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Personalizing Oncolytic Immunovirotherapy Approaches

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Abstract

Development of successful cancer therapeutics requires exploration of the differences in genetics, metabolism, and interactions with the immune system among malignant and normal cells. The clinical observation of spontaneous tumor regression following natural infection with microorganism has created the premise of their use as cancer therapeutics. Oncolytic viruses (OVs) originate from viruses with attenuated virulence in humans, well-characterized vaccine strains of known human pathogens, or engineered replication-deficient viral vectors. Their selectivity is based on receptor expression level and post entry restriction factors that favor replication in the tumor, while keeping the normal cells unharmed. Clinical trials have demonstrated a wide range of patient responses to virotherapy, with subgroups of patients significantly benefiting from OV administration. Tumor-specific gene signatures, including antiviral interferon-stimulated gene (ISG) expression profile, have demonstrated a strong correlation with tumor permissiveness to infection. Furthermore, the combination of OVs with immunotherapeutics, including anticancer vaccines and immune checkpoint inhibitors [ICIs, such as anti-PD-1/PD-L1 or anti-CTLA-4 and chimeric antigen receptor (CAR)-T or CAR-NK cells], could synergistically improve the therapeutic outcome. Creating response prediction algorithms represents an important step for the transition to individualized immunovirotherapy approaches in the clinic. Integrative predictors could include tumor mutational burden (TMB), inflammatory gene signature, phenotype of tumor-infiltrating lymphocytes, tumor microenvironment (TME), and immune checkpoint receptor expression on both immune and target cells. Additionally, the gut microbiota has recently been recognized as a systemic immunomodulatory factor and could further be used in the optimization of individualized immunovirotherapy algorithms.

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References

  1. Kelly E, Russell SJ. History of oncolytic viruses: genesis to genetic engineering. Mol Ther. 2007;15(4):651–9.

    Article  CAS  PubMed  Google Scholar 

  2. Kucerova P, Cervinkova M. Spontaneous regression of tumour and the role of microbial infection—possibilities for cancer treatment. Anticancer Drugs. 2016;27(4):269–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Murray PR, Rosenthal K, Pfaller MA. Viral classification, structure, and replication. In: Medical Microbiology, 9th ed.; 2021. p. 362–77.

  4. Santos Apolonio J, Lima de Souza Goncalves V, Cordeiro Santos ML, Silva Luz M, Silva Souza JV, Rocha Pinheiro SL, et al. Oncolytic virus therapy in cancer: a current review. World J Virol. 2021;10(5):229–55.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Hemminki O, Dos Santos JM, Hemminki A. Oncolytic viruses for cancer immunotherapy. J Hematol Oncol. 2020;13(1):84.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Gujar SA, Lee PW. Oncolytic virus-mediated reversal of impaired tumor antigen presentation. Front Oncol. 2014;4:77.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Grard M, Idjellidaine M, Arbabian A, Chatelain C, Berland L, Combredet C, et al. Oncolytic attenuated measles virus encoding NY-ESO-1 induces HLA I and II presentation of this tumor antigen by melanoma and dendritic cells. Cancer Immunol Immunother. 2023;72:3309–22.

    Article  CAS  PubMed  Google Scholar 

  8. Pol JG, Workenhe ST, Konda P, Gujar S, Kroemer G. Cytokines in oncolytic virotherapy. Cytokine Growth Factor Rev. 2020;56:4–27.

    Article  CAS  PubMed  Google Scholar 

  9. Ye K, Li F, Wang R, Cen T, Liu S, Zhao Z, et al. An armed oncolytic virus enhances the efficacy of tumor-infiltrating lymphocyte therapy by converting tumors to artificial antigen-presenting cells in situ. Mol Ther. 2022;30(12):3658–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cerullo V, Diaconu I, Romano V, Hirvinen M, Ugolini M, Escutenaire S, et al. An oncolytic adenovirus enhanced for toll-like receptor 9 stimulation increases antitumor immune responses and tumor clearance. Mol Ther. 2012;20(11):2076–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ramachandran M, Yu D, Wanders A, Essand M, Eriksson F. An infection-enhanced oncolytic adenovirus secreting H. pylori neutrophil-activating protein with therapeutic effects on neuroendocrine tumors. Mol Ther. 2013;21(11):2008–18.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Iankov ID, Allen C, Federspiel MJ, Myers RM, Peng KW, Ingle JN, et al. Expression of immunomodulatory neutrophil-activating protein of Helicobacter pylori enhances the antitumor activity of oncolytic measles virus. Mol Ther. 2012;20(6):1139–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Alard E, Butnariu AB, Grillo M, Kirkham C, Zinovkin DA, Newnham L, et al. Advances in anti-cancer immunotherapy: CAR-T cell, checkpoint inhibitors, dendritic cell vaccines, and oncolytic viruses, and emerging cellular and molecular targets. Cancers (Basel). 2020;12(7):1826.

    Article  CAS  PubMed  Google Scholar 

  14. Abbas AK, Lichtman A, Pillai S. Innate immunity: the early defense against infections. Amsterdam: Elsevier; 2023.

    Google Scholar 

  15. Jones JE, Le Sage V, Lakdawala SS. Viral and host heterogeneity and their effects on the viral life cycle. Nat Rev Microbiol. 2021;19(4):272–82.

    Article  CAS  PubMed  Google Scholar 

  16. Ikeda K, Wakimoto H, Ichikawa T, Jhung S, Hochberg FH, Louis DN, Chiocca EA. Complement depletion facilitates the infection of multiple brain tumors by an intravascular, replication-conditional herpes simplex virus mutant. J Virol. 2000;74:4765–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Magge D, Guo ZS, O’Malley ME, Francis L, Ravindranathan R, Bartlett DL. Inhibitors of C5 complement enhance vaccinia virus oncolysis. Cancer Gene Ther. 2013;20(6):342–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tesfay MZ, Ammayappan A, Federspiel MJ, Barber GN, Stojdl D, Peng KW, et al. Vesiculovirus neutralization by natural IgM and complement. J Virol. 2014;88(11):6148–57.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Li Q, Tan F, Wang Y, Liu X, Kong X, Meng J, et al. The gamble between oncolytic virus therapy and IFN. Front Immunol. 2022;13: 971674.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Takeuchi O, Akira S. Innate immunity to virus infection. Immunol Rev. 2009;227(1):75–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on toll-like receptors. Nat Immunol. 2010;11(5):373–84.

    Article  CAS  PubMed  Google Scholar 

  22. Rand U, Rinas M, Schwerk J, Nohren G, Linnes M, Kroger A, et al. Multi-layered stochasticity and paracrine signal propagation shape the type-I interferon response. Mol Syst Biol. 2012;8:584.

    Article  PubMed  PubMed Central  Google Scholar 

  23. Schneider WM, Chevillotte MD, Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol. 2014;32:513–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Ivashkiv LB, Donlin LT. Regulation of type I interferon responses. Nat Rev Immunol. 2014;14(1):36–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mazewski C, Perez RE, Fish EN, Platanias LC. Type I interferon (IFN)-regulated activation of canonical and non-canonical signaling pathways. Front Immunol. 2020;11: 606456.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Matveeva OV, Chumakov PM. Defects in interferon pathways as potential biomarkers of sensitivity to oncolytic viruses. Rev Med Virol. 2018;28(6): e2008.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chen M, Linstra R, van Vugt M. Genomic instability, inflammatory signaling and response to cancer immunotherapy. Biochim Biophys Acta Rev Cancer. 2022;1877(1): 188661.

    Article  CAS  PubMed  Google Scholar 

  28. Stojdl DFLB, tenOever BR, Paterson JM, Power AT, Knowles S, Marius R, Reynard J, Poliquin L, Atkins H, Brown EG, Durbin RK, Durbin JE, Hiscott J, Bell JC. VSV strains with defects in their ability to shutdown innate immunity are potent systemic anti-cancer agents. Cancer Cell. 2003;4:263–75.

    Article  CAS  PubMed  Google Scholar 

  29. Liu X, He B. Selective editing of herpes simplex virus 1 enables interferon induction and viral replication that destroy malignant cells. J Virol. 2019;93(2): e01761-18.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Naniche DYA, Eto D, Manchester M, Friedman RM, Oldstone MB. Evasion of host defenses by measles virus: wild-type measles virus infection interferes with induction of alpha/beta interferon production. J Virol. 2000;74:7478–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Price PJ, Torres-Dominguez LE, Brandmuller C, Sutter G, Lehmann MH. Modified Vaccinia virus Ankara: innate immune activation and induction of cellular signalling. Vaccine. 2013;31(39):4231–4.

    Article  CAS  PubMed  Google Scholar 

  32. Kurokawa C, Galanis E. Interferon signaling predicts response to oncolytic virotherapy. Oncotarget. 2019;10:1544–5.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Stojdl DF, Lichty B, Knowles S, Marius R, Atkins H, Sonenberg N, Bell JC. Exploiting tumor-specific defects in the interferon pathway with a previously unknown oncolytic virus. Nat Med. 2000;6:821–5.

    Article  CAS  PubMed  Google Scholar 

  34. Muster T, Rajtarova J, Sachet M, Unger H, Fleischhacker R, Romirer I, et al. Interferon resistance promotes oncolysis by influenza virus NS1-deletion mutants. Int J Cancer. 2004;110(1):15–21.

    Article  CAS  PubMed  Google Scholar 

  35. Ahmed M, Cramer SD, Lyles DS. Sensitivity of prostate tumors to wild type and M protein mutant vesicular stomatitis viruses. Virology. 2004;330(1):34–49.

    Article  CAS  PubMed  Google Scholar 

  36. Krishnamurthy S, Takimoto T, Scroggs RA, Portner A. Differentially regulated interferon response determines the outcome of Newcastle disease virus infection in normal and tumor cell lines. J Virol. 2006;80(11):5145–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kurokawa C, Iankov ID, Anderson SK, Aderca I, Leontovich AA, Maurer MJ, et al. Constitutive interferon pathway activation in tumors as an efficacy determinant following oncolytic virotherapy. J Natl Cancer Inst. 2018;110(10):1123–32.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Panagioti E, Kurokawa C, Viker K, Ammayappan A, Anderson SK, Sotiriou S, et al. Immunostimulatory bacterial antigen-armed oncolytic measles virotherapy significantly increases the potency of anti-PD1 checkpoint therapy. J Clin Investig. 2021;131(13): e141614.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Murphy AM, Besmer DM, Moerdyk-Schauwecker M, Moestl N, Ornelles DA, Mukherjee P, et al. Vesicular stomatitis virus as an oncolytic agent against pancreatic ductal adenocarcinoma. J Virol. 2012;86(6):3073–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Moerdyk-Schauwecker M, Shah NR, Murphy AM, Hastie E, Mukherjee P, Grdzelishvili VZ. Resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus: role of type I interferon signaling. Virology. 2013;436(1):221–34.

    Article  CAS  PubMed  Google Scholar 

  41. Paglino JC, van den Pol AN. Vesicular stomatitis virus has extensive oncolytic activity against human sarcomas: rare resistance is overcome by blocking interferon pathways. J Virol. 2011;85(18):9346–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Berchtold S, Lampe J, Weiland T, Smirnow I, Schleicher S, Handgretinger R, et al. Innate immune defense defines susceptibility of sarcoma cells to measles vaccine virus-based oncolysis. J Virol. 2013;87(6):3484–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Biswas M, Kumar SR, Allen A, Yong W, Nimmanapalli R, Samal SK, et al. Cell-type-specific innate immune response to oncolytic Newcastle disease virus. Viral Immunol. 2012;25(4):268–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Parrula MCM, Fernandez SA, Landes K, Huey D, Lairmore M, Niewiesk S. Success of measles virotherapy in ATL depends on type I interferon secretion and responsiveness. Virus Res. 2014;189:206–13.

    Article  CAS  Google Scholar 

  45. Liikanen I, Monsurro V, Ahtiainen L, Raki M, Hakkarainen T, Diaconu I, et al. Induction of interferon pathways mediates in vivo resistance to oncolytic adenovirus. Mol Ther. 2011;19(10):1858–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ruotsalainen JJ, Kaikkonen MU, Niittykoski M, Martikainen MW, Lemay CG, Cox J, et al. Clonal variation in interferon response determines the outcome of oncolytic virotherapy in mouse CT26 colon carcinoma model. Gene Ther. 2015;22(1):65–75.

    Article  CAS  PubMed  Google Scholar 

  47. Echchgadda ICT, Sabbah A, Bakri I, Ikeno Y, Hubbard GB, Chatterjee B, Bose S. Oncolytic targeting of androgen-sensitive prostate tumor by the respiratory syncytial virus (RSV): consequences of deficient interferon-dependent antiviral defense. BMC Cancer. 2011;11:43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang KX, Matsui Y, Hadaschik BA, Lee C, Jia W, Bell JC, et al. Down-regulation of type I interferon receptor sensitizes bladder cancer cells to vesicular stomatitis virus-induced cell death. Int J Cancer. 2010;127(4):830–8.

    Article  CAS  PubMed  Google Scholar 

  49. Li Q, Tainsky MA. Epigenetic silencing of IRF7 and/or IRF5 in lung cancer cells leads to increased sensitivity to oncolytic viruses. PLoS One. 2011;6(12): e28683.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  50. Suzuki M, Chiocca EA, Saeki Y. Early STAT1 activation after systemic delivery of HSV amplicon vectors suppresses transcription of the vector-encoded transgene. Mol Ther. 2007;15(11):2017–26.

    Article  CAS  PubMed  Google Scholar 

  51. Weichselbaum RR, Ishwaran H, Yoon T, Nuyten DS, Baker SW, Khodarev N, et al. An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer. Proc Natl Acad Sci USA. 2008;105(47):18490–5.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  52. Goad DW, Bressy C, Holbrook MC, Grdzelishvili VZ. Acquired chemoresistance can lead to increased resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus. Mol Ther Oncolytics. 2022;24:59–76.

    Article  CAS  PubMed  Google Scholar 

  53. Kurokawa C, Iankov ID, Galanis E. A key anti-viral protein, RSAD2/VIPERIN, restricts the release of measles virus from infected cells. Virus Res. 2019;263:145–50.

    Article  CAS  PubMed  Google Scholar 

  54. Li Y, Zhang C, Chen X, Yu J, Wang Y, Yang Y, et al. ICP34.5 protein of herpes simplex virus facilitates the initiation of protein translation by bridging eukaryotic initiation factor 2alpha (eIF2alpha) and protein phosphatase 1. J Biol Chem. 2011;286(28):24785–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhang C, Tang J, Xie J, Zhang H, Li Y, Zhang J, et al. A conserved domain of herpes simplex virus ICP34.5 regulates protein phosphatase complex in mammalian cells. FEBS Lett. 2008;582(2):171–6.

    Article  ADS  CAS  PubMed  Google Scholar 

  56. Manivanh R, Mehrbach J, Knipe DM, Leib DA. Role of herpes simplex virus 1 γ34.5 in the regulation of IRF3 signaling. J Virol. 2017;91: e01156-17.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Kambara H, Okano H, Chiocca EA, Saeki Y. An oncolytic HSV-1 mutant expressing ICP34.5 under control of a nestin promoter increases survival of animals even when symptomatic from a brain tumor. Cancer Res. 2005;65:2832–9.

    Article  CAS  PubMed  Google Scholar 

  58. Chiocca EA, Nakashima H, Kasai K, Fernandez SA, Oglesbee M. Preclinical toxicology of rQNestin34.5v.2: an oncolytic herpes virus with transcriptional regulation of the ICP34.5 neurovirulence gene. Mol Ther Methods Clin Dev. 2020;17:871–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Haralambieva I, Iankov I, Hasegawa K, Harvey M, Russell SJ, Peng KW. Engineering oncolytic measles virus to circumvent the intracellular innate immune response. Mol Ther. 2007;15(3):588–97.

    Article  CAS  PubMed  Google Scholar 

  60. Meng X, Nakamura T, Okazaki T, Inoue H, Takahashi A, Miyamoto S, et al. Enhanced antitumor effects of an engineered measles virus Edmonston strain expressing the wild-type N, P, L genes on human renal cell carcinoma. Mol Ther. 2010;18(3):544–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Felt SA, Droby G, Grdzelishvili VZ. Ruxolitinib and polycation combination treatment overcomes multiple mechanisms of resistance of pancreatic cancer cells to oncolytic vesicular stomatitis virus. J Virol. 2017;9: e00461-17.

    Article  Google Scholar 

  62. Patel MR, Dash A, Jacobson BA, Ji Y, Baumann D, Ismail K, et al. JAK/STAT inhibition with ruxolitinib enhances oncolytic virotherapy in non-small cell lung cancer models. Cancer Gene Ther. 2019;26(11–12):411–8.

    Article  CAS  PubMed  Google Scholar 

  63. Morse MA, Gwin WR 3rd, Mitchell DA. Vaccine therapies for cancer: then and now. Target Oncol. 2021;16(2):121–52.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Saxena M, van der Burg SH, Melief CJM, Bhardwaj N. Therapeutic cancer vaccines. Nat Rev Cancer. 2021;21(6):360–78.

    Article  CAS  PubMed  Google Scholar 

  65. Yamazaki H, Ohba Y, Tamaoki N, Shibuya M. A deletion mutation within the ligand binding domain is responsible for activation of epidermal growth factor receptor gene in human brain tumors. Jpn J Cancer Res. 1990;81(8):773–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Janelle V, Rulleau C, Del Testa S, Carli C, Delisle JS. T-Cell immunotherapies targeting histocompatibility and tumor antigens in hematological malignancies. Front Immunol. 2020;11:276.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Laumont CM, Vincent K, Hesnard L, Audemard E, Bonneil E, Laverdure JP, et al. Noncoding regions are the main source of targetable tumor-specific antigens. Sci Transl Med. 2018;10(470): eaau5516.

    Article  CAS  PubMed  Google Scholar 

  68. Wagner S, Mullins CS, Linnebacher M. Colorectal cancer vaccines: tumor-associated antigens vs neoantigens. World J Gastroenterol. 2018;24(48):5418–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Kim MK, Breitbach CJ, Moon A, Heo J, Lee YK, Cho M, et al. Oncolytic and immunotherapeutic vaccinia induces antibody-mediated complement-dependent cancer cell lysis in humans. Sci Transl Med. 2013;5(185): 185ra63.

    Article  PubMed  Google Scholar 

  70. Bateman A, Bullough F, Murphy S, Emiliusen L, Lavillette D, Cosset FL, et al. Fusogenic membrane glycoproteins as a novel class of genes for the local and immune-mediated control of tumor growth. Cancer Res. 2000;60(6):1492–7.

    CAS  PubMed  Google Scholar 

  71. Bateman AR, Harrington KJ, Kottke T, Ahmed A, Melcher AA, Gough MJ, et al. Viral fusogenic membrane glycoproteins kill solid tumor cells by nonapoptotic mechanisms that promote cross presentation of tumor antigens by dendritic cells. Cancer Res. 2002;62(22):6566–78.

    CAS  PubMed  Google Scholar 

  72. Ylosmaki E, Cerullo V. Design and application of oncolytic viruses for cancer immunotherapy. Curr Opin Biotechnol. 2020;65:25–36.

    Article  CAS  PubMed  Google Scholar 

  73. Jarnagin WR, Zager JS, Klimstra D, Delman KA, Malhotra S, Ebright M, et al. Neoadjuvant treatment of hepatic malignancy: an oncolytic herpes simplex virus expressing IL-12 effectively treats the parent tumor and protects against recurrence-after resection. Cancer Gene Ther. 2003;10(3):215–23.

    Article  CAS  PubMed  Google Scholar 

  74. Choi KJ, Kim JH, Lee YS, Kim J, Suh BS, Kim H, et al. Concurrent delivery of GM-CSF and B7–1 using an oncolytic adenovirus elicits potent antitumor effect. Gene Ther. 2006;13(13):1010–20.

    Article  CAS  PubMed  Google Scholar 

  75. Pol J, Kroemer G, Galluzzi L. First oncolytic virus approved for melanoma immunotherapy. Oncoimmunology. 2016;5(1): e1115641.

    Article  PubMed  Google Scholar 

  76. Andtbacka RHI, Collichio F, Harrington KJ, Middleton MR, Downey G, Ӧhrling K, et al. Final analyses of OPTiM: a randomized phase III trial of talimogene laherparepvec versus granulocyte-macrophage colony-stimulating factor in unresectable stage III-IV melanoma. J Immunother Cancer. 2019;7(1):145.

    Article  PubMed  PubMed Central  Google Scholar 

  77. Kim HS, Kim-Schulze S, Kim DW, Kaufman HL. Host lymphodepletion enhances the therapeutic activity of an oncolytic vaccinia virus expressing 4–1BB ligand. Cancer Res. 2009;69(21):8516–25.

    Article  CAS  PubMed  Google Scholar 

  78. Lu SC, Hansen MJ, Hemsath JR, Parrett BJ, Zell BN, Barry MA. Modulating oncolytic adenovirus immunotherapy by driving two axes of the immune system by expressing 4–1BBL and CD40L. Hum Gene Ther. 2022;33(5–6):250–61.

    Article  CAS  PubMed  Google Scholar 

  79. Huang JH, Zhang SN, Choi KJ, Choi IK, Kim JH, Lee MG, et al. Therapeutic and tumor-specific immunity induced by combination of dendritic cells and oncolytic adenovirus expressing IL-12 and 4–1BBL. Mol Ther. 2010;18(2):264–74.

    Article  CAS  PubMed  Google Scholar 

  80. Viker KB, Steele MB, Iankov ID, Concilio SC, Ammayappan A, Bolon B, et al. Preclinical safety assessment of MV-s-NAP, a novel oncolytic measles virus strain armed with an H. pylori immunostimulatory bacterial transgene. Mol Ther Methods Clin Dev. 2022;26:532–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Iankov ID, Haralambieva IH, Galanis E. Immunogenicity of attenuated measles virus engineered to express Helicobacter pylori neutrophil-activating protein. Vaccine. 2011;29(8):1710–20.

    Article  CAS  PubMed  Google Scholar 

  82. Laspidea V, Puigdelloses M, Labiano S, Marrodan L, Garcia-Moure M, Zalacain M, et al. Exploiting 4–1BB immune checkpoint to enhance the efficacy of oncolytic virotherapy for diffuse intrinsic pontine gliomas. JCI Insight. 2022;7(7): e154812.

    Article  PubMed  PubMed Central  Google Scholar 

  83. Martinez-Velez N, Laspidea V, Zalacain M, Labiano S, Garcia-Moure M, Puigdelloses M, et al. Local treatment of a pediatric osteosarcoma model with a 4–1BBL armed oncolytic adenovirus results in an antitumor effect and leads to immune memory. Mol Cancer Ther. 2022;21(3):471–80.

    Article  PubMed  PubMed Central  Google Scholar 

  84. Ahmed A, Tait SWG. Targeting immunogenic cell death in cancer. Mol Oncol. 2020;14(12):2994–3006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Li JL, Liu HL, Zhang XR, Xu JP, Hu WK, Liang M, et al. A phase I trial of intratumoral administration of recombinant oncolytic adenovirus overexpressing HSP70 in advanced solid tumor patients. Gene Ther. 2009;16(3):376–82.

    Article  CAS  PubMed  Google Scholar 

  86. Ino Y, Saeki Y, Fukuhara H, Todo T. Triple combination of oncolytic herpes simplex virus-1 vectors armed with interleukin-12, interleukin-18, or soluble b7–1 results in enhanced antitumor efficacy. Clin Cancer Res. 2006;12(2):643–52.

    Article  CAS  PubMed  Google Scholar 

  87. Zhao H, Janke M, Fournier P, Schirrmacher V. Recombinant Newcastle disease virus expressing human interleukin-2 serves as a potential candidate for tumor therapy. Virus Res. 2008;136(1–2):75–80.

    Article  CAS  PubMed  Google Scholar 

  88. Iankov ID, Federspiel MJ, Galanis E. Measles virus expressed Helicobacter pylori neutrophil-activating protein significantly enhances the immunogenicity of poor immunogens. Vaccine. 2013;31(42):4795–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Martinez-Perez AG, Perez-Trujillo JJ, Garza-Morales R, Ramirez-Avila NE, Loera-Arias MJ, Gomez-Gutierrez JG, et al. An oncolytic adenovirus encoding SA-4-1BBL adjuvant fused to HPV-16 E7 antigen produces a specific antitumor effect in a cancer mouse model. Vaccines (Basel). 2021;9(2):149.

    Article  CAS  PubMed  Google Scholar 

  90. Martinez-Perez AG, Perez-Trujillo JJ, Garza-Morales R, Loera-Arias MJ, Saucedo-Cardenas O, Garcia-Garcia A, et al. 4–1BBL as a mediator of cross-talk between innate, adaptive, and regulatory immunity against cancer. Int J Mol Sci. 2021;22(12):6210.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Hinterberger M, Giessel R, Fiore G, Graebnitz F, Bathke B, Wennier S, et al. Intratumoral virotherapy with 4–1BBL armed modified vaccinia Ankara eradicates solid tumors and promotes protective immune memory. J Immunother Cancer. 2021;9(2): e001586.

    Article  PubMed  PubMed Central  Google Scholar 

  92. Vigil A, Martinez O, Chua MA, Garcia-Sastre A. Recombinant Newcastle disease virus as a vaccine vector for cancer therapy. Mol Ther. 2008;16(11):1883–90.

    Article  CAS  PubMed  Google Scholar 

  93. Wongthida P, Diaz RM, Pulido C, Rommelfanger D, Galivo F, Kaluza K, et al. Activating systemic T-cell immunity against self tumor antigens to support oncolytic virotherapy with vesicular stomatitis virus. Hum Gene Ther. 2011;22(11):1343–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Das K, Belnoue E, Rossi M, Hofer T, Danklmaier S, Nolden T, et al. A modular self-adjuvanting cancer vaccine combined with an oncolytic vaccine induces potent antitumor immunity. Nat Commun. 2021;12(1):5195.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  95. Ghonime MG, Saini U, Kelly MC, Roth JC, Wang PY, Chen CY, et al. Eliciting an immune-mediated antitumor response through oncolytic herpes simplex virus-based shared antigen expression in tumors resistant to viroimmunotherapy. J Immunother Cancer. 2021;9(10): e002939.

    Article  PubMed  PubMed Central  Google Scholar 

  96. de Vries CR, Monken CE, Lattime EC. The addition of recombinant vaccinia HER2/neu to oncolytic vaccinia-GMCSF given into the tumor microenvironment overcomes MDSC-mediated immune escape and systemic anergy. Cancer Gene Ther. 2015;22(3):154–62.

    Article  PubMed  PubMed Central  Google Scholar 

  97. Ylosmaki E, Malorzo C, Capasso C, Honkasalo O, Fusciello M, Martins B, et al. Personalized cancer vaccine platform for clinically relevant oncolytic enveloped viruses. Mol Ther. 2018;26(9):2315–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Bridle BW, Stephenson KB, Boudreau JE, Koshy S, Kazdhan N, Pullenayegum E, et al. Potentiating cancer immunotherapy using an oncolytic virus. Mol Ther. 2010;18(8):1430–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Jenner AL, Cassidy T, Belaid K, Bourgeois-Daigneault MC, Craig M. In silico trials predict that combination strategies for enhancing vesicular stomatitis oncolytic virus are determined by tumor aggressivity. J Immunother Cancer. 2021;9(2): e001387.

    Article  PubMed  PubMed Central  Google Scholar 

  100. Atherton MJ, Stephenson KB, Tzelepis F, Bakhshinyan D, Nikota JK, Son HH, et al. Transforming the prostatic tumor microenvironment with oncolytic virotherapy. Oncoimmunology. 2018;7(7): e1445459.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Hummel J, Bienzle D, Morrison A, Cieplak M, Stephenson K, DeLay J, et al. Maraba virus-vectored cancer vaccines represent a safe and novel therapeutic option for cats. Sci Rep. 2017;7(1): 15738.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  102. Atherton MJ, Stephenson KB, Pol J, Wang F, Lefebvre C, Stojdl DF, et al. Customized viral immunotherapy for HPV-associated cancer. Cancer Immunol Res. 2017;5(10):847–59.

    Article  CAS  PubMed  Google Scholar 

  103. Pol JG, Acuna SA, Yadollahi B, Tang N, Stephenson KB, Atherton MJ, et al. Preclinical evaluation of a MAGE-A3 vaccination utilizing the oncolytic Maraba virus currently in first-in-human trials. Oncoimmunology. 2019;8(1): e1512329.

    Article  PubMed  Google Scholar 

  104. Roy DG, Geoffroy K, Marguerie M, Khan ST, Martin NT, Kmiecik J, et al. Adjuvant oncolytic virotherapy for personalized anti-cancer vaccination. Nat Commun. 2021;12(1):2626.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  105. Holl EK, Brown MC, Boczkowski D, McNamara MA, George DJ, Bigner DD, et al. Recombinant oncolytic poliovirus, PVSRIPO, has potent cytotoxic and innate inflammatory effects, mediating therapy in human breast and prostate cancer xenograft models. Oncotarget. 2016;7(48):79828–41.

    Article  PubMed  PubMed Central  Google Scholar 

  106. Beasley GM, Brown MC, Farrow NE, Landa K, Al-Rohil RN, Selim MA, et al. Multimodality analysis confers a prognostic benefit of a T-cell infiltrated tumor microenvironment and peripheral immune status in patients with melanoma. J Immunother Cancer. 2022;10(9): e005052.

    Article  PubMed  PubMed Central  Google Scholar 

  107. Schellhammer PF, Chodak G, Whitmore JB, Sims R, Frohlich MW, Kantoff PW. Lower baseline prostate-specific antigen is associated with a greater overall survival benefit from sipuleucel-T in the Immunotherapy for Prostate Adenocarcinoma Treatment (IMPACT) trial. Urology. 2013;81(6):1297–302.

    Article  PubMed  Google Scholar 

  108. Wei XX, Perry J, Chang E, Zhang L, Hiatt RA, Ryan CJ, et al. Clinical variables associated with overall survival in metastatic castration-resistant prostate cancer patients treated with sipuleucel-T immunotherapy. Clin Genitourin Cancer. 2018;16(3):184-90 e2.

    Article  PubMed  Google Scholar 

  109. Santos PM, Adamik J, Howes TR, Du S, Vujanovic L, Warren S, et al. Impact of checkpoint blockade on cancer vaccine-activated CD8+ T cell responses. J Exp Med. 2020;217(7): e20191369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Storkus WJ, Maurer D, Lin Y, Ding F, Bose A, Lowe D, et al. Dendritic cell vaccines targeting tumor blood vessel antigens in combination with dasatinib induce therapeutic immune responses in patients with checkpoint-refractory advanced melanoma. J Immunother Cancer. 2021;9(11): e003675.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Sasson SC, Zaunders JJ, Nahar K, Munier CML, Fairfax BP, Olsson-Brown A, et al. Mucosal-associated invariant T (MAIT) cells are activated in the gastrointestinal tissue of patients with combination ipilimumab and nivolumab therapy-related colitis in a pathology distinct from ulcerative colitis. Clin Exp Immunol. 2020;202(3):335–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Holm JS, Funt SA, Borch A, Munk KK, Bjerregaard AM, Reading JL, et al. Neoantigen-specific CD8 T cell responses in the peripheral blood following PD-L1 blockade might predict therapy outcome in metastatic urothelial carcinoma. Nat Commun. 2022;13(1):1935.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  113. Klein O, Ebert LM, Nicholaou T, Browning J, Russell SE, Zuber M, et al. Melan-A-specific cytotoxic T cells are associated with tumor regression and autoimmunity following treatment with anti-CTLA-4. Clin Cancer Res. 2009;15(7):2507–13.

    Article  CAS  PubMed  Google Scholar 

  114. Liu J, Blake SJ, Yong MC, Harjunpaa H, Ngiow SF, Takeda K, et al. Improved efficacy of neoadjuvant compared to adjuvant immunotherapy to eradicate metastatic disease. Cancer Discov. 2016;6(12):1382–99.

    Article  CAS  PubMed  Google Scholar 

  115. Bagchi S, Yuan R, Engleman EG. Immune checkpoint inhibitors for the treatment of cancer: clinical impact and mechanisms of response and resistance. Annu Rev Pathol. 2021;16:223–49.

    Article  CAS  PubMed  Google Scholar 

  116. Kiyohara E, Tanemura A, Nishioka M, Yamada M, Tanaka A, Yokomi A, et al. Intratumoral injection of hemagglutinating virus of Japan-envelope vector yielded an antitumor effect for advanced melanoma: a phase I/IIa clinical study. Cancer Immunol Immunother. 2020;69(6):1131–40.

    Article  CAS  PubMed  Google Scholar 

  117. Lang FF, Conrad C, Gomez-Manzano C, Yung WKA, Sawaya R, Weinberg JS, et al. Phase I study of DNX-2401 (Delta-24-RGD) oncolytic adenovirus: replication and immunotherapeutic effects in recurrent malignant glioma. J Clin Oncol. 2018;36(14):1419–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Malvehy J, Samoylenko I, Schadendorf D, Gutzmer R, Grob JJ, Sacco JJ, et al. Talimogene laherparepvec upregulates immune-cell populations in non-injected lesions: findings from a phase II, multicenter, open-label study in patients with stage IIIB-IVM1c melanoma. J Immunother Cancer. 2021;9(3): e001621.

    Article  PubMed  PubMed Central  Google Scholar 

  119. Santos JM, Heinio C, Cervera-Carrascon V, Quixabeira DCA, Siurala M, Havunen R, et al. Oncolytic adenovirus shapes the ovarian tumor microenvironment for potent tumor-infiltrating lymphocyte tumor reactivity. J Immunother Cancer. 2020;8(1): e000188.

    Article  PubMed  PubMed Central  Google Scholar 

  120. Yousaf I, Kaeppler J, Frost S, Seymour LW, Jacobus EJ. Attenuation of the hypoxia inducible factor pathway after oncolytic adenovirus infection coincides with decreased vessel perfusion. Cancers (Basel). 2020;12(4):851.

    Article  CAS  PubMed  Google Scholar 

  121. Hou W, Chen H, Rojas J, Sampath P, Thorne SH. Oncolytic vaccinia virus demonstrates antiangiogenic effects mediated by targeting of VEGF. Int J Cancer. 2014;135(5):1238–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Inoue M, Kim M, Inoue T, Tait M, Byrne T, Nitschke M, et al. Oncolytic vaccinia virus injected intravenously sensitizes pancreatic neuroendocrine tumors and metastases to immune checkpoint blockade. Mol Ther Oncolytics. 2022;24:299–318.

    Article  CAS  PubMed  Google Scholar 

  123. Hardcastle J, Mills L, Malo CS, Jin F, Kurokawa C, Geekiyanage H, et al. Immunovirotherapy with measles virus strains in combination with anti-PD-1 antibody blockade enhances antitumor activity in glioblastoma treatment. Neuro Oncol. 2017;19(4):493–502.

    CAS  PubMed  Google Scholar 

  124. Silk AW, O’Day SJ, Kaufman HL, Bryan J, Norrell JT, Imbergamo C, et al. A phase 1b single-arm trial of intratumoral oncolytic virus V937 in combination with pembrolizumab in patients with advanced melanoma: results from the CAPRA study. Cancer Immunol Immunother. 2023;72(6):1405–15.

    Article  CAS  PubMed  Google Scholar 

  125. Ribas A, Dummer R, Puzanov I, VanderWalde A, Andtbacka RHI, Michielin O, et al. Oncolytic virotherapy promotes intratumoral t cell infiltration and improves anti-PD-1 immunotherapy. Cell. 2017;170(6):1109-19 e10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Chesney JA, Ribas A, Long GV, Kirkwood JM, Dummer R, Puzanov I, et al. Randomized, double-blind, placebo-controlled, global phase iii trial of talimogene laherparepvec combined with pembrolizumab for advanced melanoma. J Clin Oncol. 2023;41(3):528–40.

    Article  CAS  PubMed  Google Scholar 

  127. Puzanov I, Milhem MM, Minor D, Hamid O, Li A, Chen L, et al. Talimogene laherparepvec in combination with ipilimumab in previously untreated, unresectable stage IIIB-IV melanoma. J Clin Oncol. 2016;34(22):2619–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Kelly CM, Antonescu CR, Bowler T, Munhoz R, Chi P, Dickson MA, et al. Objective response rate among patients with locally advanced or metastatic sarcoma treated with talimogene laherparepvec in combination with pembrolizumab: a phase 2 clinical trial. JAMA Oncol. 2020;6(3):402–8.

    Article  PubMed  PubMed Central  Google Scholar 

  129. Anagnostou V, Bardelli A, Chan TA, Turajlic S. The status of tumor mutational burden and immunotherapy. Nat Cancer. 2022;3(6):652–6.

    Article  PubMed  Google Scholar 

  130. Marabelle A, Le DT, Ascierto PA, Di Giacomo AM, De Jesus-Acosta A, Delord JP, et al. Efficacy of pembrolizumab in patients with noncolorectal high microsatellite instability/mismatch repair-deficient cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. 2020;38(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  131. Merino DM, McShane LM, Fabrizio D, Funari V, Chen SJ, White JR, et al. Establishing guidelines to harmonize tumor mutational burden (TMB): in silico assessment of variation in TMB quantification across diagnostic platforms: phase I of the Friends of Cancer Research TMB Harmonization Project. J Immunother Cancer. 2020;8(1): e000147.

    Article  PubMed  PubMed Central  Google Scholar 

  132. Samstein RM, Lee CH, Shoushtari AN, Hellmann MD, Shen R, Janjigian YY, et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat Genet. 2019;51(2):202–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Rousseau B, Foote MB, Maron SB, Diplas BH, Lu S, Argiles G, et al. The spectrum of benefit from checkpoint blockade in hypermutated tumors. N Engl J Med. 2021;384(12):1168–70.

    Article  PubMed  PubMed Central  Google Scholar 

  134. Marcus L, Fashoyin-Aje LA, Donoghue M, Yuan M, Rodriguez L, Gallagher PS, et al. FDA approval summary: pembrolizumab for the treatment of tumor mutational burden-high solid tumors. Clin Cancer Res. 2021;27(17):4685–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Gandara DR, Paul SM, Kowanetz M, Schleifman E, Zou W, Li Y, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nat Med. 2018;24(9):1441–8.

    Article  CAS  PubMed  Google Scholar 

  136. Gibney GT, Weiner LM, Atkins MB. Predictive biomarkers for checkpoint inhibitor-based immunotherapy. Lancet Oncol. 2016;17(12):e542–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Kato R, Yamasaki M, Urakawa S, Nishida K, Makino T, Morimoto-Okazawa A, et al. Increased Tim-3(+) T cells in PBMCs during nivolumab therapy correlate with responses and prognosis of advanced esophageal squamous cell carcinoma patients. Cancer Immunol Immunother. 2018;67(11):1673–83.

    Article  CAS  PubMed  Google Scholar 

  138. Ayers M, Lunceford J, Nebozhyn M, Murphy E, Loboda A, Kaufman DR, et al. IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade. J Clin Investig. 2017;127(8):2930–40.

    Article  PubMed  PubMed Central  Google Scholar 

  139. Masemann D, Meissner R, Schied T, Lichty BD, Rapp UR, Wixler V, et al. Synergistic anti-tumor efficacy of oncolytic influenza viruses and B7–H3 immune-checkpoint inhibitors against IC-resistant lung cancers. Oncoimmunology. 2021;10(1):1885778.

    Article  PubMed  PubMed Central  Google Scholar 

  140. Labanieh L, Majzner RG, Mackall CL. Programming CAR-T cells to kill cancer. Nat Biomed Eng. 2018;2(6):377–91.

    Article  CAS  PubMed  Google Scholar 

  141. Cappell KM, Sherry RM, Yang JC, Goff SL, Vanasse DA, McIntyre L, et al. Long-term follow-up of anti-cd19 chimeric antigen receptor t-cell therapy. J Clin Oncol. 2020;38(32):3805–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Liu E, Marin D, Banerjee P, Macapinlac HA, Thompson P, Basar R, et al. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020;382(6):545–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5(177): 177ra38.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Neelapu SS, Locke FL, Bartlett NL, Lekakis LJ, Reagan PM, Miklos DB, et al. Comparison of 2-year outcomes with CAR T cells (ZUMA-1) vs salvage chemotherapy in refractory large B-cell lymphoma. Blood Adv. 2021;5(20):4149–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Hege KM, Bergsland EK, Fisher GA, Nemunaitis JJ, Warren RS, McArthur JG, et al. Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer. J Immunother Cancer. 2017;5:22.

    Article  PubMed  PubMed Central  Google Scholar 

  146. Zhang C, Wang Z, Yang Z, Wang M, Li S, Li Y, et al. Phase I escalating-dose trial of CAR-T therapy targeting CEA(+) metastatic colorectal cancers. Mol Ther. 2017;25(5):1248–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Zhang Y, Zhang Z, Ding Y, Fang Y, Wang P, Chu W, et al. Phase I clinical trial of EGFR-specific CAR-T cells generated by the piggyBac transposon system in advanced relapsed/refractory non-small cell lung cancer patients. J Cancer Res Clin Oncol. 2021;147(12):3725–34.

    Article  CAS  PubMed  Google Scholar 

  148. O’Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette JJD, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci Transl Med. 2017;9(399): eaaa0984.

    Article  PubMed  PubMed Central  Google Scholar 

  149. Pauken KE, Wherry EJ. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015;36(4):265–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Martinez M, Moon EK. CAR T cells for solid tumors: new strategies for finding, infiltrating, and surviving in the tumor microenvironment. Front Immunol. 2019;10:128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Sgubin D, Wakimoto H, Kanai R, Rabkin SD, Martuza RL. Oncolytic herpes simplex virus counteracts the hypoxia-induced modulation of glioblastoma stem-like cells. Stem Cells Transl Med. 2012;1(4):322–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. ZarezadehMehrabadi A, Roozbahani F, Ranjbar R, Farzanehpour M, Shahriary A, Dorostkar R, et al. Overview of the pre-clinical and clinical studies about the use of CAR-T cell therapy of cancer combined with oncolytic viruses. World J Surg Oncol. 2022;20(1):16.

    Article  Google Scholar 

  153. Huang J, Zheng M, Zhang Z, Tang X, Chen Y, Peng A, et al. Interleukin-7-loaded oncolytic adenovirus improves CAR-T cell therapy for glioblastoma. Cancer Immunol Immunother. 2021;70(9):2453–65.

    Article  CAS  PubMed  Google Scholar 

  154. Watanabe K, Luo Y, Da T, Guedan S, Ruella M, Scholler J, et al. Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses. JCI Insight. 2018;3(7): e99573.

    Article  PubMed  PubMed Central  Google Scholar 

  155. Liu Y, Zheng Y, Deng T, Huang Y, Liu Z, Zhan B, et al. Oncolytic herpes simplex virus delivery of dual CAR targets of CD19 and BCMA as well as immunomodulators to enhance therapeutic efficacy in solid tumors combined with CAR T cell therapy. Front Oncol. 2022;12: 1037934.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Porter CE, Rosewell Shaw A, Jung Y, Yip T, Castro PD, Sandulache VC, et al. Oncolytic adenovirus armed with BiTE, cytokine, and checkpoint inhibitor enables CAR T cells to control the growth of heterogeneous tumors. Mol Ther. 2020;28(5):1251–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Rosewell Shaw A, Porter CE, Yip T, Mah WC, McKenna MK, Dysthe M, et al. Oncolytic adeno-immunotherapy modulates the immune system enabling CAR T-cells to cure pancreatic tumors. Commun Biol. 2021;4(1):368.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Li Y, Xiao F, Zhang A, Zhang D, Nie W, Xu T, et al. Oncolytic adenovirus targeting TGF-beta enhances anti-tumor responses of mesothelin-targeted chimeric antigen receptor T cell therapy against breast cancer. Cell Immunol. 2020;348: 104041.

    Article  CAS  PubMed  Google Scholar 

  159. Wang G, Zhang Z, Zhong K, Wang Z, Yang N, Tang X, et al. CXCL11-armed oncolytic adenoviruses enhance CAR-T cell therapeutic efficacy and reprogram tumor microenvironment in glioblastoma. Mol Ther. 2023;31(1):134–53.

    Article  CAS  PubMed  Google Scholar 

  160. Park AK, Fong Y, Kim SI, Yang J, Murad JP, Lu J, et al. Effective combination immunotherapy using oncolytic viruses to deliver CAR targets to solid tumors. Sci Transl Med. 2020;12(559): eaaz1863.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Aalipour A, Le Boeuf F, Tang M, Murty S, Simonetta F, Lozano AX, et al. Viral delivery of CAR targets to solid tumors enables effective cell therapy. Mol Ther Oncolytics. 2020;17:232–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Ma C, Han M, Heinrich B, Fu Q, Zhang Q, Sandhu M, et al. Gut microbiome-mediated bile acid metabolism regulates liver cancer via NKT cells. Science. 2018;360(6391): eaan5931.

    Article  PubMed  PubMed Central  Google Scholar 

  163. Xu X, Huang W, Heczey A, Liu D, Guo L, Wood M, et al. NKT cells coexpressing a GD2-specific chimeric antigen receptor and il15 show enhanced in vivo persistence and antitumor activity against neuroblastoma. Clin Cancer Res. 2019;25(23):7126–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Pahl JHW, Koch J, Gotz JJ, Arnold A, Reusch U, Gantke T, et al. CD16A activation of NK cells promotes NK cell proliferation and memory-like cytotoxicity against cancer cells. Cancer Immunol Res. 2018;6(5):517–27.

    Article  CAS  PubMed  Google Scholar 

  165. Wrona E, Borowiec M, Potemski P. CAR-NK cells in the treatment of solid tumors. Int J Mol Sci. 2021;22(11):5899.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Kriegsmann K, Kriegsmann M, von Bergwelt-Baildon M, Cremer M, Witzens-Harig M. NKT cells—new players in CAR cell immunotherapy? Eur J Haematol. 2018;101(6):750–7.

    Article  CAS  PubMed  Google Scholar 

  167. Ma R, Lu T, Li Z, Teng KY, Mansour AG, Yu M, et al. An oncolytic virus expressing IL15/IL15Ralpha combined with off-the-shelf EGFR-CAR NK cells targets glioblastoma. Cancer Res. 2021;81(13):3635–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Chen T, Ding X, Liao Q, Gao N, Chen Y, Zhao C, et al. IL-21 arming potentiates the anti-tumor activity of an oncolytic vaccinia virus in monotherapy and combination therapy. J Immunother Cancer. 2021;9(1): e001647.

    Article  PubMed  PubMed Central  Google Scholar 

  169. Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012;336:1268–73.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  170. Park EM, Chelvanambi M, Bhutiani N, Kroemer G, Zitvogel L, Wargo JA. Targeting the gut and tumor microbiota in cancer. Nat Med. 2022;28(4):690–703.

    Article  CAS  PubMed  Google Scholar 

  171. Vétizou M, Pitt JM, Daillère R, Lepage P, Waldschmitt N, Flament C, et al. Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota. Science. 2015;350:1078–84.

    Article  ADS  Google Scholar 

  172. Baruch EN, Youngster I, Ben-Betzalel G, Ortenberg R, Lahat A, Katz L, et al. Fecal microbiota transplant promotes response in immunotherapy-refractory melanoma patients. Science. 2021;371:602–9.

    Article  ADS  CAS  PubMed  Google Scholar 

  173. Davar D, Dzutsev A, McCulloch JA, Rodrigues RR, Chauvin JM, Morrison RM, et al. Fecal microbiota transplant overcomes resistance to anti-PD-1 therapy in melanoma patients. Science. 2021;371:595–602.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  174. Zhou J, Huang G, Wong WC, Hu DH, Zhu JW, Li R, et al. The impact of antibiotic use on clinical features and survival outcomes of cancer patients treated with immune checkpoint inhibitors. Front Immunol. 2022;13: 968729.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Viaud S, Saccheri F, Mignot G, Yamazaki T, Daillère R, Hannani D, et al. The intestinal microbiota modulates the anticancer immune effects of cyclophosphamide. Science. 2013;342(6161):971–6.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  176. Hagan T, Cortese M, Rouphael N, Boudreau C, Linde C, Maddur MS, et al. Antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans. Cell. 2019;178(6):1313-28 e13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Matson VFJ, Bao R, Chongsuwat T, Zha Y, Alegre ML, Luke JJ, Gajewski TF. The commensal microbiome is associated with anti-PD-1 efficacy in metastatic melanoma patients. Science. 2018;359:104–8.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  178. Jin Y, Dong H, Xia L, Yang Y, Zhu Y, Shen Y, et al. The diversity of gut microbiome is associated with favorable responses to anti-programmed death 1 immunotherapy in Chinese patients with NSCLC. J Thorac Oncol. 2019;14(8):1378–89.

    Article  CAS  PubMed  Google Scholar 

  179. Xie J, Li H, Zhang X, Yang T, Yue M, Zhang Y, et al. Akkermansia muciniphila protects mice against an emerging tick-borne viral pathogen. Nat Microbiol. 2023;8(1):91–106.

    Article  CAS  PubMed  Google Scholar 

  180. Mager LFBR, Pett N, Cooke NCA, Brown K, Ramay H, Paik S, Stagg J, Groves RA, Gallo M, Lewis IA, Geuking MB, McCoy KD. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science. 2020;369:1481–9.

    Article  ADS  CAS  PubMed  Google Scholar 

  181. Liikanen I, Koski A, Merisalo-Soikkeli M, Hemminki O, Oksanen M, Kairemo K, et al. Serum HMGB1 is a predictive and prognostic biomarker for oncolytic immunotherapy. Oncoimmunology. 2015;4(3): e989771.

    Article  PubMed  PubMed Central  Google Scholar 

  182. Chesney J, Puzanov I, Collichio F, Singh P, Milhem MM, Glaspy J, et al. Randomized, open-label phase II study evaluating the efficacy and safety of talimogene laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. J Clin Oncol. 2018;36(17):1658–67.

    Article  CAS  PubMed  Google Scholar 

  183. Bradbury PA, Morris DG, Nicholas G, Tu D, Tehfe M, Goffin JR, et al. Canadian Cancer Trials Group (CCTG) IND211: a randomized trial of pelareorep (Reolysin) in patients with previously treated advanced or metastatic non-small cell lung cancer receiving standard salvage therapy. Lung Cancer. 2018;120:142–8.

    Article  PubMed  Google Scholar 

  184. Harrington KJ, Kong A, Mach N, Chesney JA, Fernandez BC, Rischin D, et al. Talimogene laherparepvec and pembrolizumab in recurrent or metastatic squamous cell carcinoma of the head and neck (MASTERKEY-232): a multicenter, phase 1b study. Clin Cancer Res. 2020;26(19):5153–61.

    Article  CAS  PubMed  Google Scholar 

  185. Zhang B, Huang J, Tang J, Hu S, Luo S, Luo Z, et al. Intratumoral OH2, an oncolytic herpes simplex virus 2, in patients with advanced solid tumors: a multicenter, phase I/II clinical trial. J Immunother Cancer. 2021;9(4): e002224.

    Article  PubMed  PubMed Central  Google Scholar 

  186. Ling AL, Solomon IH, Landivar AM, Nakashima H, Woods JK, Santos A, et al. Clinical trial links oncolytic immunoactivation to survival in glioblastoma. Nature. 2023;623(7985):157–66.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr. Susanna Concilio for offering constructive feedback during the preparation of the manuscript. Figures 1 and 2 were prepared on biorender.com.

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  1. Department of Molecular Medicine, Mayo Clinic, Rochester, MN, USA

    Georgios M. Stergiopoulos, Ianko Iankov & Evanthia Galanis

  2. Department of Oncology, Mayo Clinic, Rochester, MN, USA

    Evanthia Galanis

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Correspondence to Ianko Iankov or Evanthia Galanis.

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This work was supported by the NIH grant R01 CA258239 (Galanis, PI).

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E.G. has received honoraria for advisory board participation from Kiyatec, Inc. (personal compensation), Boston Scientific for Data and Safety Monitoring Committee, Servier Pharmaceuticals for Advisory Board, and Karyopharm Therapeutics, Inc. for data safety and -onitoring board participation (compensation to employer). Her institution has received grant funding from Servier Pharmaceuticals LLC (formerly Agios Pharmaceuticals, Inc.), Celgene, MedImmune, Inc., and Denovo Biopharma. G.M.S. and I.I. report no conflicts of interest.

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Stergiopoulos, G.M., Iankov, I. & Galanis, E. Personalizing Oncolytic Immunovirotherapy Approaches. Mol Diagn Ther 28, 153–168 (2024). https://doi.org/10.1007/s40291-023-00689-4

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