (vvDD) in patients with advanced solid cancers. Mol. Ther. 24, 1492–1501 (2016). 10.1038/mt.2016.101

[18]

Francis, L. et al. Modulation of chemokines in the tumor microenvironment enhances oncolytic virotherapy for colorectal cancer. Oncotarget 7, 22174–22185 (2016). 10.18632/oncotarget.7907

[19]

Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion

Haidong Dong, Scott E. Strome, Diva R. Salomao et al.

Nature Medicine 2002 10.1038/nm730

[20]

Engagement of the Pd-1 Immunoinhibitory Receptor by a Novel B7 Family Member Leads to Negative Regulation of Lymphocyte Activation

Gordon J. Freeman, Andrew J. Long, Yoshiko Iwai et al.

Journal of Experimental Medicine 2000 10.1084/jem.192.7.1027

[21]

Restoring function in exhausted CD8 T cells during chronic viral infection

Daniel L. Barber, E. John Wherry, David Masopust et al.

Nature 2006 10.1038/nature04444

[22]

Shin, H. & Wherry, E. J. CD8 T cell dysfunction during chronic viral infection. Curr. opin. immunol. 19, 408–415 (2007). 10.1016/j.coi.2007.06.004

[23]

Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015). 10.1016/j.ccell.2015.03.001

[24]

Muhlbauer, M. et al. PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis. J. Hepatol. 45, 520–528 (2006). 10.1016/j.jhep.2006.05.007

[25]

Constitutive AP-1 Activity and EBV Infection Induce PD-L1 in Hodgkin Lymphomas and Posttransplant Lymphoproliferative Disorders: Implications for Targeted Therapy

Michael R. Green, Scott Rodig, Przemyslaw Juszczynski et al.

Clinical Cancer Research 2012 10.1158/1078-0432.ccr-11-1942

[26]

Lu, W. et al. Inflammation promotes oral squamous carcinoma immune evasion via induced programmed death ligand-1 surface expression. Oncol. Lett. 5, 1519–1526 (2013). 10.3892/ol.2013.1238

[27]

Abiko, K. et al. IFN-gamma from lymphocytes induces PD-L1 expression and promotes progression of ovarian cancer. Br. J. Cancer 112, 1501–1509 (2015). 10.1038/bjc.2015.101

[28]

Chen, L. & Han, X. Anti-PD-1/PD-L1 therapy of human cancer: past, present, and future. J. clin. invest. 125, 3384–3391 (2015). 10.1172/jci80011

[29]

Fortin, C., Huang, X. & Yang, Y. NK cell response to vaccinia virus is regulated by myeloid-derived suppressor cells. J. Immunol. 189, 1843–1849 (2012). 10.4049/jimmunol.1200584

[30]

Jiang, Y., Li, Y. & Zhu, B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 6, e1792 (2015). 10.1038/cddis.2015.162

[31]

Speiser, D. E., Ho, P. C. & Verdeil, G. Regulatory circuits of T cell function in cancer. Nat. rev. Immunol. 16, 599–611 (2016). 10.1038/nri.2016.80

[32]

Safety and Activity of Anti–PD-L1 Antibody in Patients with Advanced Cancer

Julie R. Brahmer, Scott S. Tykodi, Laura Q.M. Chow et al.

New England Journal of Medicine 2012 10.1056/nejmoa1200694

[33]

Herbst, R. S. et al. Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients. Nature 515, 563–567 (2014). 10.1038/nature14011

[34]

Dias, J. D. et al. Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4. Gene Ther. 19, 988–998 (2012). 10.1038/gt.2011.176

[35]

Engeland, C. E. et al. CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy. Mol. Ther. 22, 1949–1959 (2014). 10.1038/mt.2014.160

[36]

Zamarin, D. et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci. transl. med. 6, 226ra232 (2014). 10.1126/scitranslmed.3008095

[37]

Quetglas, J. I. et al. Virotherapy with a Semliki Forest virus-based vector encoding IL12 synergizes with PD-1/PD-L1 blockade. Cancer Immunol. Res. 3, 449–454 (2015). 10.1158/2326-6066.cir-14-0216

[38]

Rajani, K. et al. Combination therapy with reovirus and anti-PD-1 blockade controls tumor growth through innate and adaptive immune responses. Mol. Ther. 24, 166–174 (2016). 10.1038/mt.2015.156

[39]

Woller, N. et al. Viral infection of tumors overcomes resistance to PD-1-immunotherapy by broadening neoantigenome-directed T-cell responses. Mol. Ther. 23, 1630–1640 (2015). 10.1038/mt.2015.115

[40]

PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation

Muhammad Zaeem Noman, Giacomo Desantis, Bassam Janji et al.

Journal of Experimental Medicine 2014 10.1084/jem.20131916

[41]

Flies, D. B. & Chen, L. The new B7s: playing a pivotal role in tumor immunity. J. Immunother. 30, 251–260 (2007). 10.1097/cji.0b013e31802e085a

[42]

Keir, M. E., Butte, M. J., Freeman, G. J. & Sharpe, A. H. PD-1 and its ligands in tolerance and immunity. Annu. Rev. Immunol. 26, 677–704 (2008). 10.1146/annurev.immunol.26.021607.090331

[43]

Guo, Z. S., Liu, Z. & Bartlett, D. L. Oncolytic immunotherapy: dying the right way is a key to eliciting potent antitumor immunity. Front. oncol. 4, 74 (2014).

[44]

Breitbach, C. J. et al. Oncolytic vaccinia virus disrupts tumor-associated vasculature in humans. Cancer res. 73, 1265–1275 (2013). 10.1158/0008-5472.can-12-2687

[45]

Kleffel, S. et al. Melanoma cell-intrinsic PD-1 receptor functions promote tumor growth. Cell 162, 1242–1256 (2015). 10.1016/j.cell.2015.08.052

[46]

Kuang, D. M. et al. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1. J. Exp. Med. 206, 1327–1337 (2009). 10.1084/jem.20082173

[47]

Chalikonda, S. et al. Oncolytic virotherapy for ovarian carcinomatosis using a replication-selective vaccinia virus armed with a yeast cytosine deaminase gene. Cancer Gene Ther. 15, 115–125 (2008). 10.1038/sj.cgt.7701110

[48]

Li, Q., O’Malley, M. E., Bartlett, D. L. & Guo, Z. S. Homeobox gene Rhox5 is regulated by epigenetic mechanisms in cancer and stem cells and promotes cancer growth. Mol. cancer 10, 63 (2011). 10.1186/1476-4598-10-63

Cited By

296

Intravenous infusion of engineered megakaryocytes to produce oncolytic platelets in vivo for enhanced cancer immunotherapy

Yinxian Yang, Shenqiang Wang · 2026

Proceedings of the National Academy...

Precision oncolytic viral therapy in colorectal cancer: Genetic targeting and immune modulation for personalized treatment (Review)

Muhammad Haris Sultan, Qi Zhan · 2025

International Journal of Molecular...

Immunomodulatory effect of locoregional therapy in the tumor microenvironment

Lin Xie, Zhiqiang Meng · 2023

Molecular Therapy

IL-21 arming potentiates the anti-tumor activity of an oncolytic vaccinia virus in monotherapy and combination therapy

Tianyue Chen, Xiangqing Ding · 2021

Journal for ImmunoTherapy of Cancer

Modulation of the Intratumoral Immune Landscape by Oncolytic Herpes Simplex Virus Virotherapy

Jie Yin, James M. Markert · 2017

Frontiers in Oncology

Metrics

296

Citations

48

References

Details

Published: Mar 27, 2017
Vol/Issue: 8(1)
License: View

Authors

Z

Zuqiang Liu

R

Roshni Ravindranathan

Cite This Article

Zuqiang Liu, Roshni Ravindranathan, Pawel Kalinski, et al. (2017). Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy. Nature Communications, 8(1). https://doi.org/10.1038/ncomms14754

Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy

You May Also Like