To effectively build on the recent successes of immune checkpoint blockade, adoptive T cell therapy and cancer vaccines, it is critical to rationally design combination strategies that will increase and extend efficacy to a larger proportion of patients. For example, the combination of anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitors essentially doubles the response rate in certain patients with metastatic melanoma. However, given the heterogeneity of cancer, it seems likely that even more complex combinations of immunomodulatory agents may be required to obtain consistent, durable therapeutic responses against a broad spectrum of cancers. This carries serious implications in terms of toxicities for patients, feasibility for care providers and costs for health-care systems. A compelling solution is offered by oncolytic viruses (OVs), which can be engineered to selectively replicate within and destroy tumour tissue while simultaneously augmenting antitumour immunity. In this Opinion article, we argue that the future of immunotherapy will include OVs that function as multiplexed immune-modulating platforms expressing factors such as immune checkpoint inhibitors, tumour antigens, cytokines and T cell engagers. We illustrate this concept by following the trials and tribulations of tumour-reactive T cells from their initial priming through to the execution of cytotoxic effector function in the tumour bed. We highlight the myriad opportunities for OVs to help overcome critical barriers in the T cell journey, leading to new synergistic mechanisms in the battle against cancer.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Gonzalez, S. et al. Conceptual aspects of self and nonself discrimination. Self Nonself 2, 19–25 (2011).
Felix, J. & Savvides, S. N. Mechanisms of immunomodulation by mammalian and viral decoy receptors: insights from structures. Nat. Rev. Immunol. 17, 112–129 (2017).
McFadden, G., Mohamed, M. R., Rahman, M. M. & Bartee, E. Cytokine determinants of viral tropism. Nat. Rev. Immunol. 9, 645–655 (2009).
Muik, A. et al. Re-engineering vesicular stomatitis virus to abrogate neurotoxicity, circumvent humoral immunity, and enhance oncolytic potency. Cancer Res. 74, 3567–3578 (2014).
Pikor, L. A., Bell, J. C. & Diallo, J.-S. Oncolytic viruses: exploiting cancer’s deal with the devil. Trends Cancer 1, 266–277 (2015).
Parker, B. S., Rautela, J. & Hertzog, P. J. Antitumour actions of interferons: implications for cancer therapy. Nat. Rev. Cancer 16, 131–144 (2016).
Stojdl, D. F. et al. VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer Cell 4, 263–275 (2003).
Stojdl, D. F. et al. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nature Med. 6, 821–825 (2000).
Brun, J. et al. Identification of genetically modified Maraba virus as an oncolytic rhabdovirus. Mol. Ther. 18, 1440–1449 (2010).
Ott, P. A. & Hodi, F. S. Talimogene laherparepvec for the treatment of advanced melanoma. Clin. Cancer Res. 22, 3127–3131 (2016).
Poh, A. First oncolytic viral therapy for melanoma. Cancer Discov. 6, 6 (2016).
Liu, B. L. et al. ICP34.5 deleted herpes simplex virus with enhanced oncolytic, immune stimulating, and anti-tumour properties. Gene Ther. 10, 292–303 (2003).
Fruh, K. et al. A viral inhibitor of peptide transporters for antigen presentation. Nature 375, 415–418 (1995).
Hill, A. et al. Herpes simplex virus turns off the TAP to evade host immunity. Nature 375, 411–415 (1995).
US National Library of Medicine. ClinicalTrials.gov http://www.Clinicaltrials.gov/ct2/Show/NCT02562755 (2015).
Kim, J. H. et al. Systemic armed oncolytic and immunologic therapy for cancer with JX-594, a targeted poxvirus expressing GM-CSF. Mol. Ther. 14, 361–370 (2006).
Alcami, A., Symons, J. A. & Smith, G. L. The vaccinia virus soluble alpha/beta interferon (IFN) receptor binds to the cell surface and protects cells from the antiviral effects of IFN. J. Virol. 74, 11230–11239 (2000).
Prlic, M., Williams, M. A. & Bevan, M. J. Requirements for CD8 T cell priming, memory generation and maintenance. Curr. Opin. Immunol. 19, 315–319 (2007).
Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).
Brown, M. C. et al. Cancer immunotherapy with recombinant poliovirus induces IFN-dominant activation of dendritic cells and tumor antigen-specific CTLs. Sci. Transl Med. 9, pii:eaan4220 (2017).
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).
Mastrangelo, M. J. et al. Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma. Cancer Gene Ther. 6, 409–422 (1999).
Kaufman, H. L. et al. Local and distant immunity induced by intralesional vaccination with an oncolytic herpes virus encoding GM-CSF in patients with stage IIIc and IV melanoma. Ann. Surg. Oncol. 17, 718–730 (2010).
US National Library of Medicine. ClinicalTrials.gov. http://www.Clinicaltrials.gov/ct2/Show/NCT00769704 (2008).
Andtbacka, R. H. et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33, 2780–2788 (2015).
Sharp, D. W. & Lattime, E. C. Recombinant poxvirus and the tumor microenvironment: oncolysis, immune regulation and immunization. Biomedicines 4, 19 pii: (2016).
Pol, J. G. et al. Maraba virus as a potent oncolytic vaccine vector. Mol. Ther. 22, 420–429 (2014).
Bridle, B. W. et al. Privileged antigen presentation in splenic B cell follicles maximizes T cell responses in prime-boost vaccination. J. Immunol. 196, 4587–4595 (2016).
Messina, J. L. et al. 12-Chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy? Sci. Rep. 2, 765 (2012).
Bronger, H. et al. CXCL9 and CXCL10 predict survival and are regulated by cyclooxygenase inhibition in advanced serous ovarian cancer. Br. J. Cancer 115, 553–563 (2016).
Berghuis, D. et al. Pro-inflammatory chemokine-chemokine receptor interactions within the Ewing sarcoma microenvironment determine CD8(+) T-lymphocyte infiltration and affect tumour progression. J. Pathol. 223, 347–357 (2011).
Chew, V. et al. Chemokine-driven lymphocyte infiltration: an early intratumoural event determining long-term survival in resectable hepatocellular carcinoma. Gut 61, 427–438 (2012).
Mlecnik, B. et al. Biomolecular network reconstruction identifies T cell homing factors associated with survival in colorectal cancer. Gastroenterology 138, 1429–1440 (2010).
Zumwalt, T. J., Arnold, M., Goel, A. & Boland, C. R. Active secretion of CXCL10 and CCL5 from colorectal cancer microenvironments associates with GranzymeB+CD8+T cell infiltration. Oncotarget 6, 2981–2991 (2015).
Vestweber, D. How leukocytes cross the vascular endothelium. Nat. Rev. Immunol. 15, 692–704 (2015).
Gajewski, T. F. The next hurdle in cancer immunotherapy: overcoming the non-T-cell-inflamed tumor microenvironment. Semin. Oncol. 42, 663–671 (2015).
Woo, S. R., Corrales, L. & Gajewski, T. F. Innate immune recognition of cancer. Annu. Rev. Immunol. 33, 445–474 (2015).
Rabinovich, G. A., Gabrilovich, D. & Sotomayor, E. M. Immunosuppressive strategies that are mediated by tumor cells. Annu. Rev. Immunol. 25, 267–296 (2007).
Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015).
Cicchini, L. et al. Suppression of antitumor immune responses by human papillomavirus through epigenetic downregulation of CXCL14. MBio 7, pii: e00270–16 (2016).
Garcia-Sastre, A. & Biron, C. A. Type 1 interferons and the virus-host relationship: a lesson in detente. Science 312, 879–882 (2006).
Melcher, A., Parato, K., Rooney, C. M. & Bell, J. C. Thunder and lightning: immunotherapy and oncolytic viruses collide. Mol. Ther. 19, 1008–1016 (2011).
Li, X. et al. The efficacy of oncolytic adenovirus is mediated by T cell responses against virus and tumor in Syrian hamster model. Clin. Cancer Res. 23, 239–249 (2017).
Kleijn, A. et al. The in vivo therapeutic efficacy of the oncolytic adenovirus Delta24-RGD is mediated by tumor-specific immunity. PLoS ONE 9, e97495 (2014).
Benencia, F., Courreges, M. C., Fraser, N. W. & Coukos, G. Herpes virus oncolytic therapy reverses tumor immune dysfunction and facilitates tumor antigen presentation. Cancer Biol. Ther. 7, 1194–1205 (2008).
Benencia, F. et al. HSV oncolytic therapy upregulates interferon-inducible chemokines and recruits immune effector cells in ovarian cancer. Mol. Ther. 12, 789–802 (2005).
Chuang, C. M., Monie, A., Wu, A., Pai, S. I. & Hung, C. F. Combination of viral oncolysis and tumor-specific immunity to control established tumors. Clin. Cancer Res. 15, 4581–4588 (2009).
Vigil, A., Martinez, O., Chua, M. A. & Garcia-Sastre, A. Recombinant Newcastle disease virus as a vaccine vector for cancer therapy. Mol. Ther. 16, 1883–1890 (2008).
Heinzerling, L. et al. Oncolytic measles virus in cutaneous T cell lymphomas mounts antitumor immune responses in vivo and targets interferon-resistant tumor cells. Blood 106, 2287–2294 (2005).
Garcia-Carbonero, R. et al. Phase 1 study of intravenous administration of the chimeric adenovirus enadenotucirev in patients undergoing primary tumor resection. J. Immunother. Cancer 5, 71 (2017).
Samson, A. et al. Intravenous delivery of oncolytic reovirus to brain tumor patients immunologically primes for subsequent checkpoint blockade. Sci. Transl Med. 10, pii: eaam7577 (2018).
Newton, K. & Dixit, V. M. Signaling in innate immunity and inflammation. Cold Spring Harb. Perspect. Biol. 4, pii: a006049 (2012).
Haraldsen, G., Kvale, D., Lien, B., Farstad, I. N. & Brandtzaeg, P. Cytokine-regulated expression of E-selectin, intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) in human microvascular endothelial cells. J. Immunol. 156, 2558–2565 (1996).
Spertini, O. et al. Leukocyte adhesion molecule-1 (LAM-1, L-selectin) interacts with an inducible endothelial cell ligand to support leukocyte adhesion. J. Immunol. 147, 2565–2573 (1991).
Kaufman, H. L., Kohlhapp, F. J. & Zloza, A. Oncolytic viruses: a new class of immunotherapy drugs. Nat. Rev. Drug Discov. 14, 642–662 (2015).
Aurelian, L., Bollino, D. & Colunga, A. The oncolytic virus DeltaPK has multimodal anti-tumor activity. Pathog. Dis. 74, ftw050 (2016).
Errington, F. et al. Reovirus activates human dendritic cells to promote innate antitumor immunity. J. Immunol. 180, 6018–6026 (2008).
Wakimoto, H. et al. The complement response against an oncolytic virus is species-specific in its activation pathways. Mol. Ther. 5, 275–282 (2002).
Guo, Z. S., Thorne, S. H. & Bartlett, D. L. Oncolytic virotherapy: molecular targets in tumor-selective replication and carrier cell-mediated delivery of oncolytic viruses. Biochim. Biophys. Acta 1785, 217–231 (2008).
Baril, M. et al. Genome-wide RNAi screen reveals a new role of a WNT/CTNNB1 signaling pathway as negative regulator of virus-induced innate immune responses. PLoS Pathog. 9, e1003416 (2013).
Li, J. et al. Expression of CCL19 from oncolytic vaccinia enhances immunotherapeutic potential while maintaining oncolytic activity. Neoplasia 14, 1115–1121 (2012).
Li, J. et al. Chemokine expression from oncolytic vaccinia virus enhances vaccine therapies of cancer. Mol. Ther. 19, 650–657 (2011).
Nishio, N. et al. Armed oncolytic virus enhances immune functions of chimeric antigen receptor-modified T cells in solid tumors. Cancer Res. 74, 5195–5205 (2014).
Wall, E. M. et al. Spontaneous mammary tumors differ widely in their inherent sensitivity to adoptively transferred T cells. Cancer Res. 67, 6442–6450 (2007).
Martin, M. L. et al. Density of tumour stroma is correlated to outcome after adoptive transfer of CD4+ and CD8+T cells in a murine mammary carcinoma model. Breast Cancer Res. Treat. 121, 753–763 (2009).
Hartmann, N. et al. Prevailing role of contact guidance in intrastromal T cell trapping in human pancreatic cancer. Clin. Cancer Res. 20, 3422–3433 (2014).
Breitbach, C. J. et al. Targeting tumor vasculature with an oncolytic virus. Mol. Ther. 19, 886–894 (2011).
Breitbach, C. J. et al. Targeted inflammation during oncolytic virus therapy severely compromises tumor blood flow. Mol. Ther. 15, 1686–1693 (2007).
Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).
Amulic, B., Cazalet, C., Hayes, G. L., Metzler, K. D. & Zychlinsky, A. Neutrophil function: from mechanisms to disease. Annu. Rev. Immunol. 30, 459–489 (2012).
Gregory, A. D. & Houghton, A. M. Tumor-associated neutrophils: new targets for cancer therapy. Cancer Res. 71, 2411–2416 (2011).
Pham, C. T. Neutrophil serine proteases: specific regulators of inflammation. Nat. Rev. Immunol. 6, 541–550 (2006).
Tedcastle, A., Illingworth, S., Brown, A., Seymour, L. W. & Fisher, K. D. Actin-resistant DNAse I Expression from oncolytic adenovirus enadenotucirev enhances its intratumoral spread and reduces tumor growth. Mol. Ther. 24, 796–804 (2016).
Ilkow, C. S. et al. Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity. Nat. Med. 21, 530–536 (2015).
Feig, C. et al. Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc. Natl Acad. Sci. USA 110, 20212–20217 (2013).
Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).
Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).
Zhang, F. et al. TGF-beta induces M2-like macrophage polarization via SNAIL-mediated suppression of a pro-inflammatory phenotype. Oncotarget 7, 52294–52306 (2016).
Mosser, D. M. & Zhang, X. Interleukin-10: new perspectives on an old cytokine. Immunol. Rev. 226, 205–218 (2008).
Munn, D. H. & Mellor, A. L. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J. Clin. Invest. 117, 1147–1154 (2007).
Biswas, S. K. et al. A distinct and unique transcriptional program expressed by tumor-associated macrophages (defective NF-kappaB and enhanced IRF-3/STAT1 activation). Blood 107, 2112–2122 (2006).
Friberg, M. et al. Indoleamine 2,3-dioxygenase contributes to tumor cell evasion of T cell-mediated rejection. Int. J. Cancer 101, 151–155 (2002).
Gabrilovich, D. I., Velders, M. P., Sotomayor, E. M. & Kast, W. M. Mechanism of immune dysfunction in cancer mediated by immature Gr-1+ myeloid cells. J. Immunol. 166, 5398–5406 (2001).
Gorelik, L. & Flavell, R. A. Transforming growth factor-beta in T cell biology. Nat. Rev. Immunol. 2, 46–53 (2002).
Mellor, A. L., Keskin, D. B., Johnson, T., Chandler, P. & Munn, D. H. Cells expressing indoleamine 2,3-dioxygenase inhibit T cell responses. J. Immunol. 168, 3771–3776 (2002).
Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).
Rodriguez, P. C. et al. Arginase I production in the tumor microenvironment by mature myeloid cells inhibits T cell receptor expression and antigen-specific T cell responses. Cancer Res. 64, 5839–5849 (2004).
Serafini, P. et al. Derangement of immune responses by myeloid suppressor cells. Cancer Immunol. Immunother. 53, 64–72 (2004).
Prestwich, R. J. et al. Tumor infection by oncolytic reovirus primes adaptive antitumor immunity. Clin. Cancer Res. 14, 7358–7366 (2008).
Gyotoku, T., Ono, F. & Aurelian, L. Development of HSV-specific CD4 + Th1 responses and CD8+ cytotoxic T lymphocytes with antiviral activity by vaccination with the HSV-2 mutant ICP10DeltaPK. Vaccine 20, 2796–2807 (2002).
Fournier, P., Arnold, A., Wilden, H. & Schirrmacher, V. Newcastle disease virus induces pro-inflammatory conditions and type I interferon for counter-acting Treg activity. Int. J. Oncol. 40, 840–850 (2012).
Bourgeois-Daigneault, M. C. et al. Oncolytic vesicular stomatitis virus expressing interferon-gamma has enhanced therapeutic activity. Mol. Ther. Oncolytics 3, 16001 (2016).
Wongthida, P. et al. VSV oncolytic virotherapy in the B16 model depends upon intact MyD88 signaling. Mol. Ther. 19, 150–158 (2011).
Errington, F. et al. Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma. Gene Ther. 15, 1257–1270 (2008).
Obermajer, N., Muthuswamy, R., Odunsi, K., Edwards, R. P. & Kalinski, P. PGE(2)-induced CXCL12 production and CXCR4 expression controls the accumulation of human MDSCs in ovarian cancer environment. Cancer Res. 71, 7463–7470 (2011).
Kalinski, P. Regulation of immune responses by prostaglandin E2. J. Immunol. 188, 21–28 (2012).
Hou, W., Sampath, P., Rojas, J. J. & Thorne, S. H. Oncolytic virus-mediated targeting of PGE2 in the tumor alters the immune status and sensitizes established and resistant tumors to immunotherapy. Cancer Cell 30, 108–119 (2016).
Tahtinen, S. et al. Adenovirus improves the efficacy of adoptive T cell therapy by recruiting immune cells to and promoting their activity at the tumor. Cancer Immunol. Res. 3, 915–925 (2015).
McKinney, E. F. & Smith, K. G. T cell exhaustion: understanding the interface of chronic viral and autoinflammatory diseases. Immunol. Cell Biol. 94, 935–942 (2016).
Cornberg, M. et al. Clonal exhaustion as a mechanism to protect against severe immunopathology and death from an overwhelming CD8 T cell response. Front. Immunol. 4, 475 (2013).
Lichty, B. D., Breitbach, C. J., Stojdl, D. F. & Bell, J. C. Going viral with cancer immunotherapy. Nat. Rev. Cancer 14, 559–567 (2014).
Bourgeois-Daigneault, M. C. et al. Neoadjuvant oncolytic virotherapy before surgery sensitizes triple-negative breast cancer to immune checkpoint therapy. Sci. Transl. Med. 10, pii: eaao1641 (2018).
Liu, 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. 8, 14754 (2017).
Engeland, C. E. et al. CTLA-4 and PD-L1 checkpoint blockade enhances oncolytic measles virus therapy. Mol. Ther. 22, 1949–1959 (2014).
Saha, D., Martuza, R. L. & Rabkin, S. D. Macrophage polarization contributes to glioblastoma eradication by combination immunovirotherapy and immune checkpoint blockade. Cancer Cell 32, 253–267 e255 (2017).
Ilett, E. et al. Prime-boost using separate oncolytic viruses in combination with checkpoint blockade improves anti-tumour therapy. Gene Ther. 24, 21–30 (2017).
Zamarin, D. et al. Intratumoral modulation of the inducible co-stimulator ICOS by recombinant oncolytic virus promotes systemic anti-tumour immunity. Nat. Commun. 8, 14340 (2017).
Hardcastle, J. et al. Immunovirotherapy with measles virus strains in combination with anti-PD-1 antibody blockade enhances antitumor activity in glioblastoma treatment. Neuro Oncol. 19, 493–502 (2017).
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).
Chen, C. Y. et al. Cooperation of oncolytic herpes virotherapy and PD-1 blockade in murine rhabdomyosarcoma models. Sci. Rep. 7, 2396 (2017).
Zamarin, D. et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci. Transl. Med. 6, 226ra232 (2014).
Ribas, A. et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 170, 1109–1119 e1110 (2017).
Puzanov, I. et al. Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma. J. Clin. Oncol. 34, 2619–2626 (2016).
Zamarin, D. et al. PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy. J. Clin. Invest. https://doi.org/10.1172/JCI98047 (2018).
Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).
Dempke, W. C. M., Fenchel, K., Uciechowski, P. & Dale, S. P. Second- and third-generation drugs for immuno-oncology treatment-the more the better? Eur. J. Cancer 74, 55–72 (2017).
Kleinpeter, P. et al. 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 (2016).
Bartee, M. Y., Dunlap, K. M. & Bartee, E. Tumor-localized secretion of soluble PD1 enhances oncolytic virotherapy. Cancer Res. 77, 2952–2963 (2017).
Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
Simon, S. & Labarriere, N. PD-1 expression on tumor-specific T cells: friend or foe for immunotherapy? Oncoimmunology 7, e1364828 (2017).
Concha-Benavente, F., Srivastava, R., Ferrone, S. & Ferris, R. L. Immunological and clinical significance of HLA class I antigen processing machinery component defects in malignant cells. Oral Oncol. 58, 52–58 (2016).
Reeves, E. & James, E. Antigen processing and immune regulation in the response to tumours. Immunology 150, 16–24 (2016).
Atkins, D. et al. MHC class I antigen processing pathway defects, ras mutations and disease stage in colorectal carcinoma. Int. J. Cancer 109, 265–273 (2004).
Khong, H. T., Wang, Q. J. & Rosenberg, S. A. Identification of multiple antigens recognized by tumor-infiltrating lymphocytes from a single patient: tumor escape by antigen loss and loss of MHC expression. J. Immunother. 27, 184–190 (2004).
Restifo, N. P. et al. Loss of functional beta 2-microglobulin in metastatic melanomas from five patients receiving immunotherapy. J. Natl Cancer Inst. 88, 100–108 (1996).
McGranahan, N. et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171, 1259–1271 e1211 (2017).
Marty, R. et al. MHC-I genotype restricts the oncogenic mutational landscape. Cell 171, 1272–1283 e1215 (2017).
Gujar, S. A. & Lee, P. W. Oncolytic virus-mediated reversal of impaired tumor antigen presentation. Front. Oncol. 4, 77 (2014).
Fonteneau, J. F., Guillerme, J. B., Tangy, F. & Gregoire, M. Attenuated measles virus used as an oncolytic virus activates myeloid and plasmacytoid dendritic cells. Oncoimmunology 2, e24212 (2013).
Guillerme, J. B. et al. Measles virus vaccine-infected tumor cells induce tumor antigen cross-presentation by human plasmacytoid dendritic cells. Clin. Cancer Res. 19, 1147–1158 (2013).
Gujar, S. et al. Multifaceted therapeutic targeting of ovarian peritoneal carcinomatosis through virus-induced immunomodulation. Mol. Ther. 21, 338–347 (2013).
Gujar, S. A., Marcato, P., Pan, D. & Lee, P. W. Reovirus virotherapy overrides tumor antigen presentation evasion and promotes protective antitumor immunity. Mol. Cancer Ther. 9, 2924–2933 (2010).
Todo, T., Martuza, R. L., Rabkin, S. D. & Johnson, P. A. Oncolytic herpes simplex virus vector with enhanced MHC class I presentation and tumor cell killing. Proc. Natl Acad. Sci. USA 98, 6396–6401 (2001).
Bhat, R. & Rommelaere, J. Emerging role of natural killer cells in oncolytic virotherapy. Immunotargets Ther. 4, 65–77 (2015).
Kantarjian, H. et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N. Engl. J. Med. 376, 836–847 (2017).
Viardot, A. et al. Phase 2 study of the bispecific T cell engager (BiTE) antibody blinatumomab in relapsed/refractory diffuse large B cell lymphoma. Blood 127, 1410–1416 (2016).
Zugmaier, G. et al. Long-term survival and T cell kinetics in relapsed/refractory ALL patients who achieved MRD response after blinatumomab treatment. Blood 126, 2578–2584 (2015).
Scott, E. M., Duffy, M. R., Freedman, J. D., Fisher, K. D. & Seymour, L. W. Solid tumor immunotherapy with T cell engager-armed oncolytic viruses. Macromol. Biosci. https://doi.org/10.1002/mabi.201700187 (2017).
Yu, F. et al. T cell engager-armed oncolytic vaccinia virus significantly enhances antitumor therapy. Mol. Ther. 22, 102–111 (2014).
Freedman, J. D. et al. Oncolytic adenovirus expressing bispecific antibody targets T cell cytotoxicity in cancer biopsies. EMBO Mol. Med. 9, 1067–1087 (2017).
Kuhn, I. et al. Directed evolution generates a novel oncolytic virus for the treatment of colon cancer. PloS ONE 3, e2409 (2008).
Paul, S. et al. Tumor gene therapy by MVA-mediated expression of T cell-stimulating antibodies. Cancer Gene Ther. 9, 470–477 (2002).
US National Library of Medicine. ClinicalTrials.gov. http://www.Clinicaltrials.gov/ct2/Show/NCT02028442 (2014).
Breitbach, C. J. et al. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature 477, 99–102 (2011).
Dudley, M. E. et al. Adoptive cell transfer therapy following non-myeloablative but lymphodepleting chemotherapy for the treatment of patients with refractory metastatic melanoma. J. Clin. Oncol. 23, 2346–2357 (2005).
Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).
Besser, M. J. et al. Clinical responses in a phase II study using adoptive transfer of short-term cultured tumor infiltration lymphocytes in metastatic melanoma patients. Clin. Cancer Res. 16, 2646–2655 (2010).
Redeker, A. & Arens, R. Improving adoptive T cell therapy: the particular role of T cell costimulation, cytokines, and post-transfer vaccination. Front. Immunol. 7, 345 (2016).
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).
Hinrichs, C. S. et al. Adoptively transferred effector cells derived from naive rather than central memory CD8+ T cells mediate superior antitumor immunity. Proc. Natl Acad. Sci. USA 106, 17469–17474 (2009).
Hinrichs, C. S. et al. IL-2 and IL-21 confer opposing differentiation programs to CD8+ T cells for adoptive immunotherapy. Blood 111, 5326–5333 (2008).
Crompton, J. G., Sukumar, M. & Restifo, N. P. Uncoupling T cell expansion from effector differentiation in cell-based immunotherapy. Immunol. Rev. 257, 264–276 (2014).
Donia, M. et al. Characterization and comparison of ‘standard’ and ‘young’ tumour-infiltrating lymphocytes for adoptive cell therapy at a Danish translational research institution. Scand. J. Immunol. 75, 157–167 (2012).
Gattinoni, L. et al. Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells. J. Clin. Invest. 115, 1616–1626 (2005).
Yang, S. et al. Modulating the differentiation status of ex vivo-cultured anti-tumor T cells using cytokine cocktails. Cancer Immunol. Immunother. 62, 727–736 (2013).
Litterman, A. J., Zellmer, D. M., LaRue, R. S., Jameson, S. C. & Largaespada, D. A. Antigen-specific culture of memory-like CD8 T cells for adoptive immunotherapy. Cancer Immunol. Res. 2, 839–845 (2014).
Klebanoff, C. A. et al. Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells. Proc. Natl Acad. Sci. USA 102, 9571–9576 (2005).
Berger, C. et al. Adoptive transfer of effector CD8+ T cells derived from central memory cells establishes persistent T cell memory in primates. J. Clin. Invest. 118, 294–305 (2008).
Diaz, R. M. et al. Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus. Cancer Res. 67, 2840–2848 (2007).
Kaczanowska, S., Joseph, A. M. & Davila, E. TLR agonists: our best frenemy in cancer immunotherapy. J. Leukoc. Biol. 93, 847–863 (2013).
Adams, S. Toll-like receptor agonists in cancer therapy. Immunotherapy 1, 949–964 (2009).
Guha, M. Anticancer TLR agonists on the ropes. Nat. Rev. Drug Discov. 11, 503–505 (2012).
Rosewell Shaw, A. et al. Adenovirotherapy delivering cytokine and checkpoint inhibitor augments CAR T cells against metastatic head and neck cancer. Mol. Ther. 25, 2440–2451 (2017).
Arulanandam, R. et al. Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing. Nat. Commun. 6, 6410 (2015).
Diallo, J. S. et al. A high-throughput pharmacoviral approach identifies novel oncolytic virus sensitizers. Mol. Ther. 18, 1123–1129 (2010).
Dornan, M. H. et al. First-in-class small molecule potentiators of cancer virotherapy. Sci. Rep. 6, 26786 (2016).
Rojas, J. J. et al. Manipulating TLR signaling increases the anti-tumor T cell response induced by viral cancer therapies. Cell Rep. 15, 264–273 (2016).
Tober, R. et al. VSV-GP: a potent viral vaccine vector that boosts the immune response upon repeated applications. J. Virol. 88, 4897–4907 (2014).
Carlisle, R. et al. Enhanced tumor uptake and penetration of virotherapy using polymer stealthing and focused ultrasound. J. Natl Cancer Inst. 105, 1701–1710 (2013).
Kim, J., Hall, R. R., Lesniak, M. S. & Ahmed, A. U. Stem cell-based cell carrier for targeted oncolytic virotherapy: translational opportunity and open questions. Viruses 7, 6200–6217 (2015).
Roy, D. G. et al. Programmable insect cell carriers for systemic delivery of integrated cancer biotherapy. J. Control Release 220, 210–221 (2015).
Leoni, V. et al. Systemic delivery of HER2-retargeted oncolytic-HSV by mesenchymal stromal cells protects from lung and brain metastases. Oncotarget 6, 34774–34787 (2015).
Roy, D. G. & Bell, J. C. Cell carriers for oncolytic viruses: current challenges and future directions. Oncolytic Virother. 2, 47–56 (2013).
Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).
Nistal-Villan, E. et al. Enhanced therapeutic effect using sequential administration of antigenically distinct oncolytic viruses expressing oncostatin M in a Syrian hamster orthotopic pancreatic cancer model. Mol. Cancer 14, 210 (2015).
Le Boeuf, F. et al. Synergistic interaction between oncolytic viruses augments tumor killing. Mol. Ther. 18, 888–895 (2010).
Yang, Z. et al. Expression profiling of the intermediate and late stages of poxvirus replication. J. Virol. 85, 9899–9908 (2011).
Yang, Z., Maruri-Avidal, L., Sisler, J., Stuart, C. A. & Moss, B. Cascade regulation of vaccinia virus gene expression is modulated by multistage promoters. Virology 447, 213–220 (2013).
Prestwich, R. J. et al. The case of oncolytic viruses versus the immune system: waiting on the judgment of Solomon. Hum. Gene Ther. 20, 1119–1132 (2009).
Miller, C. G. & Fraser, N. W. Requirement of an integrated immune response for successful neuroattenuated HSV-1 therapy in an intracranial metastatic melanoma model. Mol. Ther. 7, 741–747 (2003).
Sobol, P. T. et al. Adaptive antiviral immunity is a determinant of the therapeutic success of oncolytic virotherapy. Mol. Ther. 19, 335–344 (2011).
Blankenstein, T., Coulie, P. G., Gilboa, E. & Jaffee, E. M. The determinants of tumour immunogenicity. Nat. Rev. Cancer 12, 307–313 (2012).
Aleksic, M. et al. Different affinity windows for virus and cancer-specific T cell receptors: implications for therapeutic strategies. Eur. J. Immunol. 42, 3174–3179 (2012).
Kotturi, M. F. et al. Naive precursor frequencies and MHC binding rather than the degree of epitope diversity shape CD8+ T cell immunodominance. J. Immunol. 181, 2124–2133 (2008).
Obar, J. J., Khanna, K. M. & Lefrancois, L. Endogenous naive CD8+ T cell precursor frequency regulates primary and memory responses to infection. Immunity 28, 859–869 (2008).
Bridle, B. W. et al. Vesicular stomatitis virus as a novel cancer vaccine vector to prime antitumor immunity amenable to rapid boosting with adenovirus. Mol. Ther. 17, 1814–1821 (2009).
Verdegaal, E. M. et al. Neoantigen landscape dynamics during human melanoma-T cell interactions. Nature 536, 91–95 (2016).
Ruella, M. & June, C. H. Chimeric antigen receptor T cells for B cell neoplasms: choose the right CAR for you. Curr. Hematol. Malig Rep. 11, 368–384 (2016).
Getts, D. R., Chastain, E. M., Terry, R. L. & Miller, S. D. Virus infection, antiviral immunity, and autoimmunity. Immunol. Rev. 255, 197–209 (2013).
Shlomchik, M. J. Activating systemic autoimmunity: B’s, T’s, and tolls. Curr. Opin. Immunol. 21, 626–633 (2009).
Vanderlugt, C. L. & Miller, S. D. Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat. Rev. Immunol. 2, 85–95 (2002).
Mamula, M. J. Epitope spreading: the role of self peptides and autoantigen processing by B lymphocytes. Immunol. Rev. 164, 231–239 (1998).
Tesniere, A. et al. Molecular characteristics of immunogenic cancer cell death. Cell Death Differ. 15, 3–12 (2008).
Garg, A. D., Romano, E., Rufo, N. & Agostinis, P. Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation. Cell Death Differ. 23, 938–951 (2016).
Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28, 690–714 (2015).
Vacchelli, E. et al. Trial Watch: Immunotherapy plus radiation therapy for oncological indications. Oncoimmunology 5, e1214790 (2016).
Greiner, S. et al. The highly attenuated vaccinia virus strain modified virus Ankara induces apoptosis in melanoma cells and allows bystander dendritic cells to generate a potent anti-tumoral immunity. Clin. Exp. Immunol. 146, 344–353 (2006).
Moehler, M. H. et al. Parvovirus H-1-induced tumor cell death enhances human immune response in vitro via increased phagocytosis, maturation, and cross-presentation by dendritic cells. Hum. Gene Ther. 16, 996–1005 (2005).
Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013).
Green, D. R., Ferguson, T., Zitvogel, L. & Kroemer, G. Immunogenic and tolerogenic cell death. Nat. Rev. Immunol. 9, 353–363 (2009).
Workenhe, S. T. & Mossman, K. L. Oncolytic virotherapy and immunogenic cancer cell death: sharpening the sword for improved cancer treatment strategies. Mol. Ther. 22, 251–256 (2014).
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).
Liikanen, I. et al. Oncolytic adenovirus with temozolomide induces autophagy and antitumor immune responses in cancer patients. Mol. Ther. 21, 1212–1223 (2013).
Diaconu, I. et al. Immune response is an important aspect of the antitumor effect produced by a CD40L-encoding oncolytic adenovirus. Cancer Res. 72, 2327–2338 (2012).
Workenhe, S. T. et al. Immunogenic HSV-mediated oncolysis shapes the antitumor immune response and contributes to therapeutic efficacy. Mol. Ther. 22, 123–131 (2014).
Miyamoto, S. et al. Coxsackievirus B3 is an oncolytic virus with immunostimulatory properties that is active against lung adenocarcinoma. Cancer Res. 72, 2609–2621 (2012).
Donnelly, O. G. et al. Measles virus causes immunogenic cell death in human melanoma. Gene Ther. 20, 7–15 (2013).
Pulido, J. et al. Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma. Nat. Biotechnol. 30, 337–343 (2012).
Yang, J. C. & Rosenberg, S. A. Adoptive T-cell therapy for cancer. Adv. Immunol. 130, 279–294 (2016).
Rosenberg, S. A. et al. Durable complete responses in heavily pretreated patients with metastatic melanoma using T cell transfer immunotherapy. Clin. Cancer Res. 17, 4550–4557 (2011).
Robbins, P. F. et al. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T cell receptor: long-term follow-up and correlates with response. Clin. Cancer Res. 21, 1019–1027 (2015).
Robbins, P. F. et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 29, 917–924 (2011).
Fesnak, A. D., June, C. H. & Levine, B. L. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat. Rev. Cancer 16, 566–581 (2016).
Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).
Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).
Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2015).
Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).
Kochenderfer, J. N. et al. Chemotherapy-refractory diffuse large B cell lymphoma and indolent B cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J. Clin. Oncol. 33, 540–549 (2015).
Kochenderfer, J. N. et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels. J. Clin. Oncol. 35, 1803–1813 (2017).
Kershaw, M. H. et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin. Cancer Res. 12, 6106–6115 (2006).
Ahmed, N. et al. Human epidermal growth factor receptor 2 (HER2) -specific chimeric antigen receptor-modified t cells for the immunotherapy of HER2-positive sarcoma. J. Clin. Oncol. 33, 1688–1696 (2015).
Kageyama, S. et al. Adoptive transfer of MAGE-A4 T cell receptor gene-transduced lymphocytes in patients with recurrent esophageal cancer. Clin. Cancer Res. 21, 2268–2277 (2015).
K.T.-B. was supported by a postdoctoral fellowship from the Susan G. Komen Foundation. B.H.N. receives support from the British Columbia Cancer Foundation. J.C.B. and B.H.N. receive support from the Canadian Institutes of Health Research, the Canadian Cancer Society Research Institute and The Terry Fox Foundation. J.C.B. also receives funding from the Ontario Institute for Cancer Research.
Nature Reviews Cancer thanks A. Melcher and the other anonymous reviewer(s) for their contribution to the peer review of this work.
J.C.B. is co-founder of Turnstone Biologics, a paid consultant for Turnstone Biologics and on the Board of Directors for Turnstone Biologics. K.T.-B., J.L.P., Y.Y.E.K. and B.H.N. declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
PsiOxus Therapeutics: http://psioxus.com
About this article
Cite this article
Twumasi-Boateng, K., Pettigrew, J.L., Kwok, Y.Y.E. et al. Oncolytic viruses as engineering platforms for combination immunotherapy. Nat Rev Cancer 18, 419–432 (2018). https://doi.org/10.1038/s41568-018-0009-4
Oncolytic virotherapy reverses the immunosuppressive tumor microenvironment and its potential in combination with immunotherapy
Cancer Cell International (2021)
Journal of Hematology & Oncology (2021)
Nature Reviews Immunology (2021)
Nature Chemical Biology (2021)
Modulating the tumor microenvironment via oncolytic virus and PI3K inhibition synergistically restores immune checkpoint therapy response in PTEN-deficient glioblastoma
Signal Transduction and Targeted Therapy (2021)