Beyond cancer cells: Targeting the tumor microenvironment with gene therapy and armed oncolytic virus

Molecular Therapy - Tập 29 - Trang 1668-1682 - 2021
Peter Kok-Ting Wan1, Anderson J. Ryan1, Leonard W. Seymour1
1Department Oncology, University of Oxford, Oxford OX3 7DQ, UK

Tài liệu tham khảo

Balkwill, 2012, The tumor microenvironment at a glance, J. Cell Sci., 125, 5591, 10.1242/jcs.116392 Lamagna, 2006, The bone marrow constitutes a reservoir of pericyte progenitors, J. Leukoc. Biol., 80, 677, 10.1189/jlb.0506309 Motz, 2014, Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors, Nat. Med., 20, 607, 10.1038/nm.3541 Quail, 2013, Microenvironmental regulation of tumor progression and metastasis, Nat. Med., 19, 1423, 10.1038/nm.3394 Roma-Rodrigues, 2019, Targeting tumor microenvironment for cancer therapy, Int. J. Mol. Sci., 20, 840, 10.3390/ijms20040840 Zhang, 2018, The first approved gene therapy product for cancer Ad-p53 (Gendicine): 12 years in the clinic, Hum. Gene Ther., 29, 160, 10.1089/hum.2017.218 McGranahan, 2017, Clonal heterogeneity and tumor evolution: Past, present, and the future, Cell, 168, 613, 10.1016/j.cell.2017.01.018 Kakarla, 2012, Cancer-associated fibroblasts as targets for immunotherapy, Immunotherapy, 4, 1129, 10.2217/imt.12.112 Toro Bejarano, 2015, Targeting tumor vasculature through oncolytic virotherapy: recent advances, Oncolytic Virother., 4, 169 Marchand, 2020, BT-001, an oncolytic vaccinia virus armed with a Treg-depletion-optimized recombinant human anti-CTLA4 antibody and GM-CSF to target the tumor microenvironment, Cancer Res, 80, 5602, 10.1158/1538-7445.AM2020-5602 Seymour, 2016, Oncolytic viruses: Finally delivering, Br. J. Cancer, 114, 357, 10.1038/bjc.2015.481 Dhar, 2012, Syrian hamster tumor model to study oncolytic Ad5-based vectors, Methods Mol. Biol., 797, 53, 10.1007/978-1-61779-340-0_4 Guerin, 2020, Preclinical murine tumor models: A structural and functional perspective, eLife, 9, e50740, 10.7554/eLife.50740 Yamaguchi, 2018, Animal models for studying tumor microenvironment (TME) and resistance to lymphocytic infiltration, Cancer Biol. Ther., 19, 745, 10.1080/15384047.2018.1470722 Yoshida, 2020, Applications of patient-derived tumor xenograft models and tumor organoids, J. Hematol. Oncol., 13, 4, 10.1186/s13045-019-0829-z Scott, 2020, Use of liquid patient ascites fluids as a preclinical model for oncolytic virus activity, Methods Mol. Biol., 2058, 261, 10.1007/978-1-4939-9794-7_17 Hutt, 2012, Plasma half-life extension of small recombinant antibodies by fusion to immunoglobulin-binding domains, J. Biol. Chem., 287, 4462, 10.1074/jbc.M111.311522 Hamers-Casterman, 1993, Naturally occurring antibodies devoid of light chains, Nature, 363, 446, 10.1038/363446a0 Hermiston, 2002, Armed therapeutic viruses: strategies and challenges to arming oncolytic viruses with therapeutic genes, Cancer Gene Ther., 9, 1022, 10.1038/sj.cgt.7700542 Robinson, 2008, Comparison of the E3 and L3 regions for arming oncolytic adenoviruses to achieve a high level of tumor-specific transgene expression, Cancer Gene Ther., 15, 9, 10.1038/sj.cgt.7701093 Wirth, 2003, A telomerase-dependent conditionally replicating adenovirus for selective treatment of cancer, Cancer Res., 63, 3181 DeWeese, 2001, A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy, Cancer Res., 61, 7464 Chen, 2019, Turning foes to friends: Targeting cancer-associated fibroblasts, Nat. Rev. Drug Discov., 18, 99, 10.1038/s41573-018-0004-1 Lakins, 2018, Cancer-associated fibroblasts induce antigen-specific deletion of CD8 + T cells to protect tumour cells, Nat. Commun., 9, 948, 10.1038/s41467-018-03347-0 McKee, 2006, Degradation of fibrillar collagen in a human melanoma xenograft improves the efficacy of an oncolytic herpes simplex virus vector, Cancer Res., 66, 2509, 10.1158/0008-5472.CAN-05-2242 Erdogan, 2017, Cancer-associated fibroblasts modulate growth factor signaling and extracellular matrix remodeling to regulate tumor metastasis, Biochem. Soc. Trans., 45, 229, 10.1042/BST20160387 Henke, 2020, Extracellular matrix in the tumor microenvironment and its impact on cancer therapy, Front. Mol. Biosci., 6, 160, 10.3389/fmolb.2019.00160 Vähä-Koskela, 2014, Tumor restrictions to oncolytic virus, Biomedicines, 2, 163, 10.3390/biomedicines2020163 Cheng, 2007, Human matrix metalloproteinase-8 gene delivery increases the oncolytic activity of a replicating adenovirus, Mol. Ther, 15, 1982, 10.1038/sj.mt.6300264 Kim, 2006, Relaxin expression from tumor-targeting adenoviruses and its intratumoral spread, apoptosis induction, and efficacy, J. Natl. Cancer Inst., 98, 1482, 10.1093/jnci/djj397 Choi, 2010, Effect of decorin on overcoming the extracellular matrix barrier for oncolytic virotherapy, Gene Ther., 17, 190, 10.1038/gt.2009.142 Jung, 2017, Oncolytic adenovirus expressing relaxin (YDC002) enhances therapeutic efficacy of gemcitabine against pancreatic cancer, Cancer Lett., 396, 155, 10.1016/j.canlet.2017.03.009 Thompson, 2010, Enzymatic depletion of tumor hyaluronan induces antitumor responses in preclinical animal models, Mol. Cancer Ther., 9, 3052, 10.1158/1535-7163.MCT-10-0470 Guedan, 2010, Hyaluronidase expression by an oncolytic adenovirus enhances its intratumoral spread and suppresses tumor growth, Mol. Ther, 18, 1275, 10.1038/mt.2010.79 Ganesh, 2008, Intratumoral coadministration of hyaluronidase enzyme and oncolytic adenoviruses enhances virus potency in metastatic tumor models, Clin. Cancer Res, 14, 3933, 10.1158/1078-0432.CCR-07-4732 Bookbinder, 2006, A recombinant human enzyme for enhanced interstitial transport of therapeutics, J. Control. Release, 114, 230, 10.1016/j.jconrel.2006.05.027 Garcia-Carbonero, 2019, Systemic administration of the hyaluronidase-expressing oncolytic adenovirus VCN-01 in patients with advanced or metastatic pancreatic cancer: First-in-human clinical trial, Ann. Oncol., 30, v271, 10.1093/annonc/mdz247.037 Tedcastle, 2016, Actin-resistant DNAse I expression from oncolytic adenovirus enadenotucirev enhances its intratumoral spread and reduces tumor growth, Mol. Ther, 24, 796, 10.1038/mt.2015.233 Yasui, 2011, Tumor-stroma interactions reduce the efficacy of adenoviral therapy through the HGF-MET pathway, Cancer Sci., 102, 484, 10.1111/j.1349-7006.2010.01783.x Nemerow, 2009, Insights into adenovirus host cell interactions from structural studies, Virology, 384, 380, 10.1016/j.virol.2008.10.016 Vähä-Koskela, 2006, Oncolytic capacity of attenuated replicative Semliki Forest virus in human melanoma xenografts in severe combined immunodeficient mice, Cancer Res., 66, 7185, 10.1158/0008-5472.CAN-05-2214 Boire, 2005, PAR1 is a matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells, Cell, 120, 303, 10.1016/j.cell.2004.12.018 Hanahan, 2012, Accessories to the crime: functions of cells recruited to the tumor microenvironment, Cancer Cell, 21, 309, 10.1016/j.ccr.2012.02.022 Sottile, 2004, Regulation of angiogenesis by extracellular matrix, Biochim. Biophys. Acta, 1654, 13 Sahai, 2020, A framework for advancing our understanding of cancer-associated fibroblasts, Nat. Rev. Cancer, 20, 174, 10.1038/s41568-019-0238-1 Lopez, 2012, A tumor-stroma targeted oncolytic adenovirus replicated in human ovary cancer samples and inhibited growth of disseminated solid tumors in mice, Mol. Ther., 20, 2222, 10.1038/mt.2012.147 Viale, 2013, Therapeutic improvement of a stroma-targeted CRAd by incorporating motives responsive to the melanoma microenvironment, J. Invest. Dermatol., 133, 2576, 10.1038/jid.2013.191 Jing, 2017, Molecular effects of stromal-selective targeting by uPAR-retargeted oncolytic virus in breast cancer, Mol. Cancer Res, 15, 1410, 10.1158/1541-7786.MCR-17-0016 Garin-Chesa, 1990, Cell surface glycoprotein of reactive stromal fibroblasts as a potential antibody target in human epithelial cancers, Proc. Natl. Acad. Sci. USA, 87, 7235, 10.1073/pnas.87.18.7235 Wikberg, 2013, High intratumoral expression of fibroblast activation protein (FAP) in colon cancer is associated with poorer patient prognosis, Tumour Biol., 34, 1013, 10.1007/s13277-012-0638-2 Sandberg, 2019, Increased expression of cancer-associated fibroblast markers at the invasive front and its association with tumor-stroma ratio in colorectal cancer, BMC Cancer, 19, 284, 10.1186/s12885-019-5462-2 Brennen, 2012, Rationale behind targeting fibroblast activation protein-expressing carcinoma-associated fibroblasts as a novel chemotherapeutic strategy, Mol. Cancer Ther., 11, 257, 10.1158/1535-7163.MCT-11-0340 Hofheinz, 2003, Stromal antigen targeting by a humanised monoclonal antibody: An early phase II trial of sibrotuzumab in patients with metastatic colorectal cancer, Onkologie, 26, 44 Narra, 2007, Phase II trial of single agent Val-boroPro (talabostat) inhibiting fibroblast activation protein in patients with metastatic colorectal cancer, Cancer Biol. Ther., 6, 1691, 10.4161/cbt.6.11.4874 Roberts, 2013, Depletion of stromal cells expressing fibroblast activation protein-α from skeletal muscle and bone marrow results in cachexia and anemia, J. Exp. Med., 210, 1137, 10.1084/jem.20122344 Angell, 2014, MHC class I loss is a frequent mechanism of immune escape in papillary thyroid cancer that is reversed by interferon and selumetinib treatment in vitro, Clin. Cancer Res, 20, 6034, 10.1158/1078-0432.CCR-14-0879 Freedman, 2018, An oncolytic virus expressing a T-cell engager simultaneously targets cancer and immunosuppressive stromal cells, Cancer Res., 78, 6852, 10.1158/0008-5472.CAN-18-1750 de Sostoa, 2019, Targeting the tumor stroma with an oncolytic adenovirus secreting a fibroblast activation protein-targeted bispecific T-cell engager, J. Immunother. Cancer, 7, 19, 10.1186/s40425-019-0505-4 Illingworth, 2017, Preclinical safety studies of enadenotucirev, a chimeric group B human-specific oncolytic adenovirus, Mol. Ther. Oncolytics, 5, 62, 10.1016/j.omto.2017.03.003 Yu, 2017, A T-cell engager-armed oncolytic vaccinia virus to target the tumor stroma, Cancer Transl. Med., 3, 122, 10.4103/ctm.ctm_13_17 Huang, 2015, Expression of anti-VEGF antibody together with anti-EGFR or anti-FAP enhances tumor regression as a result of vaccinia virotherapy, Mol. Ther. Oncolytics, 2, 15003, 10.1038/mto.2015.3 Wen, 2010, Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model, Cancer Sci., 101, 2325, 10.1111/j.1349-7006.2010.01695.x Xia, 2016, Anti-tumor effects of DNA vaccine targeting human fibroblast activation protein α by producing specific immune responses and altering tumor microenvironment in the 4T1 murine breast cancer model, Cancer Immunol. Immunother., 65, 613, 10.1007/s00262-016-1827-4 Geng, 2019, A DNA vaccine expressing an optimized secreted FAPα induces enhanced anti-tumor activity by altering the tumor microenvironment in a murine model of breast cancer, Vaccine, 37, 4382, 10.1016/j.vaccine.2019.06.012 Siemann, 2011, The unique characteristics of tumor vasculature and preclinical evidence for its selective disruption by tumor-vascular disrupting agents, Cancer Treat. Rev., 37, 63, 10.1016/j.ctrv.2010.05.001 Hashizume, 2000, Openings between defective endothelial cells explain tumor vessel leakiness, Am. J. Pathol., 156, 1363, 10.1016/S0002-9440(10)65006-7 Carmeliet, 2011, Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases, Nat. Rev. Drug Discov., 10, 417, 10.1038/nrd3455 Vasudev, 2014, Anti-angiogenic therapy for cancer: Current progress, unresolved questions and future directions, Angiogenesis, 17, 471, 10.1007/s10456-014-9420-y Carmeliet, 2005, VEGF as a key mediator of angiogenesis in cancer, Oncology, 69, 4, 10.1159/000088478 Ikeda, 2009, A novel antiangiogenic effect for telomerase-specific virotherapy through host immune system, J. Immunol, 182, 1763, 10.4049/jimmunol.182.3.1763 Breitbach, 2011, Targeting tumor vasculature with an oncolytic virus, Mol. Ther., 19, 886, 10.1038/mt.2011.26 Yousaf, 2020, Attenuation of the hypoxia inducible factor pathway after oncolytic adenovirus infection coincides with decreased vessel perfusion, Cancers (Basel), 12, 851, 10.3390/cancers12040851 Guse, 2010, Antiangiogenic arming of an oncolytic vaccinia virus enhances antitumor efficacy in renal cell cancer models, J. Virol., 84, 856, 10.1128/JVI.00692-09 Frentzen, 2009, Anti-VEGF single-chain antibody GLAF-1 encoded by oncolytic vaccinia virus significantly enhances antitumor therapy, Proc. Natl. Acad. Sci. USA, 106, 12915, 10.1073/pnas.0900660106 Weibel, 2013, Treatment of malignant effusion by oncolytic virotherapy in an experimental subcutaneous xenograft model of lung cancer, J. Transl. Med., 11, 106, 10.1186/1479-5876-11-106 Buckel, 2013, Combination of fractionated irradiation with anti-VEGF expressing vaccinia virus therapy enhances tumor control by simultaneous radiosensitization of tumor associated endothelium, Int. J. Cancer, 133, 2989, 10.1002/ijc.28296 Kuo, 2001, Comparative evaluation of the antitumor activity of antiangiogenic proteins delivered by gene transfer, Proc. Natl. Acad. Sci. USA, 98, 4605, 10.1073/pnas.081615298 Thorne, 2006, Selective intratumoral amplification of an antiangiogenic vector by an oncolytic virus produces enhanced antivascular and anti-tumor efficacy, Mol. Ther, 13, 938, 10.1016/j.ymthe.2005.12.010 Hou, 2014, Oncolytic vaccinia virus demonstrates antiangiogenic effects mediated by targeting of VEGF, Int. J. Cancer, 135, 1238, 10.1002/ijc.28747 Domanska, 2013, A review on CXCR4/CXCL12 axis in oncology: No place to hide, Eur. J. Cancer, 49, 219, 10.1016/j.ejca.2012.05.005 Liang, 2007, CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway, Biochem. Biophys. Res. Commun., 359, 716, 10.1016/j.bbrc.2007.05.182 Guo, 2016, CXCL12/CXCR4: A symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks, Oncogene, 35, 816, 10.1038/onc.2015.139 Gil, 2013, Targeting CXCL12/CXCR4 signaling with oncolytic virotherapy disrupts tumor vasculature and inhibits breast cancer metastases, Proc. Natl. Acad. Sci. USA, 110, E1291, 10.1073/pnas.1220580110 Gil, 2014, CXCL12/CXCR4 blockade by oncolytic virotherapy inhibits ovarian cancer growth by decreasing immunosuppression and targeting cancer-initiating cells, J. Immunol, 193, 5327, 10.4049/jimmunol.1400201 Patil, 2012, Virotherapy of canine tumors with oncolytic vaccinia virus GLV-1h109 expressing an anti-VEGF single-chain antibody, PLoS ONE, 7, e47472, 10.1371/journal.pone.0047472 Gholami, 2014, A novel vaccinia virus with dual oncolytic and anti-angiogenic therapeutic effects against triple-negative breast cancer, Breast Cancer Res. Treat., 148, 489, 10.1007/s10549-014-3180-7 Adelfinger, 2015, Preclinical testing oncolytic vaccinia virus strain GLV-5b451 expressing an anti-VEGF single-chain antibody for canine cancer therapy, Viruses, 7, 4075, 10.3390/v7072811 Adelfinger, 2014, Evaluation of a new recombinant oncolytic vaccinia virus strain GLV-5b451 for feline mammary carcinoma therapy, PLoS ONE, 9, e104337, 10.1371/journal.pone.0104337 Xie, 2014, AAV-mediated persistent bevacizumab therapy suppresses tumor growth of ovarian cancer, Gynecol. Oncol., 135, 325, 10.1016/j.ygyno.2014.07.105 Guse, 2009, Ad5/3-9HIF-Delta24-VEGFR-1-Ig, an infectivity enhanced, dual-targeted and antiangiogenic oncolytic adenovirus for kidney cancer treatment, Gene Ther., 16, 1009, 10.1038/gt.2009.56 Niethammer, 2002, A DNA vaccine against VEGF receptor 2 prevents effective angiogenesis and inhibits tumor growth, Nat. Med., 8, 1369, 10.1038/nm1202-794 Morera, 2010, Immunogenicity and some safety features of a VEGF-based cancer therapeutic vaccine in rats, rabbits and non-human primates, Vaccine, 28, 3453, 10.1016/j.vaccine.2010.02.069 Jarosz, 2013, Therapeutic antitumor potential of endoglin-based DNA vaccine combined with immunomodulatory agents, Gene Ther., 20, 262, 10.1038/gt.2012.28 Haller, 2010, Therapeutic efficacy of a DNA vaccine targeting the endothelial tip cell antigen delta-like ligand 4 in mammary carcinoma, Oncogene, 29, 4276, 10.1038/onc.2010.176 Wagner, 2016, Safety of targeting tumor endothelial cell antigens, J. Transl. Med., 14, 90, 10.1186/s12967-016-0842-8 Ichim, 2015, Induction of tumor inhibitory anti-angiogenic response through immunization with interferon Gamma primed placental endothelial cells: ValloVax™, J. Transl. Med., 13, 90, 10.1186/s12967-015-0441-0 Kuo, 2015, Development of recombinant adeno-associated virus serotype 2/8 carrying kringle domains of human plasminogen for sustained expression and cancer therapy, Hum. Gene Ther., 26, 603, 10.1089/hum.2013.220 Chu, 2014, Human placenta mesenchymal stem cells expressing exogenous kringle1-5 protein by fiber-modified adenovirus suppress angiogenesis, Cancer Gene Ther., 21, 200, 10.1038/cgt.2014.19 Cao, 1999, Suppression of angiogenesis and tumor growth by the inhibitor K1–5 generated by plasmin-mediated proteolysis, Proc. Natl. Acad. Sci. USA, 96, 5728, 10.1073/pnas.96.10.5728 Zhang, 2011, Mesenchymal stem cells modified to express lentivirus TNF-α Tumstatin45–132 inhibit the growth of prostate cancer, J. Cell. Mol. Med., 15, 433, 10.1111/j.1582-4934.2009.00920.x Daugimont, 2011, Antitumoral and antimetastatic effect of antiangiogenic plasmids in B16 melanoma: Higher efficiency of the recombinant disintegrin domain of ADAM 15, Eur. J. Pharm. Biopharm., 78, 314, 10.1016/j.ejpb.2011.02.001 Matsumoto, 2005, Mechanisms and significance of bifunctional NK4 in cancer treatment, Biochem. Biophys. Res. Commun., 333, 316, 10.1016/j.bbrc.2005.05.131 Kishi, 2009, Systemic NK4 gene therapy inhibits tumor growth and metastasis of melanoma and lung carcinoma in syngeneic mouse tumor models, Cancer Sci., 100, 1351, 10.1111/j.1349-7006.2009.01184.x Tomioka, 2001, Inhibition of growth, invasion, and metastasis of human pancreatic carcinoma cells by NK4 in an orthotopic mouse model, Cancer Res., 61, 7518 Zhu, 2014, Mesenchymal stem cell-based NK4 gene therapy in nude mice bearing gastric cancer xenografts, Drug Des. Devel. Ther., 8, 2449, 10.2147/DDDT.S71466 Matsumoto, 2011, NK4 gene therapy combined with cisplatin inhibits tumour growth and metastasis of squamous cell carcinoma, Anticancer Res., 31, 105 Ogura, 2006, Peritumoral injection of adenovirus vector expressing NK4 combined with gemcitabine treatment suppresses growth and metastasis of human pancreatic cancer cells implanted orthotopically in nude mice and prolongs survival, Cancer Gene Ther., 13, 520, 10.1038/sj.cgt.7700921 Dolinsek, 2013, Multiple delivery of siRNA against endoglin into murine mammary adenocarcinoma prevents angiogenesis and delays tumor growth, PLoS ONE, 8, e58723, 10.1371/journal.pone.0058723 Tesic, 2015, Endoglin (CD105) silencing mediated by shRNA under the control of endothelin-1 promoter for targeted gene therapy of melanoma, Mol. Ther. Nucleic Acids, 4, e239, 10.1038/mtna.2015.12 Curiel, 2004, Specific recruitment of regulatory T cells in ovarian carcinoma fosters immune privilege and predicts reduced survival, Nat. Med., 10, 942, 10.1038/nm1093 Noy, 2014, Tumor-associated macrophages: From mechanisms to therapy, Immunity, 41, 49, 10.1016/j.immuni.2014.06.010 Wherry, 2015, Molecular and cellular insights into T cell exhaustion, Nat. Rev. Immunol., 15, 486, 10.1038/nri3862 Groth, 2019, Immunosuppression mediated by myeloid-derived suppressor cells (MDSCs) during tumour progression, Br. J. Cancer, 120, 16, 10.1038/s41416-018-0333-1 Gajewski, 2013, Innate and adaptive immune cells in the tumor microenvironment, Nat. Immunol., 14, 1014, 10.1038/ni.2703 Scott, 2019, Bi- and tri-valent T cell engagers deplete tumour-associated macrophages in cancer patient samples, J. Immunother. Cancer, 7, 320, 10.1186/s40425-019-0807-6 Kleinpeter, 2016, Vectorization in an oncolytic vaccinia virus of an antibody, a Fab and a scFv against programmed cell death -1 (PD-1) allows their intratumoral delivery and an improved tumor-growth inhibition, OncoImmunology, 5, e1220467, 10.1080/2162402X.2016.1220467 Engeland, 2014, CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy, Mol. Ther, 22, 1949, 10.1038/mt.2014.160 Lin, 2020, Intratumoral delivery of a PD-1-blocking scFv encoded in oncolytic HSV-1 promotes antitumor immunity and synergizes with TIGIT blockade, Cancer Immunol. Res, 8, 632, 10.1158/2326-6066.CIR-19-0628 Du, 2014, Tumor-specific oncolytic adenoviruses expressing granulocyte macrophage colony-stimulating factor or anti-CTLA4 antibody for the treatment of cancers, Cancer Gene Ther., 21, 340, 10.1038/cgt.2014.34 Dias, 2012, Targeted cancer immunotherapy with oncolytic adenovirus coding for a fully human monoclonal antibody specific for CTLA-4, Gene Ther., 19, 988, 10.1038/gt.2011.176 Hamilton, 2018, A recombinant antibody-expressing influenza virus delays tumor growth in a mouse model, Cell Rep., 22, 1, 10.1016/j.celrep.2017.12.025 Thomas, 2019, Development of a new fusion-enhanced oncolytic immunotherapy platform based on herpes simplex virus type 1, J. Immunother. Cancer, 7, 214, 10.1186/s40425-019-0682-1 Vijayakumar, 2019, Oncolytic Newcastle disease virus expressing a checkpoint inhibitor as a radioenhancing agent for murine melanoma, EBioMedicine, 49, 96, 10.1016/j.ebiom.2019.10.032 Yang, 2019, An oncolytic adenovirus targeting transforming growth factor β inhibits protumorigenic signals and produces immune activation: A novel approach to enhance anti-PD-1 and anti-CTLA-4 therapy, Hum. Gene Ther., 30, 1117, 10.1089/hum.2019.059 Xu, 2014, Ad5/48 hexon oncolytic virus expressing sTGFβRIIFc produces reduced hepatic and systemic toxicities and inhibits prostate cancer bone metastases, Mol. Ther, 22, 1504, 10.1038/mt.2014.80 Hu, 2012, Systemic delivery of oncolytic adenoviruses targeting transforming growth factor-β inhibits established bone metastasis in a prostate cancer mouse model, Hum. Gene Ther., 23, 871, 10.1089/hum.2012.040 Hu, 2011, Oncolytic adenovirus expressing soluble TGFβ receptor II-Fc-mediated inhibition of established bone metastases: A safe and effective systemic therapeutic approach for breast cancer, Mol. Ther, 19, 1609, 10.1038/mt.2011.114 Gujar, 2014, Oncolytic virus-mediated reversal of impaired tumor antigen presentation, Front. Oncol., 4, 77, 10.3389/fonc.2014.00077 Hervas-Stubbs, 2011, Direct effects of type I interferons on cells of the immune system, Clin. Cancer Res, 17, 2619, 10.1158/1078-0432.CCR-10-1114 Kawai, 2006, Innate immune recognition of viral infection, Nat. Immunol., 7, 131, 10.1038/ni1303 Nesslinger, 2010, A viral vaccine encoding prostate-specific antigen induces antigen spreading to a common set of self-proteins in prostate cancer patients, Clin. Cancer Res, 16, 4046, 10.1158/1078-0432.CCR-10-0948 Brossart, 2020, The role of antigen spreading in the efficacy of immunotherapies, Clin. Cancer. Res, 26, 4442, 10.1158/1078-0432.CCR-20-0305 Woller, 2015, Viral infection of tumors overcomes resistance to PD-1-immunotherapy by broadening neoantigenome-directed T-cell responses, Mol. Ther., 23, 1630, 10.1038/mt.2015.115 Gujar, 2013, Multifaceted therapeutic targeting of ovarian peritoneal carcinomatosis through virus-induced immunomodulation, Mol. Ther, 21, 338, 10.1038/mt.2012.228 Gujar, 2010, Reovirus virotherapy overrides tumor antigen presentation evasion and promotes protective antitumor immunity, Mol. Cancer Ther, 9, 2924, 10.1158/1535-7163.MCT-10-0590 Curtsinger, 2010, Inflammatory cytokines as a third signal for T cell activation, Curr. Opin. Immunol., 22, 333, 10.1016/j.coi.2010.02.013 Hervas-Stubbs, 2010, Effects of IFN-α as a signal-3 cytokine on human naïve and antigen-experienced CD8(+) T cells, Eur. J. Immunol., 40, 3389, 10.1002/eji.201040664 Lapteva, 2009, Attraction and activation of dendritic cells at the site of tumor elicits potent antitumor immunity, Mol. Ther, 17, 1626, 10.1038/mt.2009.111 Sobol, 2011, Adaptive antiviral immunity is a determinant of the therapeutic success of oncolytic virotherapy, Mol. Ther, 19, 335, 10.1038/mt.2010.264 Twumasi-Boateng, 2018, Oncolytic viruses as engineering platforms for combination immunotherapy, Nat. Rev. Cancer, 18, 419, 10.1038/s41568-018-0009-4 Liu, 2013, Induction of antiviral genes by the tumor microenvironment confers resistance to virotherapy, Sci. Rep., 3, 2375, 10.1038/srep02375 Currier, 2013, VEGF blockade enables oncolytic cancer virotherapy in part by modulating intratumoral myeloid cells, Mol. Ther, 21, 1014, 10.1038/mt.2013.39 Puig-Kröger, 2009, Folate receptor β is expressed by tumor-associated macrophages and constitutes a marker for M2 anti-inflammatory/regulatory macrophages, Cancer Res., 69, 9395, 10.1158/0008-5472.CAN-09-2050 Lynn, 2015, Targeting of folate receptor β on acute myeloid leukemia blasts with chimeric antigen receptor-expressing T cells, Blood, 125, 3466, 10.1182/blood-2014-11-612721 Sharpe, 2018, The diverse functions of the PD1 inhibitory pathway, Nat. Rev. Immunol., 18, 153, 10.1038/nri.2017.108 Wei, 2018, Fundamental mechanisms of immune checkpoint blockade therapy, Cancer Discov., 8, 1069, 10.1158/2159-8290.CD-18-0367 Kahounová, 2018, The fibroblast surface markers FAP, anti-fibroblast, and FSP are expressed by cells of epithelial origin and may be altered during epithelial-to-mesenchymal transition, Cytometry A, 93, 941, 10.1002/cyto.a.23101 Sugimoto, 2006, Identification of fibroblast heterogeneity in the tumor microenvironment, Cancer Biol. Ther., 5, 1640, 10.4161/cbt.5.12.3354 Skokos, 2020, A class of costimulatory CD28-bispecific antibodies that enhance the antitumor activity of CD3-bispecific antibodies, Sci. Transl. Med, 12, eaaw7888, 10.1126/scitranslmed.aaw7888 Gleason, 2014, CD16xCD33 bispecific killer cell engager (BiKE) activates NK cells against primary MDS and MDSC CD33+ targets, Blood, 123, 3016, 10.1182/blood-2013-10-533398 Gauthier, 2019, Multifunctional natural killer cell engagers targeting NKp46 trigger protective tumor immunity, Cell, 177, 1701, 10.1016/j.cell.2019.04.041