OPINION

Oncolytic viruses as engineering platforms for combination immunotherapy

A Publisher Correction to this article was published on 04 May 2018

This article has been updated

Abstract

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.

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Fig. 1: Mechanisms by which oncolytic viruses stimulate antitumour immunity.
Fig. 2: Design elements of a multiplexed immune-modulating oncolytic virus.

Change history

  • 04 May 2018

    In the online html version of this article, the affiliations for Jessica L. Pettigrew and John C. Bell were not correct. Jessica L. Pettigrew is at the Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada and John C. Bell is at the Center for Innovative Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada. This is correct in the print and PDF versions of the article and has been corrected in the html version.

References

  1. 1.

    Gonzalez, S. et al. Conceptual aspects of self and nonself discrimination. Self Nonself 2, 19–25 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Felix, J. & Savvides, S. N. Mechanisms of immunomodulation by mammalian and viral decoy receptors: insights from structures. Nat. Rev. Immunol. 17, 112–129 (2017).

    PubMed  Article  CAS  Google Scholar 

  3. 3.

    McFadden, G., Mohamed, M. R., Rahman, M. M. & Bartee, E. Cytokine determinants of viral tropism. Nat. Rev. Immunol. 9, 645–655 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  4. 4.

    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).

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Pikor, L. A., Bell, J. C. & Diallo, J.-S. Oncolytic viruses: exploiting cancer’s deal with the devil. Trends Cancer 1, 266–277 (2015).

    PubMed  Article  Google Scholar 

  6. 6.

    Parker, B. S., Rautela, J. & Hertzog, P. J. Antitumour actions of interferons: implications for cancer therapy. Nat. Rev. Cancer 16, 131–144 (2016).

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    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).

    PubMed  Article  CAS  Google Scholar 

  8. 8.

    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).

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Brun, J. et al. Identification of genetically modified Maraba virus as an oncolytic rhabdovirus. Mol. Ther. 18, 1440–1449 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  10. 10.

    Ott, P. A. & Hodi, F. S. Talimogene laherparepvec for the treatment of advanced melanoma. Clin. Cancer Res. 22, 3127–3131 (2016).

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Poh, A. First oncolytic viral therapy for melanoma. Cancer Discov. 6, 6 (2016).

    PubMed  Google Scholar 

  12. 12.

    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).

    PubMed  Article  CAS  Google Scholar 

  13. 13.

    Fruh, K. et al. A viral inhibitor of peptide transporters for antigen presentation. Nature 375, 415–418 (1995).

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Hill, A. et al. Herpes simplex virus turns off the TAP to evade host immunity. Nature 375, 411–415 (1995).

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    US National Library of Medicine. ClinicalTrials.gov http://www.Clinicaltrials.gov/ct2/Show/NCT02562755 (2015).

  16. 16.

    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).

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  18. 18.

    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).

    PubMed  Article  CAS  Google Scholar 

  19. 19.

    Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic beta-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).

    PubMed  Article  CAS  Google Scholar 

  20. 20.

    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).

    Article  Google Scholar 

  21. 21.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 22.

    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).

    PubMed  Article  CAS  Google Scholar 

  23. 23.

    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).

    PubMed  Article  Google Scholar 

  24. 24.

    US National Library of Medicine. ClinicalTrials.gov. http://www.Clinicaltrials.gov/ct2/Show/NCT00769704 (2008).

  25. 25.

    Andtbacka, R. H. et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J. Clin. Oncol. 33, 2780–2788 (2015).

    PubMed  Article  CAS  Google Scholar 

  26. 26.

    Sharp, D. W. & Lattime, E. C. Recombinant poxvirus and the tumor microenvironment: oncolysis, immune regulation and immunization. Biomedicines 4, 19 pii: (2016).

    Article  CAS  Google Scholar 

  27. 27.

    Pol, J. G. et al. Maraba virus as a potent oncolytic vaccine vector. Mol. Ther. 22, 420–429 (2014).

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    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).

    PubMed  Article  CAS  Google Scholar 

  29. 29.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. 30.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  31. 31.

    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).

    PubMed  Article  CAS  Google Scholar 

  32. 32.

    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).

    PubMed  Article  CAS  Google Scholar 

  33. 33.

    Mlecnik, B. et al. Biomolecular network reconstruction identifies T cell homing factors associated with survival in colorectal cancer. Gastroenterology 138, 1429–1440 (2010).

    PubMed  Article  CAS  Google Scholar 

  34. 34.

    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).

    PubMed  Article  Google Scholar 

  35. 35.

    Vestweber, D. How leukocytes cross the vascular endothelium. Nat. Rev. Immunol. 15, 692–704 (2015).

    PubMed  Article  CAS  Google Scholar 

  36. 36.

    Gajewski, T. F. The next hurdle in cancer immunotherapy: overcoming the non-T-cell-inflamed tumor microenvironment. Semin. Oncol. 42, 663–671 (2015).

    PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Woo, S. R., Corrales, L. & Gajewski, T. F. Innate immune recognition of cancer. Annu. Rev. Immunol. 33, 445–474 (2015).

    PubMed  Article  CAS  Google Scholar 

  38. 38.

    Rabinovich, G. A., Gabrilovich, D. & Sotomayor, E. M. Immunosuppressive strategies that are mediated by tumor cells. Annu. Rev. Immunol. 25, 267–296 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  39. 39.

    Peng, D. et al. Epigenetic silencing of TH1-type chemokines shapes tumour immunity and immunotherapy. Nature 527, 249–253 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  40. 40.

    Cicchini, L. et al. Suppression of antitumor immune responses by human papillomavirus through epigenetic downregulation of CXCL14. MBio 7, pii: e00270–16 (2016).

    Article  Google Scholar 

  41. 41.

    Garcia-Sastre, A. & Biron, C. A. Type 1 interferons and the virus-host relationship: a lesson in detente. Science 312, 879–882 (2006).

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Melcher, A., Parato, K., Rooney, C. M. & Bell, J. C. Thunder and lightning: immunotherapy and oncolytic viruses collide. Mol. Ther. 19, 1008–1016 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  43. 43.

    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).

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  45. 45.

    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).

    PubMed  Article  CAS  Google Scholar 

  46. 46.

    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).

    PubMed  Article  CAS  Google Scholar 

  47. 47.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  48. 48.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  49. 49.

    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).

    PubMed  Article  CAS  Google Scholar 

  50. 50.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  51. 51.

    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).

    Article  Google Scholar 

  52. 52.

    Newton, K. & Dixit, V. M. Signaling in innate immunity and inflammation. Cold Spring Harb. Perspect. Biol. 4, pii: a006049 (2012).

    Article  CAS  Google Scholar 

  53. 53.

    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).

    PubMed  CAS  Google Scholar 

  54. 54.

    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).

    PubMed  CAS  Google Scholar 

  55. 55.

    Kaufman, H. L., Kohlhapp, F. J. & Zloza, A. Oncolytic viruses: a new class of immunotherapy drugs. Nat. Rev. Drug Discov. 14, 642–662 (2015).

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Aurelian, L., Bollino, D. & Colunga, A. The oncolytic virus DeltaPK has multimodal anti-tumor activity. Pathog. Dis. 74, ftw050 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  57. 57.

    Errington, F. et al. Reovirus activates human dendritic cells to promote innate antitumor immunity. J. Immunol. 180, 6018–6026 (2008).

    PubMed  Article  CAS  Google Scholar 

  58. 58.

    Wakimoto, H. et al. The complement response against an oncolytic virus is species-specific in its activation pathways. Mol. Ther. 5, 275–282 (2002).

    PubMed  Article  CAS  Google Scholar 

  59. 59.

    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).

    PubMed  PubMed Central  CAS  Google Scholar 

  60. 60.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  61. 61.

    Li, J. et al. Expression of CCL19 from oncolytic vaccinia enhances immunotherapeutic potential while maintaining oncolytic activity. Neoplasia 14, 1115–1121 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  62. 62.

    Li, J. et al. Chemokine expression from oncolytic vaccinia virus enhances vaccine therapies of cancer. Mol. Ther. 19, 650–657 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  63. 63.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  64. 64.

    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).

    PubMed  Article  CAS  Google Scholar 

  65. 65.

    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).

    PubMed  Article  Google Scholar 

  66. 66.

    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).

    PubMed  Article  CAS  Google Scholar 

  67. 67.

    Breitbach, C. J. et al. Targeting tumor vasculature with an oncolytic virus. Mol. Ther. 19, 886–894 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  68. 68.

    Breitbach, C. J. et al. Targeted inflammation during oncolytic virus therapy severely compromises tumor blood flow. Mol. Ther. 15, 1686–1693 (2007).

    PubMed  Article  CAS  Google Scholar 

  69. 69.

    Fridlender, Z. G. et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 16, 183–194 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. 70.

    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).

    PubMed  Article  CAS  Google Scholar 

  71. 71.

    Gregory, A. D. & Houghton, A. M. Tumor-associated neutrophils: new targets for cancer therapy. Cancer Res. 71, 2411–2416 (2011).

    PubMed  Article  CAS  Google Scholar 

  72. 72.

    Pham, C. T. Neutrophil serine proteases: specific regulators of inflammation. Nat. Rev. Immunol. 6, 541–550 (2006).

    PubMed  Article  CAS  Google Scholar 

  73. 73.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  74. 74.

    Ilkow, C. S. et al. Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity. Nat. Med. 21, 530–536 (2015).

    PubMed  Article  CAS  Google Scholar 

  75. 75.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  76. 76.

    Noy, R. & Pollard, J. W. Tumor-associated macrophages: from mechanisms to therapy. Immunity 41, 49–61 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  77. 77.

    Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  78. 78.

    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).

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Mosser, D. M. & Zhang, X. Interleukin-10: new perspectives on an old cytokine. Immunol. Rev. 226, 205–218 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  80. 80.

    Munn, D. H. & Mellor, A. L. Indoleamine 2,3-dioxygenase and tumor-induced tolerance. J. Clin. Invest. 117, 1147–1154 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  81. 81.

    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).

    PubMed  Article  CAS  Google Scholar 

  82. 82.

    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).

    PubMed  Article  CAS  Google Scholar 

  83. 83.

    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).

    PubMed  Article  CAS  Google Scholar 

  84. 84.

    Gorelik, L. & Flavell, R. A. Transforming growth factor-beta in T cell biology. Nat. Rev. Immunol. 2, 46–53 (2002).

    PubMed  Article  CAS  Google Scholar 

  85. 85.

    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).

    PubMed  Article  CAS  Google Scholar 

  86. 86.

    Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).

    PubMed  Article  CAS  Google Scholar 

  87. 87.

    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).

    PubMed  Article  CAS  Google Scholar 

  88. 88.

    Serafini, P. et al. Derangement of immune responses by myeloid suppressor cells. Cancer Immunol. Immunother. 53, 64–72 (2004).

    PubMed  Article  CAS  Google Scholar 

  89. 89.

    Prestwich, R. J. et al. Tumor infection by oncolytic reovirus primes adaptive antitumor immunity. Clin. Cancer Res. 14, 7358–7366 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  90. 90.

    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).

    PubMed  Article  CAS  Google Scholar 

  91. 91.

    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).

    PubMed  CAS  Google Scholar 

  92. 92.

    Bourgeois-Daigneault, M. C. et al. Oncolytic vesicular stomatitis virus expressing interferon-gamma has enhanced therapeutic activity. Mol. Ther. Oncolytics 3, 16001 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  93. 93.

    Wongthida, P. et al. VSV oncolytic virotherapy in the B16 model depends upon intact MyD88 signaling. Mol. Ther. 19, 150–158 (2011).

    PubMed  Article  CAS  Google Scholar 

  94. 94.

    Errington, F. et al. Inflammatory tumour cell killing by oncolytic reovirus for the treatment of melanoma. Gene Ther. 15, 1257–1270 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  95. 95.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. 96.

    Kalinski, P. Regulation of immune responses by prostaglandin E2. J. Immunol. 188, 21–28 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  97. 97.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  98. 98.

    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).

    PubMed  Article  CAS  Google Scholar 

  99. 99.

    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).

    PubMed  Article  CAS  Google Scholar 

  100. 100.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  101. 101.

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

    PubMed  Article  CAS  Google Scholar 

  102. 102.

    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).

    Article  Google Scholar 

  103. 103.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  104. 104.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  105. 105.

    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).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  106. 106.

    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).

    PubMed  Article  CAS  Google Scholar 

  107. 107.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. 108.

    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).

    PubMed  Google Scholar 

  109. 109.

    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).

    PubMed  Article  CAS  Google Scholar 

  110. 110.

    Chen, C. Y. et al. Cooperation of oncolytic herpes virotherapy and PD-1 blockade in murine rhabdomyosarcoma models. Sci. Rep. 7, 2396 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  111. 111.

    Zamarin, D. et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci. Transl. Med. 6, 226ra232 (2014).

    Article  CAS  Google Scholar 

  112. 112.

    Ribas, A. et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 170, 1109–1119 e1110 (2017).

    PubMed  Article  CAS  Google Scholar 

  113. 113.

    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).

    PubMed  Article  CAS  Google Scholar 

  114. 114.

    Zamarin, D. et al. PD-L1 in tumor microenvironment mediates resistance to oncolytic immunotherapy. J. Clin. Invest. https://doi.org/10.1172/JCI98047 (2018).

  115. 115.

    Wolchok, J. D. et al. Overall survival with combined nivolumab and ipilimumab in advanced melanoma. N. Engl. J. Med. 377, 1345–1356 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  116. 116.

    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).

    PubMed  Article  CAS  Google Scholar 

  117. 117.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  118. 118.

    Bartee, M. Y., Dunlap, K. M. & Bartee, E. Tumor-localized secretion of soluble PD1 enhances oncolytic virotherapy. Cancer Res. 77, 2952–2963 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  119. 119.

    Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  120. 120.

    Simon, S. & Labarriere, N. PD-1 expression on tumor-specific T cells: friend or foe for immunotherapy? Oncoimmunology 7, e1364828 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  122. 122.

    Reeves, E. & James, E. Antigen processing and immune regulation in the response to tumours. Immunology 150, 16–24 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  123. 123.

    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).

    PubMed  Article  CAS  Google Scholar 

  124. 124.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  126. 126.

    McGranahan, N. et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171, 1259–1271 e1211 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  127. 127.

    Marty, R. et al. MHC-I genotype restricts the oncogenic mutational landscape. Cell 171, 1272–1283 e1215 (2017).

    PubMed  Article  CAS  Google Scholar 

  128. 128.

    Gujar, S. A. & Lee, P. W. Oncolytic virus-mediated reversal of impaired tumor antigen presentation. Front. Oncol. 4, 77 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  130. 130.

    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).

    PubMed  Article  CAS  Google Scholar 

  131. 131.

    Gujar, S. et al. Multifaceted therapeutic targeting of ovarian peritoneal carcinomatosis through virus-induced immunomodulation. Mol. Ther. 21, 338–347 (2013).

    PubMed  Article  CAS  Google Scholar 

  132. 132.

    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).

    PubMed  Article  CAS  Google Scholar 

  133. 133.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  134. 134.

    Bhat, R. & Rommelaere, J. Emerging role of natural killer cells in oncolytic virotherapy. Immunotargets Ther. 4, 65–77 (2015).

    PubMed  PubMed Central  CAS  Google Scholar 

  135. 135.

    Kantarjian, H. et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N. Engl. J. Med. 376, 836–847 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  136. 136.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  137. 137.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  138. 138.

    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).

  139. 139.

    Yu, F. et al. T cell engager-armed oncolytic vaccinia virus significantly enhances antitumor therapy. Mol. Ther. 22, 102–111 (2014).

    PubMed  Article  CAS  Google Scholar 

  140. 140.

    Freedman, J. D. et al. Oncolytic adenovirus expressing bispecific antibody targets T cell cytotoxicity in cancer biopsies. EMBO Mol. Med. 9, 1067–1087 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  141. 141.

    Kuhn, I. et al. Directed evolution generates a novel oncolytic virus for the treatment of colon cancer. PloS ONE 3, e2409 (2008).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  142. 142.

    Paul, S. et al. Tumor gene therapy by MVA-mediated expression of T cell-stimulating antibodies. Cancer Gene Ther. 9, 470–477 (2002).

    PubMed  Article  CAS  Google Scholar 

  143. 143.

    US National Library of Medicine. ClinicalTrials.gov. http://www.Clinicaltrials.gov/ct2/Show/NCT02028442 (2014).

  144. 144.

    Breitbach, C. J. et al. Intravenous delivery of a multi-mechanistic cancer-targeted oncolytic poxvirus in humans. Nature 477, 99–102 (2011).

    PubMed  Article  CAS  Google Scholar 

  145. 145.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  146. 146.

    Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).

    PubMed  Article  CAS  Google Scholar 

  147. 147.

    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).

    PubMed  Article  CAS  Google Scholar 

  148. 148.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  149. 149.

    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).

    PubMed  Article  CAS  Google Scholar 

  150. 150.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  152. 152.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  153. 153.

    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).

    PubMed  Article  CAS  Google Scholar 

  154. 154.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  155. 155.

    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).

    PubMed  Article  CAS  Google Scholar 

  156. 156.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  157. 157.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  158. 158.

    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).

    PubMed  Article  CAS  Google Scholar 

  159. 159.

    Diaz, R. M. et al. Oncolytic immunovirotherapy for melanoma using vesicular stomatitis virus. Cancer Res. 67, 2840–2848 (2007).

    PubMed  Article  CAS  Google Scholar 

  160. 160.

    Kaczanowska, S., Joseph, A. M. & Davila, E. TLR agonists: our best frenemy in cancer immunotherapy. J. Leukoc. Biol. 93, 847–863 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  161. 161.

    Adams, S. Toll-like receptor agonists in cancer therapy. Immunotherapy 1, 949–964 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  162. 162.

    Guha, M. Anticancer TLR agonists on the ropes. Nat. Rev. Drug Discov. 11, 503–505 (2012).

    PubMed  Article  CAS  Google Scholar 

  163. 163.

    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).

    PubMed  Article  CAS  Google Scholar 

  164. 164.

    Arulanandam, R. et al. Microtubule disruption synergizes with oncolytic virotherapy by inhibiting interferon translation and potentiating bystander killing. Nat. Commun. 6, 6410 (2015).

    PubMed  Article  CAS  Google Scholar 

  165. 165.

    Diallo, J. S. et al. A high-throughput pharmacoviral approach identifies novel oncolytic virus sensitizers. Mol. Ther. 18, 1123–1129 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  166. 166.

    Dornan, M. H. et al. First-in-class small molecule potentiators of cancer virotherapy. Sci. Rep. 6, 26786 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  167. 167.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  168. 168.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  169. 169.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  170. 170.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  171. 171.

    Roy, D. G. et al. Programmable insect cell carriers for systemic delivery of integrated cancer biotherapy. J. Control Release 220, 210–221 (2015).

    PubMed  Article  CAS  Google Scholar 

  172. 172.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  173. 173.

    Roy, D. G. & Bell, J. C. Cell carriers for oncolytic viruses: current challenges and future directions. Oncolytic Virother. 2, 47–56 (2013).

    PubMed  PubMed Central  Google Scholar 

  174. 174.

    Chen, D. S. & Mellman, I. Oncology meets immunology: the cancer-immunity cycle. Immunity 39, 1–10 (2013).

    PubMed  Article  CAS  Google Scholar 

  175. 175.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  176. 176.

    Le Boeuf, F. et al. Synergistic interaction between oncolytic viruses augments tumor killing. Mol. Ther. 18, 888–895 (2010).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  177. 177.

    Yang, Z. et al. Expression profiling of the intermediate and late stages of poxvirus replication. J. Virol. 85, 9899–9908 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  178. 178.

    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).

    PubMed  Article  CAS  Google Scholar 

  179. 179.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  180. 180.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  181. 181.

    Sobol, P. T. et al. Adaptive antiviral immunity is a determinant of the therapeutic success of oncolytic virotherapy. Mol. Ther. 19, 335–344 (2011).

    PubMed  Article  CAS  Google Scholar 

  182. 182.

    Blankenstein, T., Coulie, P. G., Gilboa, E. & Jaffee, E. M. The determinants of tumour immunogenicity. Nat. Rev. Cancer 12, 307–313 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  183. 183.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  184. 184.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  185. 185.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  186. 186.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  187. 187.

    Verdegaal, E. M. et al. Neoantigen landscape dynamics during human melanoma-T cell interactions. Nature 536, 91–95 (2016).

    PubMed  Article  CAS  Google Scholar 

  188. 188.

    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).

    PubMed  Article  Google Scholar 

  189. 189.

    Getts, D. R., Chastain, E. M., Terry, R. L. & Miller, S. D. Virus infection, antiviral immunity, and autoimmunity. Immunol. Rev. 255, 197–209 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  190. 190.

    Shlomchik, M. J. Activating systemic autoimmunity: B’s, T’s, and tolls. Curr. Opin. Immunol. 21, 626–633 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  191. 191.

    Vanderlugt, C. L. & Miller, S. D. Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat. Rev. Immunol. 2, 85–95 (2002).

    PubMed  Article  CAS  Google Scholar 

  192. 192.

    Mamula, M. J. Epitope spreading: the role of self peptides and autoantigen processing by B lymphocytes. Immunol. Rev. 164, 231–239 (1998).

    PubMed  Article  CAS  Google Scholar 

  193. 193.

    Tesniere, A. et al. Molecular characteristics of immunogenic cancer cell death. Cell Death Differ. 15, 3–12 (2008).

    PubMed  Article  CAS  Google Scholar 

  194. 194.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  195. 195.

    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).

    PubMed  Article  CAS  Google Scholar 

  196. 196.

    Vacchelli, E. et al. Trial Watch: Immunotherapy plus radiation therapy for oncological indications. Oncoimmunology 5, e1214790 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  197. 197.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  198. 198.

    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).

    PubMed  Article  CAS  Google Scholar 

  199. 199.

    Kroemer, G., Galluzzi, L., Kepp, O. & Zitvogel, L. Immunogenic cell death in cancer therapy. Annu. Rev. Immunol. 31, 51–72 (2013).

    PubMed  Article  CAS  Google Scholar 

  200. 200.

    Green, D. R., Ferguson, T., Zitvogel, L. & Kroemer, G. Immunogenic and tolerogenic cell death. Nat. Rev. Immunol. 9, 353–363 (2009).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  201. 201.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  202. 202.

    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).

    PubMed  PubMed Central  Google Scholar 

  203. 203.

    Liikanen, I. et al. Oncolytic adenovirus with temozolomide induces autophagy and antitumor immune responses in cancer patients. Mol. Ther. 21, 1212–1223 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  204. 204.

    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).

    PubMed  Article  CAS  Google Scholar 

  205. 205.

    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).

    PubMed  Article  CAS  Google Scholar 

  206. 206.

    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).

    PubMed  Article  CAS  Google Scholar 

  207. 207.

    Donnelly, O. G. et al. Measles virus causes immunogenic cell death in human melanoma. Gene Ther. 20, 7–15 (2013).

    PubMed  Article  CAS  Google Scholar 

  208. 208.

    Pulido, J. et al. Using virally expressed melanoma cDNA libraries to identify tumor-associated antigens that cure melanoma. Nat. Biotechnol. 30, 337–343 (2012).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  209. 209.

    Yang, J. C. & Rosenberg, S. A. Adoptive T-cell therapy for cancer. Adv. Immunol. 130, 279–294 (2016).

    PubMed  Article  Google Scholar 

  210. 210.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  211. 211.

    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).

    PubMed  Article  CAS  Google Scholar 

  212. 212.

    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).

    PubMed  PubMed Central  Article  Google Scholar 

  213. 213.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  214. 214.

    Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  215. 215.

    Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  216. 216.

    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).

    PubMed  Article  CAS  Google Scholar 

  217. 217.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  218. 218.

    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).

    PubMed  Article  CAS  Google Scholar 

  219. 219.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  220. 220.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  221. 221.

    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).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  222. 222.

    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).

    PubMed  Article  CAS  Google Scholar 

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Acknowledgements

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.

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Nature Reviews Cancer thanks A. Melcher and the other anonymous reviewer(s) for their contribution to the peer review of this work.

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K.T.-B. and J.L.P. researched the data for the article. All authors provided a substantial contribution to discussions of the content. Y.Y.E.K. drafted figures with input from K.T.-B., B.H.N. and J.C.B. K.T.-B. wrote the initial article and B.H.N., J.C.B. and K.T.-B. reviewed and edited the manuscript before submission.

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Correspondence to John C. Bell or Brad H. Nelson.

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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.

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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

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