Oncolytic Viruses and Immune Checkpoint Inhibition: The Best of Both Worlds
2019; Elsevier BV; Volume: 13; Linguagem: Inglês
10.1016/j.omto.2019.04.003
ISSN2372-7705
AutoresVenkatesh Sivanandam, Christopher J. LaRocca, Nanhai G. Chen, Yuman Fong, Susanne G. Warner,
Tópico(s)Viral Infectious Diseases and Gene Expression in Insects
ResumoCancer immunotherapy and the emergence of immune checkpoint inhibitors have markedly changed the treatment paradigm for many cancers. They function to disrupt cancer cell evasion of the immune response and activate sustained anti-tumor immunity. Oncolytic viruses have also emerged as an additional therapeutic agent for cancer treatment. These viruses are designed to target and kill tumor cells while leaving the normal cells unharmed. As part of this process, oncolytic virus infection stimulates anti-cancer immune responses that augment the efficacy of checkpoint inhibition. These viruses have the capability of transforming a "cold" tumor microenvironment with few immune effector cells into a "hot" environment with increased immune cell and cytokine infiltration. For this reason, there are multiple ongoing clinical trials that combine oncolytic virotherapy and immune checkpoint inhibitors. This review will detail the key oncolytic viruses in preclinical and clinical studies and highlight the results of their testing with checkpoint inhibitors. Cancer immunotherapy and the emergence of immune checkpoint inhibitors have markedly changed the treatment paradigm for many cancers. They function to disrupt cancer cell evasion of the immune response and activate sustained anti-tumor immunity. Oncolytic viruses have also emerged as an additional therapeutic agent for cancer treatment. These viruses are designed to target and kill tumor cells while leaving the normal cells unharmed. As part of this process, oncolytic virus infection stimulates anti-cancer immune responses that augment the efficacy of checkpoint inhibition. These viruses have the capability of transforming a "cold" tumor microenvironment with few immune effector cells into a "hot" environment with increased immune cell and cytokine infiltration. For this reason, there are multiple ongoing clinical trials that combine oncolytic virotherapy and immune checkpoint inhibitors. This review will detail the key oncolytic viruses in preclinical and clinical studies and highlight the results of their testing with checkpoint inhibitors. As the worldwide cancer incidence continues to rise,1Sylla B.S. Wild C.P. A million Africans a year dying from cancer by 2030: what can cancer research and control offer to the continent? Int..J. Cancer. 2012; 130: 245-250Crossref PubMed Scopus (0) Google Scholar the need for novel treatment strategies has become increasingly important. Targeting cancers at the molecular level is an attractive option, as demonstrated by the recent successes of systemically delivered immunotherapeutics (Figure 1). The field of immunotherapy seeks to develop treatments that effectively augment the body's own immune response to cancer in an effort to achieve local and systemic anti-tumor immunity. Unfortunately, certain cancers (e.g., pancreatic cancer) have a unique tumor microenvironment that has a relative paucity of circulating immune effector cells.2Torphy R.J. Zhu Y. Schulick R.D. Immunotherapy for pancreatic cancer: Barriers and breakthroughs.Ann. Gastroenterol. Surg. 2018; 2: 274-281Crossref PubMed Scopus (21) Google Scholar This scenario creates a "cold" tumor microenvironment and results in the tumor's being less responsive to immunotherapies. Conversely, "hot" tumor microenvironments are known to be immunogenic and have a much higher response rate to immunotherapy.3Haanen J.B.A.G. Converting Cold into Hot Tumors by Combining Immunotherapies.Cell. 2017; 170: 1055-1056Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Therefore, strategies to transform cold tumor microenvironments to hot ones are especially attractive, as they will help to increase the effectiveness of immune checkpoint inhibitors (ICIs).4Brahmer J.R. Tykodi S.S. Chow L.Q. Hwu W.J. Topalian S.L. Hwu P. Drake C.G. Camacho L.H. Kauh J. Odunsi K. et al.Safety and activity of anti-PD-L1 antibody in patients with advanced cancer.N. Engl. J. Med. 2012; 366: 2455-2465Crossref PubMed Scopus (3777) Google Scholar OVs are able to target and kill cancer cells while minimizing toxicities to surrounding normal tissues.5Russell S.J. Peng K.W. Bell J.C. Oncolytic virotherapy.Nat. Biotechnol. 2012; 30: 658-670Crossref PubMed Scopus (626) Google Scholar After infection with these viruses, the local tumor microenvironment is altered with an increase in activated T cells, natural killer (NK) cells, and cytokines.6Kaufman H.L. Kohlhapp F.J. Zloza A. Oncolytic viruses: a new class of immunotherapy drugs.Nat. Rev. Drug Discov. 2015; 14: 642-662Crossref PubMed Scopus (257) Google Scholar This review will explore the combination of ICIs with OVs for cancer therapy and will highlight key preclinical data, along with notable clinical trials. Immune checkpoints are inhibitory pathways in the immune system that modulate the amplitude and duration of immune responses. In some instances, tumors manipulate these immune-checkpoint pathways, resulting in a resistance to the body's native immune system. ICIs work by disrupting the cancer cells' signals, thereby exposing the tumors' T lymphocytes to attack (Figure 2). T lymphocytes have been the major focus of efforts to therapeutically manipulate endogenous antitumor immunity because of their functions in (1) selective peptide recognition, (2) direct cytotoxicity to certain antigen-expressing cells (by CD8+ effector T cells), and (3) their ability to orchestrate diverse immune responses (by CD4+ helper T cells), which involves both adaptive and innate effector mechanisms. T cell-mediated immunity includes multiple sequential steps involving the clonal selection of antigen-specific cells, their activation and proliferation in lymphoid tissues, their translocation (trafficking) to sites where the antigen is presented, the execution of direct effector function, and the provision of help (through cytokines and membrane ligands) for a multitude of effector immune cells. Each of these steps is regulated by counterbalancing stimulatory and inhibitory signals that fine-tune the immune response. Specificity is conferred to the response via antigen-independent second signals that modify the initial signal, which was provided by the interaction of antigenic peptides with T cell receptors.7Pardoll D.M. The blockade of immune checkpoints in cancer immunotherapy.Nat. Rev. Cancer. 2012; 12: 252-264Crossref PubMed Scopus (4365) Google Scholar The inhibitory signals in the immune response are triggered through membrane receptors, such as those for B7, programmed death receptor ligand-1 (PD-L1), and high-mobility group protein box1 (HMGB-1), and are overexpressed on tumor cells, and hence the interactions of these inhibitory receptor with their ligands (both membrane bound and soluble), such as cytotoxic T lymphocyte-associated antigen-4-B7 (CTLA4-B7), programmed death receptor-1 (PD-1)-PD-L1, and T cell immunoglobulin and mucin domain 3 (TIM3)-HMGB1, limit T cell activation (Figure 3).8Wolchok J.D. Hodi F.S. Weber J.S. Allison J.P. Urba W.J. Robert C. O'Day S.J. Hoos A. Humphrey R. Berman D.M. et al.Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma.Ann. N Y Acad. Sci. 2013; 1291: 1-13Crossref PubMed Scopus (114) Google Scholar, 9Dong H. Strome S.E. Salomao D.R. Tamura H. Hirano F. Flies D.B. Roche P.C. Lu J. Zhu G. Tamada K. et al.Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.Nat. Med. 2002; 8: 793-800Crossref PubMed Scopus (0) Google Scholar, 10Zhu C. Anderson A.C. Schubart A. Xiong H. Imitola J. Khoury S.J. Zheng X.X. Strom T.B. Kuchroo V.K. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity.Nat. Immunol. 2005; 6: 1245-1252Crossref PubMed Scopus (951) Google Scholar, 11Greenwald R.J. Freeman G.J. Sharpe A.H. The B7 family revisited.Annu. Rev. Immunol. 2005; 23: 515-548Crossref PubMed Scopus (1624) Google Scholar These aforementioned interactions are the targets for currently used ICIs and are explained in more detail in the following sections.Figure 3Key Receptor-Ligand Interactions That Turn OFF the T CellShow full captionOncolytic viruses induce immune responses that, upon infecting tumor cells, induce apoptosis or express the transgenes that, when presented or released by tumor cells, attract immune cells. The transgenes could be (1) key epitopes that attract immune cells, (2) immune-stimulatory blockers of immune checkpoints, or (3) key genes from non-human species that have anti-tumor effects.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Oncolytic viruses induce immune responses that, upon infecting tumor cells, induce apoptosis or express the transgenes that, when presented or released by tumor cells, attract immune cells. The transgenes could be (1) key epitopes that attract immune cells, (2) immune-stimulatory blockers of immune checkpoints, or (3) key genes from non-human species that have anti-tumor effects. CTLA-4, also known as CD152, is an inhibitory molecule on the surface of activated T cells12Brunet J.F. Denizot F. Luciani M.F. Roux-Dosseto M. Suzan M. Mattei M.G. Golstein P. A new member of the immunoglobulin superfamily--CTLA-4.Nature. 1987; 328: 267-270Crossref PubMed Scopus (0) Google Scholar that inhibits the binding of B7 to CD28.13Camacho L.H. CTLA-4 blockade with ipilimumab: biology, safety, efficacy, and future considerations.Cancer Med. 2015; 4: 661-672Crossref PubMed Scopus (31) Google Scholar Its mechanism functions to halt the initial stage of naive T cell activation in the lymph nodes and results in decreased T cell responses.14Buchbinder E.I. Desai A. CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition.Am. J. Clin. Oncol. 2016; 39: 98-106Crossref PubMed Scopus (316) Google Scholar Anti-CTLA-4 antibodies are designed to block CTLA-4 binding and prevent the inhibition of T cell function. A notable example is ipilimumab, which was approved by the U.S. Food and Drug Administration (FDA) in 2010 for the treatment of advanced melanoma.8Wolchok J.D. Hodi F.S. Weber J.S. Allison J.P. Urba W.J. Robert C. O'Day S.J. Hoos A. Humphrey R. Berman D.M. et al.Development of ipilimumab: a novel immunotherapeutic approach for the treatment of advanced melanoma.Ann. N Y Acad. Sci. 2013; 1291: 1-13Crossref PubMed Scopus (114) Google Scholar PD-1 has emerged as a promising target that is capable of inducing antitumor immune responses. In contrast to CTLA-4, it is more broadly expressed and functions to limit the activity of T cells in peripheral tissues at the time of an inflammatory response to minimize potential autoimmunity.15Keir M.E. Butte M.J. Freeman G.J. Sharpe A.H. PD-1 and its ligands in tolerance and immunity.Annu. Rev. Immunol. 2008; 26: 677-704Crossref PubMed Scopus (2359) Google Scholar, 16Okazaki T. Honjo T. PD-1 and PD-1 ligands: from discovery to clinical application.Int. Immunol. 2007; 19: 813-824Crossref PubMed Scopus (532) Google Scholar, 17Terme M. Ullrich E. Aymeric L. Meinhardt K. Desbois M. Delahaye N. Viaud S. Ryffel B. Yagita H. Kaplanski G. et al.IL-18 induces PD-1-dependent immunosuppression in cancer.Cancer Res. 2011; 71: 5393-5399Crossref PubMed Scopus (165) Google Scholar PD-1 is highly expressed on regulatory T (Treg) cells;18Ishida Y. Agata Y. Shibahara K. Honjo T. Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death.EMBO J. 1992; 11: 3887-3895Crossref PubMed Google Scholar therefore, blockade of the PD-1 pathway may enhance antitumor immune responses by diminishing the number and/or suppressive activity of intratumoral Treg cells.19Francisco L.M. Salinas V.H. Brown K.E. Vanguri V.K. Freeman G.J. Kuchroo V.K. Sharpe A.H. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells.J. Exp. Med. 2009; 206: 3015-3029Crossref PubMed Scopus (872) Google Scholar PD-L1 and -L2 are the main ligands for PD-1. High expression levels of PD-L1 are reported in most melanoma, ovarian, and lung cancer samples.9Dong H. Strome S.E. Salomao D.R. Tamura H. Hirano F. Flies D.B. Roche P.C. Lu J. Zhu G. Tamada K. et al.Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion.Nat. Med. 2002; 8: 793-800Crossref PubMed Scopus (0) Google Scholar Additionally, PD-L1 is commonly expressed on myeloid cells in the tumor microenvironment,20Kuang D.M. Zhao Q. Peng C. Xu J. Zhang J.P. Wu C. Zheng L. Activated monocytes in peritumoral stroma of hepatocellular carcinoma foster immune privilege and disease progression through PD-L1.J. Exp. Med. 2009; 206: 1327-1337Crossref PubMed Scopus (374) Google Scholar suggesting that PD-L1 is adaptively induced as a consequence of immune responses within the tumor microenvironment. Multiple anti-PD-1 and anti-PD-L1 agents have been developed in recent years. For instance, pembrolizumab was the first PD-1 inhibitor approved by the FDA in 2014 for the treatment of melanoma.21Khoja L. Butler M.O. Kang S.P. Ebbinghaus S. Joshua A.M. Pembrolizumab.J. Immunother. Cancer. 2015; 3: 36Crossref PubMed Google Scholar It was later approved in combination with nivolumab for the treatment of metastatic non-small-cell lung cancer and head and neck squamous cell carcinoma.22Rizvi N.A. Hellmann M.D. Snyder A. Kvistborg P. Makarov V. Havel J.J. Lee W. Yuan J. Wong P. Ho T.S. et al.Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer.Science. 2015; 348: 124-128Crossref PubMed Scopus (2539) Google Scholar Also, atezolizumab is a fully humanized IgG1 antibody against PD-L1 that was FDA approved in 2016 for the treatment of urothelial carcinoma and non-small-cell lung cancer. Furthermore, avelumab and durvalumab are fully humanized IgG1 antibodies that are FDA approved to treat Merkel cell carcinoma, urothelial carcinoma, and non-small-cell lung cancer (H.C. Chung et al., 2016, Am. Soc. Clin. Oncol., abstract).23PACIFIC Investigators.Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer.N. Engl. J. Med. 2017; 377: 1919-1929Crossref PubMed Scopus (532) Google Scholar Lymphocyte activation gene-3 (Lag-3) is another immune checkpoint receptor, and it is upregulated on activated CD4+/CD8+ T cells and NK cells and has a high affinity for major histocompatibility complex (MHC) class II molecules.24Anderson A.C. Joller N. Kuchroo V.K. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation.Immunity. 2016; 44: 989-1004Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar Clinical trials are ongoing wherein the antibody against LAG-3 is being tested as a monotherapy or in combination with other checkpoint inhibitors.25Andrews L.P. Marciscano A.E. Drake C.G. Vignali D.A. LAG3 (CD223) as a cancer immunotherapy target.Immunol. Rev. 2017; 276: 80-96Crossref PubMed Scopus (68) Google Scholar For instance, a soluble LAG-3Ig fusion protein was tested in patients with advanced renal cell carcinoma and was well tolerated and led to stabilization of disease in those who received higher doses of the drug in a dose-escalation study.26Brignone C. Escudier B. Grygar C. Marcu M. Triebel F. A phase I pharmacokinetic and biological correlative study of IMP321, a novel MHC class II agonist, in patients with advanced renal cell carcinoma.Clin. Cancer Res. 2009; 15: 6225-6231Crossref PubMed Scopus (96) Google Scholar TIM-3, is a member of the TIM gene family that plays a critical role in regulating immune response and is expressed on Th1 (T helper), Th17, and CD8+ T cells (Figure 3). Interactions between TIM-3 and its ligands result in suppression of Th1 and Th17 responses and induce immune tolerance, supporting an inhibitory role of TIM-3 in T cell-mediated immune responses.10Zhu C. Anderson A.C. Schubart A. Xiong H. Imitola J. Khoury S.J. Zheng X.X. Strom T.B. Kuchroo V.K. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity.Nat. Immunol. 2005; 6: 1245-1252Crossref PubMed Scopus (951) Google Scholar Four relevant ligands have been shown to interact with TIM-3 including galectin-9 (Gal-9), HMGB1, carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM 1), and phosphatidylserine (PS).24Anderson A.C. Joller N. Kuchroo V.K. Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation.Immunity. 2016; 44: 989-1004Abstract Full Text Full Text PDF PubMed Scopus (291) Google Scholar In cancer patients, administration of TIM-3 antibodies increases proliferation and cytokine production by tumor-antigen-specific T cells.27Fourcade J. Sun Z. Benallaoua M. Guillaume P. Luescher I.F. Sander C. Kirkwood J.M. Kuchroo V. Zarour H.M. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients.J. Exp. Med. 2010; 207: 2175-2186Crossref PubMed Scopus (580) Google Scholar Preclinical studies with TIM-3 show that it is expressed along with PD-1 on tumor-infiltrating lymphocytes, and combination therapy targeting these two domains may augment anti-tumor responses.28Sakuishi K. Apetoh L. Sullivan J.M. Blazar B.R. Kuchroo V.K. Anderson A.C. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity.J. Exp. Med. 2010; 207: 2187-2194Crossref PubMed Scopus (784) Google Scholar OVs are native or recombinant viruses that target cancer cells. The viruses cause the cancerous cells to die at the end of its replication cycles through lysis or by the activation of an antitumor immune response, thus minimizing damage to normal tissues (Figure 4).29Warner S.G. O'Leary M.P. Fong Y. Therapeutic oncolytic viruses: clinical advances and future directions.Curr. Opin. Oncol. 2017; 29: 359-365Crossref PubMed Scopus (1) Google Scholar, 30Liu T.C. Galanis E. Kirn D. Clinical trial results with oncolytic virotherapy: a century of promise, a decade of progress.Nat. Clin. Pract. Oncol. 2007; 4: 101-117Crossref PubMed Scopus (323) Google Scholar Historically, virologists have been concerned that the immune system may hamper the success of oncolytic virotherapy because of immune-mediated viral clearance, and toxicities have been noted in immune-compromised patients receiving non-engineered viruses.31Garber K. China approves world's first oncolytic virus therapy for cancer treatment.J. Natl. Cancer Inst. 2006; 98: 298-300Crossref PubMed Google Scholar, 32Russell L. Peng K.W. The emerging role of oncolytic virus therapy against cancer.Linchuang Zhongliuxue Zazhi. 2018; 7: 16Google Scholar, 33Kelly E. Russell S.J. History of oncolytic viruses: genesis to genetic engineering.Mol. Ther. 2007; 15: 651-659Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar Although immune clearance of virus is still a concern, OVs are now recognized as efficient immune-stimulatory agents capable of activating and redirecting innate and adaptive immune responses against the tumor (Figure 5).34Chaurasiya S. Warner S. Viroimmunotherapy for Colorectal Cancer: Clinical Studies.Biomedicines. 2017; 5: 11Crossref Scopus (4) Google Scholar, 35LaRocca C.J. Warner S.G. Oncolytic viruses and checkpoint inhibitors: combination therapy in clinical trials.Clin. Transl. Med. 2018; 7: 35Crossref PubMed Google Scholar It is these interactions between immune cells and signaling factors (i.e., cytokines and chemokines) that are critical to the induction of antitumor immunity and thus successful immunotherapy. Recent understanding of the mechanism of OV infection and of the resulting changes in the surrounding tumor immune microenvironment further characterizes this unique class of cancer therapeutics and underscores the importance of the field of oncolytic immunotherapy.36Melcher A. Parato K. Rooney C.M. Bell J.C. Thunder and lightning: immunotherapy and oncolytic viruses collide.Mol. Ther. 2011; 19: 1008-1016Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar The activity of an OV is a reflection of the biology of the virus from which it was derived and its host-virus interactions. Typically, OVs fall into two classes. The first class includes naturally replicating viruses that replicate only in cancer cells and are non-pathogenic in humans because of their sensitivity to innate antiviral immunity. These include the parvoviruses, myxoma virus (MYXV), Reovirus, Newcastle disease virus (NDV), and Seneca Valley virus (SVV). The second class includes those that are genetically manipulated for use as vaccines or vectors, such as poliovirus (PV), measles virus (MV), vaccinia virus (VACV), adenovirus, herpes simplex virus (HSV), and vesicular stomatitis virus (VSV).5Russell S.J. Peng K.W. Bell J.C. Oncolytic virotherapy.Nat. Biotechnol. 2012; 30: 658-670Crossref PubMed Scopus (626) Google Scholar, 37Cattaneo R. Miest T. Shashkova E.V. Barry M.A. Reprogrammed viruses as cancer therapeutics: targeted, armed and shielded.Nat. Rev. Microbiol. 2008; 6: 529-540Crossref PubMed Scopus (249) Google Scholar These viruses target the tumor cells directly or indirectly, replicate and express proteins that are deemed cytotoxic to the cell's survival,38Shtrichman R. Kleinberger T. Adenovirus type 5 E4 open reading frame 4 protein induces apoptosis in transformed cells.J. Virol. 1998; 72: 2975-2982Crossref PubMed Google Scholar and/or induce anti-tumor response upon expressing key tumor epitopes.39Marelli G. Howells A. Lemoine N.R. Wang Y. Oncolytic Viral Therapy and the Immune System: A Double-Edged Sword Against Cancer.Front. Immunol. 2018; 9 (article): 866Crossref PubMed Scopus (7) Google Scholar The specific targeting mechanism is different for different OVs and is based on the viral engineering performed,40Lin C.-Z. Xiang G.L. Zhu X.H. Xiu L.L. Sun J.X. Zhang X.Y. Advances in the mechanisms of action of cancer-targeting oncolytic viruses.Oncol. Lett. 2018; 15: 4053-4060PubMed Google Scholar, 41Singh P.K. Doley J. Kumar G.R. Sahoo A.P. Tiwari A.K. Oncolytic viruses & their specific targeting to tumour cells.Indian J. Med. Res. 2012; 136: 571-584PubMed Google Scholar and replication mechanisms can be controlled by using gene promoters that are activated only in tumor cells. 42Howells A. Marelli G. Lemoine N.R. Wang Y. Oncolytic Viruses-Interaction of Virus and Tumor Cells in the Battle to Eliminate Cancer.Front. Oncol. 2017; 7 (article 195)Crossref PubMed Scopus (12) Google Scholar ICIs have helped revolutionize cancer treatment, but oftentimes, even the best response rates to these agents do not exceed 35% to 40%.43Zamarin D. Holmgaard R.B. Subudhi S.K. Park J.S. Mansour M. Palese P. Merghoub T. Wolchok J.D. Allison J.P. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy.Sci. Transl. Med. 2014; 6: 226ra32Crossref PubMed Scopus (269) Google Scholar, 44Rajani K.R. Vile R.G. Harnessing the Power of Onco-Immunotherapy with Checkpoint Inhibitors.Viruses. 2015; 7: 5889-5901Crossref PubMed Scopus (13) Google Scholar, 45Callahan M.K. Postow M.A. Wolchok J.D. Targeting T Cell Co-receptors for Cancer Therapy.Immunity. 2016; 44: 1069-1078Abstract Full Text Full Text PDF PubMed Scopus (159) Google Scholar, 46Johnson D.B. Peng C. Sosman J.A. Nivolumab in melanoma: latest evidence and clinical potential.Ther. Adv. Med. Oncol. 2015; 7: 97-106Crossref PubMed Scopus (69) Google Scholar The goal of combining OVs and checkpoint inhibitors is to use the viral infection to prime the tumor by altering the local immune microenvironment to one that is more immunogenic, with the understanding that ICI's work best in these hot environments.43Zamarin D. Holmgaard R.B. Subudhi S.K. Park J.S. Mansour M. Palese P. Merghoub T. Wolchok J.D. Allison J.P. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy.Sci. Transl. Med. 2014; 6: 226ra32Crossref PubMed Scopus (269) Google Scholar, 44Rajani K.R. Vile R.G. Harnessing the Power of Onco-Immunotherapy with Checkpoint Inhibitors.Viruses. 2015; 7: 5889-5901Crossref PubMed Scopus (13) Google Scholar Because of the preclinical success of this type of combination therapy, there are multiple ongoing clinical trials that combine OVs and checkpoint inhibitors (Table 1).47Puzanov I. Milhem M.M. Minor D. Hamid O. Li A. Chen L. Chastain M. Gorski K.S. Anderson A. Chou J. et al.Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma.J. Clin. Oncol. 2016; 34: 2619-2626Crossref PubMed Scopus (164) Google Scholar, 48Chaurasiya S. Chen N.G. Fong Y. Oncolytic viruses and immunity.Curr. Opin. Immunol. 2018; 51: 83-90Crossref PubMed Scopus (8) Google Scholar, 49Fonteneau J.-F. Achard C. Zaupa C. Foloppe J. Erbs P. Oncolytic immunotherapy: The new clinical outbreak.OncoImmunology. 2015; 5: e1066961Crossref PubMed Scopus (4) Google ScholarTable 1OVs in Combination with Immune Checkpoint Inhibitors That Are in Preclinical and Clinical TestingPre-clinical WorksClinical TrialsVirusDNA/ RNA VirusViral EngineeringImmune Checkpoint InhibitorDisease TreatedViral EngineeringImmune Checkpoint InhibitorDisease TreatedReferenceMeasles virus–ssRNAfor expression of anti-PDL1 and anti-CTLA4anti- PDL1 and anti-CTLA4malignant melanoma–––118Engeland C.E. Grossardt C. Veinalde R. Bossow S. Lutz D. Kaufmann J.K. Shevchenko I. Umansky V. Nettelbeck D.M. Weichert W. et al.CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy.Mol. Ther. 2014; 22: 1949-1959Abstract Full Text Full Text PDF PubMed Scopus (111) Google ScholarAdenovirusdsDNAfor expression of TNFα or IL-2anti- PD-1melanomaDNX-2401 (express modified E1A gene) and ONCOS-102 (express modified GM-CSF, E1A gene and fiber knob region)pembrolizumab (anti-PD1)glioblastoma and advanced melanoma74Cervera-Carrascon V. Siurala M. Santos J.M. Havunen R. Tähtinen S. Karell P. Sorsa S. Kanerva A. Hemminki A. TNFa and IL-2 armed adenoviruses enable complete responses by anti-PD-1 checkpoint blockade.OncoImmunology. 2018; 7: e1412902Crossref PubMed Scopus (7) Google Scholar, 76Lang F.F. Conrad C. Gomez-Manzano C. Yung W.K.A. Sawaya R. Weinberg J.S. Prabhu S.S. Rao G. Fuller G.N. Aldape K.D. et al.Phase I Study of DNX-2401 (Delta-24-RGD) Oncolytic Adenovirus: Replication and Immunotherapeutic Effects in Recurrent Malignant Glioma.J. Clin. Oncol. 2018; 36: 1419-1427Crossref PubMed Scopus (12) Google Scholar ClinicalTrials.gov: NCT02798406,81 and NCT03003676Herpes simplex virusdsDNAfor expression of GM-CSF and IL-12anti- PD-L1 and anti-CTLA4glioblastoma multiformeT-VEC (express GM-CSF gene)ipilimumab (anti-CTLA4) and pembrolizumab (anti-PD1)advanced melanoma47Puzanov I. Milhem M.M. Minor D. Hamid O. Li A. Chen L. Chastain M. Gorski K.S. Anderson A. Chou J. et al.Talimogene Laherparepvec in Combination With Ipilimumab in Previously Untreated, Unresectable Stage IIIB-IV Melanoma.J. Clin. Oncol. 2016; 34: 2619-2626Crossref PubMed Scopus (164) Google Scholar, 63Chesney J. Puzanov I. Collichio F. Singh P. Milhem M.M. Glaspy J. Hamid O. Ross M. Friedlander P. Garbe C. et al.Randomized, Open-Label Phase II Study Evaluating the Efficacy and Safety of Talimogene Laherparepvec in Combination With Ipilimumab Versus Ipilimumab Alone in Patients With Advanced, Unresectable Melanoma.J. Clin. Oncol. 2018; 36: 1658-1667Crossref PubMed Scopus (0) Google Scholar, 119Saha D. Martuza R.L. Rabkin S.D. Oncolytic herpes simplex virus immunovirotherapy in combination with immune checkpoint blockade to treat glioblastoma.Immunotherapy. 2018; 10: 779-786Crossref PubMed Scopus (0) Google Scholar, 120Saha D. Martuza R.L. Rabkin S.D. Macrophage Polarization Contributes to Glioblastoma Eradication by Combination Immunovirotherapy and Immune Checkpoint Blockade.Cancer Cell. 2017; 32: 253-267.e5Abstract Full Text Full Text PDF PubMed Scopus (60) Google ScholarVaccinia virusdsDNAfor expression of CXCL-11anti-PD-L1colon and ovarian cancerJX-594 phase 3 clinical trialPDL1 and CTLA-1renal carcinoma68Liu Z. Ravindranathan R. Kalinski P. Guo Z.S. Bartlett D.L. Rational combination of oncolytic vaccinia virus and PD-L1 blockade works synergistically to enhance therapeutic efficacy.Nat. Commun. 2017; 8: 14754Crossref PubMed Scopus (53) Google Scholar, 69Rojas J.J. Sampath P. Hou W. Thorne S.H. Defining Effective Combinations of Immune Checkpoint Blockade and Oncolytic Virotherapy.Clin. Cancer Res. 2015; 21: 5543-5551Crossref PubMed Scopus (52) Google Scholar, 70Fend L. Yamazaki T. Remy C. Fahrner C. Gantzer M. Nourtier V. Préville X. Quéméneur E. Kepp O. Adam J. et al.Immune Checkpoint Blockade, Immunogenic Chemotherapy or IFN-α Blockade Boost the Local and Abscopal Effects of Oncolytic Virotherapy.Cancer Res. 2017; 77: 4146-4157Crossref PubMed Scopus (0) Google Scholar H. Chon and C. Kim, 2018, Am. Soc. CancerRes., abstractWR.B18R-.TKanti-CTLA4renal adenocarcinoma––––VVWR/TK−RR−/FCU1anti-PD-1 and anti-CTLA-4sarcoma––––Maraba virus−ssRNAMG1 strain (native)anti-PD-L1 and anti-CTLA4breast cancerMG1-MAGEA3 (express the melanoma-associated antigen A3 [MAGE-A3])pembrolizumab (anti-PD1)non-small cell lung cancer, metastatic melanoma, and cutaneous squamous cell carcinoma92Bourgeois-Daigneault M.C. Roy D.G. Aitken A.S. El Sayes N. Martin N.T. Varette O. Falls T. St-Germain L.E. Pelin A. Lichty B.D. et al.Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy.Sci. Transl. Med. 2018; 10: eaao1641Crossref PubMed Scopus (43) Google Scholar ClinicalTrials.gov: NCT02879760 and NCT03773744ReovirusdsRNAno engineeringanti-PD1melanomaReolysinpembrolizumab (anti-PD1)–83Rajani K. Parrish C. Kottke T. Thompson J. Zaidi S. Ilett L. Shim K.G. Diaz R.M. Pa
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