Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Combination therapy with CAR T cells and oncolytic viruses: a new era in cancer immunotherapy

Abstract

Chimeric antigen receptor (CAR) T-cell therapy is an encouraging and fast-growing platform used for the treatment of various types of tumors in human body. Despite the recent success of CAR T-cell therapy in hematologic malignancies, especially in B-cell lymphoma and acute lymphoblastic leukemia, the application of this treatment approach in solid tumors faced several obstacles resulted from the heterogeneous expression of antigens as well as the induction of immunosuppressive tumor microenvironment. Oncolytic virotherapy (OV) is a new cancer treatment modality by the use of competent or genetically engineered viruses to replicate in tumor cells selectively. OVs represent potential candidates to synergize the current setbacks of CAR T-cell application in solid tumors and then and overcome them. As well, the application of OVs gives researches the ability to engineer the virus with payloads in the way that it selectively deliver a specific therapeutic agents in tumor milieu to reinforce the cytotoxic activity of CAR T cells. Herein, we made a comprehensive review on the outcomes resulted from the combination of CAR T-cell immunotherapy and oncolytic virotherapy for the treatment of solid cancers. In the current study, we also provided brief details on some challenges that remained in this field and attempted to shed a little light on the future perspectives.

This is a preview of subscription content, access via your institution

Access options

Buy this article

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: CAR T-cell application in the treatment of solid tumors.
Fig. 2: Oncolytic virus and CAR T-cells combination therapy in solid cancers.
Fig. 3: Oncolytic virus-mediated delivery of tumor-selective surface antigens.

Similar content being viewed by others

References

  1. Hargadon KM, Johnson CE, Williams CJ. Immune checkpoint blockade therapy for cancer: an overview of FDA-approved immune checkpoint inhibitors. Int Immunopharmacol. 2018;62:29–39.

    Article  CAS  PubMed  Google Scholar 

  2. Rossig C, Brenner MK. Genetic modification of T lymphocytes for adoptive immunotherapy. Mol Ther. 2004;10:5–18.

    Article  CAS  PubMed  Google Scholar 

  3. Guedan S, Calderon H, Posey AD Jr, Maus MV. Engineering and design of chimeric antigen receptors. Mol Ther Methods Clin Dev. 2019;12:145–56.

    Article  CAS  PubMed  Google Scholar 

  4. Stoiber S, Cadilha BL, Benmebarek M-R, Lesch S, Endres S, Kobold S. Limitations in the design of chimeric antigen receptors for cancer therapy. Cells. 2019;8:472.

    Article  CAS  PubMed Central  Google Scholar 

  5. Abken H, Chmielewski M, Hombach AA. Antigen-specific T-cell activation independently of the MHC: chimeric antigen receptor-redirected T cells. Front Immunol. 2013;4:371.

    PubMed  PubMed Central  Google Scholar 

  6. Dai H, Wang Y, Lu X, Han W. Chimeric antigen receptors modified T-cells for cancer therapy. J Natl Cancer Inst. 2016;108:1–14.

    Article  CAS  Google Scholar 

  7. Yu W-L, Hua Z-C. Chimeric antigen receptor T-cell (CAR T) therapy for hematologic and solid malignancies: efficacy and safety—a systematic review with meta-analysis. Cancers (Basel). 2019;11:47.

    Article  CAS  Google Scholar 

  8. Wang X, Wu Z, Qiu W, Chen P, Xu X, Han W. Programming CAR T cells to enhance anti-tumor efficacy through remodeling of the immune system. Front Med. 2020;14:1–20.

    Article  PubMed  Google Scholar 

  9. Tahmasebi S, Elahi R, Esmaeilzadeh A. Solid tumors challenges and new insights of CAR T cell engineering. Stem Cell Rev Rep. 2019;15:619–36.

    Article  PubMed  Google Scholar 

  10. Abreu TR, Fonseca NA, Gonçalves N, Moreira JN. Current challenges and emerging opportunities of CAR-T cell therapies. J Control Release. 2020;319:246–61.

    Article  CAS  PubMed  Google Scholar 

  11. Russell SJ, Barber GN. Oncolytic viruses as antigen-agnostic cancer vaccines. Cancer Cell. 2018;33:599–605.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Andtbacka R, Kaufman HL, Collichio F, Amatruda T, Senzer N, Chesney J, et al. Talimogene laherparepvec improves durable response rate in patients with advanced melanoma. J Clin Oncol. 2015;33:2780–8.

    Article  CAS  PubMed  Google Scholar 

  13. 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;36:1658.

    Article  CAS  PubMed  Google Scholar 

  14. Marelli G, Howells A, Lemoine NR, Wang Y. Oncolytic viral therapy and the immune system: a double-edged sword against cancer. Front Immunol. 2018;9:866.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Bommareddy PK, Shettigar M, Kaufman HL. Integrating oncolytic viruses in combination cancer immunotherapy. Nat Rev Immunol. 2018;18:498.

    Article  CAS  PubMed  Google Scholar 

  16. Bauzon M, Hermiston T. Armed therapeutic viruses–a disruptive therapy on the horizon of cancer immunotherapy. Front Immunol. 2014;5:74.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Twumasi-Boateng K, Pettigrew JL, Kwok YE, Bell JC, Nelson BH. Oncolytic viruses as engineering platforms for combination immunotherapy. Nat Rev Cancer. 2018;18:419–32.

    Article  CAS  PubMed  Google Scholar 

  18. Cao G-D, He X-B, Sun Q, Chen S, Wan K, Xu X, et al. The oncolytic virus in cancer diagnosis and treatment. Front Oncol. 2020;10:1–12.

    Article  CAS  Google Scholar 

  19. Ma J, Ramachandran M, Jin C, Quijano-Rubio C, Martikainen M, Yu D, et al. Characterization of virus-mediated immunogenic cancer cell death and the consequences for oncolytic virus-based immunotherapy of cancer. Cell Death Dis. 2020;11:1–15.

    Article  CAS  Google Scholar 

  20. Ghaleh HEG, Bolandian M, Dorostkar R, Jafari A, Pour MF. Concise review on optimized methods in production and transduction of lentiviral vectors in order to facilitate immunotherapy and gene therapy. Biomed Pharmacother. 2020;128:110276.

    Article  CAS  Google Scholar 

  21. Larocca CA, LeBoeuf NR, Silk AW, Kaufman HL. An update on the role of talimogene laherparepvec (T-VEC) in the treatment of melanoma: best practices and future directions. Am J Clin Dermatol. 2020;21:1–12.

    Article  Google Scholar 

  22. Packiam VT, Lamm DL, Barocas DA, Trainer A, Fand B, Davis RL, III, et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: Interim results. Urol Oncol. 2018;36:440–7.

    Article  CAS  PubMed  Google Scholar 

  23. Park SH, Breitbach CJ, Lee J, Park JO, Lim HY, Kang WK, et al. Phase 1b trial of biweekly intravenous Pexa-Vec (JX-594), an oncolytic and immunotherapeutic vaccinia virus in colorectal cancer. Mol Ther. 2015;23:1532–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Heo J, Breitbach C, Cho M, Hwang T-H, Kim CW, Jeon UB, et al. Phase II trial of Pexa-Vec (pexastimogene devacirepvec; JX-594), an oncolytic and immunotherapeutic vaccinia virus, followed by sorafenib in patients with advanced hepatocellular carcinoma (HCC). Am Soc Clin Oncol. 2013;31:1–15.

    Google Scholar 

  25. Galanis E, Markovic SN, Suman VJ, Nuovo GJ, Vile RG, Kottke TJ, et al. Phase II trial of intravenous administration of Reolysin®(Reovirus Serotype-3-dearing Strain) in patients with metastatic melanoma. Mol Ther. 2012;20:1998–2003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mahalingam D, Goel S, Aparo S, Patel Arora S, Noronha N, Tran H, et al. A phase II study of pelareorep (REOLYSIN®) in combination with gemcitabine for patients with advanced pancreatic adenocarcinoma. Cancers (Basel). 2018;10:160.

    Article  CAS  Google Scholar 

  27. Todo T, Martuza RL, Rabkin SD, Johnson PA. Oncolytic herpes simplex virus vector with enhanced MHC class I presentation and tumor cell killing. Proc Natl Acad Sci USA. 2001;98:6396–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Sugawara K, Iwai M, Yajima S, Tanaka M, Yanagihara K, Seto Y, et al. Efficacy of a third-generation oncolytic herpes virus G47Δ in advanced stage models of human gastric cancer. Mol Ther Oncolytics. 2020;17:205–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Mondal M, Guo J, He P, Zhou D. Recent advances of oncolytic virus in cancer therapy. Hum Vaccin Immunother. 2020;16:2389–402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Esaki S, Goshima F, Kimura H, Murakami S, Nishiyama Y. Enhanced antitumoral activity of oncolytic herpes simplex virus with gemcitabine using colorectal tumor models. Int J Cancer. 2013;132:1592–601.

    Article  CAS  PubMed  Google Scholar 

  31. Trager MH, Geskin LJ, Saenger YM. Oncolytic viruses for the treatment of metastatic melanoma. Curr Treat Options Oncol. 2020;21:1–16.

    Article  Google Scholar 

  32. Hashiguchi T, Kajikawa M, Maita N, Takeda M, Kuroki K, Sasaki K, et al. Crystal structure of measles virus hemagglutinin provides insight into effective vaccines. Proc Natl Acad Sci USA. 2007;104:19535–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Bhattacharjee S, Yadava PK. Measles virus: background and oncolytic virotherapy. Biochem Biophysics Rep. 2018;13:58–62.

    Google Scholar 

  34. Russell SJ, Peng K-W, Bell JC. Oncolytic virotherapy. Nat Biotechnol. 2012;30:658.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. MacKay M, Afshinnekoo E, Rub J, Hassan C, Khunte M, Baskaran N, et al. The therapeutic landscape for cells engineered with chimeric antigen receptors. Nat Biotechnol. 2020;38:233–44.

    Article  CAS  PubMed  Google Scholar 

  36. Eyquem J, Mansilla-Soto J, Giavridis T, van der Stegen SJ, Hamieh M, Cunanan KM, et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature. 2017;543:113–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Wang X, Rivière I. Clinical manufacturing of CAR T cells: foundation of a promising therapy. Mol Ther Oncolytics. 2016;3:16015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Ellis J. Silencing and variegation of gammaretrovirus and lentivirus vectors. Hum Gene Ther. 2005;16:1241–6.

    Article  CAS  PubMed  Google Scholar 

  39. Von Kalle C, Deichmann A, Schmidt M. Vector integration and tumorigenesis. Hum Gene Ther. 2014;25:475–81.

    Article  CAS  Google Scholar 

  40. MacLeod DT, Antony J, Martin AJ, Moser RJ, Hekele A, Wetzel KJ, et al. Integration of a CD19 CAR into the TCR alpha chain locus streamlines production of allogeneic gene-edited CAR T cells. Mol Ther. 2017;25:949–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Habib R, Nagrial A, Micklethwaite K, Gowrishankar K. Chimeric antigen receptors for the tumour microenvironment. Tumor Microenviron. 2020;1263:117–43.

    Article  CAS  Google Scholar 

  42. Wu L, Wei Q, Brzostek J, Gascoigne NR. Signaling from T cell receptors (TCRs) and chimeric antigen receptors (CARs) on T cells. Cell Mol Immunol. 2020;17:1–13.

    Article  CAS  Google Scholar 

  43. Pan J, Yang J, Deng B, Zhao X, Zhang X, Lin Y, et al. High efficacy and safety of low-dose CD19-directed CAR-T cell therapy in 51 refractory or relapsed B acute lymphoblastic leukemia patients. Leukemia. 2017;31:2587–93.

    Article  CAS  PubMed  Google Scholar 

  44. Moon EK, Wang L-C, Dolfi DV, Wilson CB, Ranganathan R, Sun J, et al. Multifactorial T-cell hypofunction that is reversible can limit the efficacy of chimeric antigen receptor–transduced human T cells in solid tumors. Clin Cancer Res. 2014;20:4262–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, et al. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res. 2006;12:6106–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Xu J, Tian K, Zhang H, Li L, Liu H, Liu J, et al. Chimeric antigen receptor-T cell therapy for solid tumors require new clinical regimens. Expert Rev Anticancer Ther. 2017;17:1099–106.

    Article  CAS  PubMed  Google Scholar 

  47. Lamers CH, Klaver Y, Gratama JW, Sleijfer S, Debets R. Treatment of metastatic renal cell carcinoma (mRCC) with CAIX CAR-engineered T-cells—a completed study overview. Biochem Soc Trans. 2016;44:951–9.

    Article  CAS  PubMed  Google Scholar 

  48. Li J, Li W, Huang K, Zhang Y, Kupfer G, Zhao Q. Chimeric antigen receptor T cell (CAR-T) immunotherapy for solid tumors: lessons learned and strategies for moving forward. J Hematol Oncol. 2018;11:22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kaufman HL, Kohlhapp FJ, Zloza A. Oncolytic viruses: a new class of immunotherapy drugs. Nat Rev Drug Discov. 2015;14:642–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. DeRenzo C, Gottschalk S. Genetic modification strategies to enhance CAR T cell persistence for patients with solid tumors. Front Immunol. 2019;10:218.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Labarta-Bajo L, Nilsen SP, Humphrey G, Schwartz T, Sanders K, Swafford A, et al. Type I IFNs and CD8 T cells increase intestinal barrier permeability after chronic viral infection. J Exp Med. 2020;217:1–19.

    Article  CAS  Google Scholar 

  52. Zhao Z, Condomines M, van der Stegen SJ, Perna F, Kloss CC, Gunset G, et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell. 2015;28:415–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Pikor LA, Bell JC, Diallo J-S. Oncolytic viruses: exploiting cancer’s deal with the devil. Trends Cancer. 2015;1:266–77.

    Article  PubMed  Google Scholar 

  54. Benmebarek M-R, Karches CH, Cadilha BL, Lesch S, Endres S, Kobold S. Killing mechanisms of chimeric antigen receptor (CAR) T cells. Int J Mol Sci. 2019;20:1283.

    Article  CAS  PubMed Central  Google Scholar 

  55. Garg AD, Galluzzi L, Apetoh L, Baert T, Birge RB, Pedro B-S, et al. Molecular and translational classifications of DAMPs in immunogenic cell death. Front Immunol. 2015;6:588.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Basu S, Binder RJ, Suto R, Anderson KM, Srivastava PK. Necrotic but not apoptotic cell death releases heat shock proteins, which deliver a partial maturation signal to dendritic cells and activate the NF-κB pathway. Int Immunol. 2000;12:1539–46.

    Article  CAS  PubMed  Google Scholar 

  57. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418:191–5.

    Article  CAS  PubMed  Google Scholar 

  58. Corrales L, Matson V, Flood B, Spranger S, Gajewski TF. Innate immune signaling and regulation in cancer immunotherapy. Cell Res. 2017;27:96–108.

    Article  CAS  PubMed  Google Scholar 

  59. Kohlhapp FJ, Kaufman HL. Molecular pathways: mechanism of action for talimogene laherparepvec, a new oncolytic virus immunotherapy. Clin Cancer Res. 2016;22:1048–54.

    Article  CAS  PubMed  Google Scholar 

  60. Fujiwara T, Urata Y, Tanaka N. Telomerase-specific oncolytic virotherapy for human cancer with the hTERT promoter. Curr Cancer Drug Targets. 2007;7:191–201.

    Article  CAS  PubMed  Google Scholar 

  61. Parker BS, Rautela J, Hertzog PJ. Antitumour actions of interferons: implications for cancer therapy. Nat Rev Cancer. 2016;16:131.

    Article  PubMed  CAS  Google Scholar 

  62. Dumitriu IE, Baruah P, Valentinis B, Voll RE, Herrmann M, Nawroth PP, et al. Release of high mobility group box 1 by dendritic cells controls T cell activation via the receptor for advanced glycation end products. J Immunol. 2005;174:7506–15.

    Article  CAS  PubMed  Google Scholar 

  63. Moser B, Desai DD, Downie MP, Chen Y, Yan SF, Herold K, et al. Receptor for advanced glycation end products expression on T cells contributes to antigen-specific cellular expansion in vivo. J Immunol. 2007;179:8051–8.

    Article  CAS  PubMed  Google Scholar 

  64. Haile ST, Conner J, Mackall C. Attenuated oncolytic virus HSV1716 increases in vivo expansion of GD2-targeting CAR T cells in murine solid tumor models. Cancer Res. 2016;76:111–2.

    Article  Google Scholar 

  65. Chen X, Han J, Chu J, Zhang L, Zhang J, Chen C, et al. A combinational therapy of EGFR-CAR NK cells and oncolytic herpes simplex virus 1 for breast cancer brain metastases. Oncotarget. 2016;7:27764.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Tähtinen S, Grönberg-Vähä-Koskela S, Lumen D, Merisalo-Soikkeli M, Siurala M, Airaksinen AJ, 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. 2015;3:915–25.

    Article  PubMed  CAS  Google Scholar 

  67. Nakamura K, Smyth MJ. Myeloid immunosuppression and immune checkpoints in the tumor microenvironment. Cell Mol Immunol. 2020;17:1–12.

    Article  CAS  PubMed  Google Scholar 

  68. Lindau D, Gielen P, Kroesen M, Wesseling P, Adema GJ. The immunosuppressive tumour network: myeloid‐derived suppressor cells, regulatory T cells and natural killer T cells. Immunology. 2013;138:105–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Whiteside T. The tumor microenvironment and its role in promoting tumor growth. Oncogene. 2008;27:5904–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Gurusamy D, Clever D, Eil R, Restifo NP. Novel “elements” of immune suppression within the tumor microenvironment. Cancer Immunol Res. 2017;5:426–33.

    Article  PubMed  PubMed Central  Google Scholar 

  71. Azemati F, Kondori BJ, Ghaleh HEG. Therapeutic potential of nanoparticle-loaded hydroxyurea on proliferation of human breast adenocarcinoma cell line. Iran J Pharm Res. 2020;19:271.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Achard C, Surendran A, Wedge M-E, Ungerechts G, Bell J, Ilkow CS. Lighting a fire in the tumor microenvironment using oncolytic immunotherapy. EBioMedicine. 2018;31:17–24.

    Article  PubMed  PubMed Central  Google Scholar 

  73. Harrington K, Freeman DJ, Kelly B, Harper J, Soria J-C. Optimizing oncolytic virotherapy in cancer treatment. Nat Rev Drug Discov. 2019;18:689–706.

    Article  CAS  PubMed  Google Scholar 

  74. Gauvrit A, Brandler S, Sapede-Peroz C, Boisgerault N, Tangy F, Gregoire M. Measles virus induces oncolysis of mesothelioma cells and allows dendritic cells to cross-prime tumor-specific CD8 response. Cancer Res. 2008;68:4882–92.

    Article  CAS  PubMed  Google Scholar 

  75. Guillerme J-B, Boisgerault N, Roulois D, Ménager J, Combredet C, Tangy F, et al. Measles virus vaccine–infected tumor cells induce tumor antigen cross-presentation by human plasmacytoid dendritic cells. Clin Cancer Res. 2013;19:1147–58.

    Article  CAS  PubMed  Google Scholar 

  76. Moehler MH, Zeidler M, Wilsberg V, Cornelis JJ, Woelfel T, Rommelaere J, 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. 2005;16:996–1005.

    Article  CAS  PubMed  Google Scholar 

  77. Delaunay T, Violland M, Boisgerault N, Dutoit S, Vignard V, Münz C, et al. Oncolytic viruses sensitize human tumor cells for NY-ESO-1 tumor antigen recognition by CD4+ effector T cells. Oncoimmunology. 2018;7:e1407897.

    Article  PubMed  Google Scholar 

  78. Ilkow CS, Marguerie M, Batenchuk C, Mayer J, Neriah DB, Cousineau S, et al. Reciprocal cellular cross-talk within the tumor microenvironment promotes oncolytic virus activity. Nat Med. 2015;21:530.

    Article  CAS  PubMed  Google Scholar 

  79. Li Y, Xiao F, Zhang A, Zhang D, Nie W, Xu T, et al. Oncolytic adenovirus targeting TGF-β 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 

  80. 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;170:1109. e10

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Li Y, Rogoff HA, Keates S, Gao Y, Murikipudi S, Mikule K, et al. Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci USA. 2015;112:1839–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Kottke T, Boisgerault N, Diaz RM, Donnelly O, Rommelfanger-Konkol D, Pulido J, et al. Detecting and targeting tumor relapse by its resistance to innate effectors at early recurrence. Nat Med. 2013;19:1625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Cerullo V, Koski A, V„h„-Koskela M, Hemminki A. Oncolytic adenoviruses for cancer immunotherapy: data from mice, hamsters, and humans. Adv Cancer Res. 2012;115:265–318.

    Article  CAS  PubMed  Google Scholar 

  84. Jahan N, Lee JM, Shah K, Wakimoto H. Therapeutic targeting of chemoresistant and recurrent glioblastoma stem cells with a proapoptotic variant of oncolytic herpes simplex virus. Int J Cancer. 2017;141:1671–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Lang FF, Conrad C, Gomez-Manzano C, Yung WA, 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;36:1419.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nat Rev Immunol. 2015;15:486–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Jin H-T, Anderson AC, Tan WG, West EE, Ha S-J, Araki K, et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc Natl Acad Sci USA. 2010;107:14733–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Anderson AC. Tim-3: an emerging target in the cancer immunotherapy landscape. Cancer Immunol Res. 2014;2:393–8.

    Article  CAS  PubMed  Google Scholar 

  89. Esaki S, Nigim F, Moon E, Luk S, Kiyokawa J, Curry W Jr, et al. Blockade of transforming growth factor‐β signaling enhances oncolytic herpes simplex virus efficacy in patient‐derived recurrent glioblastoma models. Int J Cancer. 2017;141:2348–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Hau P, Jachimczak P, Schlaier J, Bogdahn U. TGF-β2 signaling in high-grade gliomas. Curr Pharm Biotechnol. 2011;12:2150–7.

    Article  CAS  PubMed  Google Scholar 

  91. Sotillo E, Barrett DM, Black KL, Bagashev A, Oldridge D, Wu G, et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 2015;5:1282–95.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329–60.

    Article  CAS  PubMed  Google Scholar 

  93. Fry TJ, Shah NN, Orentas RJ, Stetler-Stevenson M, Yuan CM, Ramakrishna S, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018;24:20–28.

    Article  CAS  PubMed  Google Scholar 

  94. Wing A, Fajardo CA, Posey AD Jr., Shaw C, Da T, Young RM, et al. Improving CART-cell therapy of solid tumors with oncolytic virus-driven production of a bispecific T-cell engager. Cancer Immunol Res. 2018;6:605–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Berraondo P, Sanmamed MF, Ochoa MC, Etxeberria I, Aznar MA, Pérez-Gracia JL, et al. Cytokines in clinical cancer immunotherapy. Br J Cancer. 2019;120:6–15.

    Article  CAS  PubMed  Google Scholar 

  96. Havunen R, Santos JM, Sorsa S, Rantapero T, Lumen D, Siurala M, et al. Abscopal effect in non-injected tumors achieved with cytokine-armed oncolytic adenovirus. Mol Ther Oncolytics. 2018;11:109–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Durham NM, Mulgrew K, McGlinchey K, Monks NR, Ji H, Herbst R, et al. Oncolytic VSV primes differential responses to immuno-oncology therapy. Mol Ther. 2017;25:1917–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Cervera-Carrascon V, Siurala M, Santos J, Havunen R, Tähtinen S, Karell P, et al. TNFa and IL-2 armed adenoviruses enable complete responses by anti-PD-1 checkpoint blockade. Oncoimmunology. 2018;7:e1412902.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Yang C, Cao H, Liu N, Xu K, Ding M, Mao L-J. Oncolytic adenovirus expressing interleukin-18 improves antitumor activity of dacarbazine for malignant melanoma. Drug Des Devel Ther. 2016;10:3755.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Post DE, Sandberg EM, Kyle MM, Devi NS, Brat DJ, Xu Z, et al. Targeted cancer gene therapy using a hypoxia inducible factor–dependent oncolytic adenovirus armed with interleukin-4. Cancer Res. 2007;67:6872–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kowalsky SJ, Liu Z, Feist M, Berkey SE, Ma C, Ravindranathan R, et al. Superagonist IL-15-armed oncolytic virus elicits potent antitumor immunity and therapy that are enhanced with PD-1 blockade. Mol Ther. 2018;26:2476–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Leoni V, Vannini A, Gatta V, Rambaldi J, Sanapo M, Barboni C, et al. A fully-virulent retargeted oncolytic HSV armed with IL-12 elicits local immunity and vaccine therapy towards distant tumors. PLoS Pathog. 2018;14:e1007209.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Meisen WH, Kaur B. How can we trick the immune system into overcoming the detrimental effects of oncolytic viral therapy to treat glioblastoma? Expert Rev Neurother. 2013;13:341–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Choi I, Lee J, Zhang S, Park J, Lee K-M, Sonn C, et al. Oncolytic adenovirus co-expressing IL-12 and IL-18 improves tumor-specific immunity via differentiation of T cells expressing IL-12Rβ 2 or IL-18Rα. Gene Ther. 2011;18:898–909.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Bai F-L, Yu Y-H, Tian H, Ren G-P, Wang H, Zhou B, et al. Genetically engineered Newcastle disease virus expressing interleukin-2 and TNF-related apoptosis-inducing ligand for cancer therapy. Cancer Biol Ther. 2014;15:1226–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Patel MR, Jacobson BA, Ji Y, Drees J, Tang S, Xiong K, et al. Vesicular stomatitis virus expressing interferon-β is oncolytic and promotes antitumor immune responses in a syngeneic murine model of non-small cell lung cancer. Oncotarget. 2015;6:33165.

    Article  PubMed  PubMed Central  Google Scholar 

  107. 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;3:1–17.

    Article  Google Scholar 

  108. Hurton LV, Singh H, Najjar AM, Switzer KC, Mi T, Maiti S, et al. Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc Natl Acad Sci USA. 2016;113:E7788–E7797.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Springuel L, Lonez C, Alexandre B, Van Cutsem E, Machiels J-PH, Van Den Eynde M, et al. Chimeric antigen receptor-T cells for targeting solid tumors: current challenges and existing strategies. Biodrugs. 2019;33:515–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Moon EK, Wang L-CS, Bekdache K, Lynn RC, Lo A, Thorne SH, et al. Intra-tumoral delivery of CXCL11 via a vaccinia virus, but not by modified T cells, enhances the efficacy of adoptive T cell therapy and vaccines. Oncoimmunology. 2018;7:e1395997.

    Article  PubMed  PubMed Central  Google Scholar 

  111. Yeku OO, Brentjens RJ, Armored CAR. T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy. Biochem Soc Trans. 2016;44:412–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Eckert EC, Nace RA, Tonne JM, Evgin L, Vile RG, Russell SJ. Generation of a tumor-specific chemokine gradient using oncolytic vesicular stomatitis virus encoding CXCL9. Mol Ther Oncolytics. 2020;16:63–74.

    Article  CAS  PubMed  Google Scholar 

  113. Liu Z, Ravindranathan R, Li J, Kalinski P, Guo ZS, Bartlett DL. CXCL11-Armed oncolytic poxvirus elicits potent antitumor immunity and shows enhanced therapeutic efficacy. Oncoimmunology. 2016;5:e1091554.

    Article  PubMed  CAS  Google Scholar 

  114. Suryadevara CM, Gedeon PC, Sanchez-Perez L, Verla T, Alvarez-Breckenridge C, Choi BD, et al. Are BiTEs the “missing link” in cancer therapy? Oncoimmunology. 2015;4:e1008339.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. Kantarjian H, Stein A, Gökbuget N, Fielding AK, Schuh AC, Ribera J-M, et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N Engl J Med. 2017;376:836–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wang X, Gottschalk S, Song X-T. Synergistic antitumor effects of Chimeric antigen receptor-modified T cells and Oncolytic Virotherapy. Am Soc Hematol. 2014;124:1–21.

    Google Scholar 

  117. Dagher O, King TR, Wellhausen N, Posey AD Jr. Combination therapy for solid tumors: taking a classic CAR on new adventures. Cancer Cell. 2020;38:621–3.

    Article  CAS  PubMed  Google Scholar 

  118. Scott EM, Duffy MR, Freedman JD, Fisher KD, Seymour LW. Solid tumor immunotherapy with T cell engager‐armed oncolytic viruses. Macromol Biosci. 2018;18:1700187.

    Article  CAS  Google Scholar 

  119. Yu F, Hong B, Song X-T. A T-cell engager-armed oncolytic vaccinia virus to target the tumor stroma. Cancer Transl Med. 2017;3:122.

    Article  CAS  Google Scholar 

  120. de Sostoa J, Fajardo CA, Moreno R, Ramos MD, Farrera-Sal M, Alemany R. Targeting the tumor stroma with an oncolytic adenovirus secreting a fibroblast activation protein-targeted bispecific T-cell engager. J Immunother Cancer. 2019;7:1–15.

    Article  Google Scholar 

  121. Porter CE, Shaw AR, 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 growth of heterogeneous tumors. Mol Ther. 2020;28:1251–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Fajardo CA, Guedan S, Rojas LA, Moreno R, Arias-Badia M, de Sostoa J, et al. Oncolytic adenoviral delivery of an EGFR-targeting T-cell engager improves antitumor efficacy. Cancer Res. 2017;77:2052–63.

    Article  CAS  PubMed  Google Scholar 

  123. Wing A, Fajardo CA, Posey AD, Shaw C, Da T, Young RM, et al. Improving CART-cell therapy of solid tumors with oncolytic virus–driven production of a bispecific T-cell engager. Cancer Immunol Res. 2018;6:605–16.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Zhang S, Rabkin SD. The discovery and development of oncolytic viruses: are they the future of cancer immunotherapy?. Exp Opin Drug Discov. 2020;16:391–410.

    Article  CAS  Google Scholar 

  125. Le Saux O, Ray-Coquard I, Labidi-Galy SI. Challenges for immunotherapy for the treatment of platinum resistant ovarian cancer. Semin Cancer Biol. 2020;7:135–47.

    Google Scholar 

  126. Arcangeli S, Mestermann K, Weber J, Bonini C, Casucci M, Hudecek M. Overcoming key challenges in cancer immunotherapy with engineered T cells. Curr Opin Oncol. 2020;32:398–407.

    Article  CAS  PubMed  Google Scholar 

  127. 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 

  128. Tang X, Li Y, Ma J, Wang X, Zhao W, Hossain MA, et al. Adenovirus-mediated specific tumor tagging facilitates CAR-T therapy against antigen mismatched solid tumors. Cancer Lett. 2020;487:1–19.

    Article  CAS  PubMed  Google Scholar 

  129. Park AK, Fong Y, Kim S-I, 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;12:1–13.

    Article  Google Scholar 

  130. Tagliamonte M, Mauriello A, Cavalluzzo B, Ragone C, Manolio C, Petrizzo A, et al. Tackling hepatocellular carcinoma with individual or combinatorial immunotherapy approaches. Cancer Lett. 2020;473:25–32.

    Article  CAS  PubMed  Google Scholar 

  131. Hai J, Zhang H, Zhou J, Wu Z, Chen T, Papadopoulos E, et al. Generation of genetically engineered mouse lung organoid models for squamous cell lung cancers allows for the study of combinatorial immunotherapy. Clin Cancer Res. 2020;26:3431–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Garcia-Carbonero R, Salazar R, Duran I, Osman-Garcia I, Paz-Ares L, Bozada JM, et al. Phase 1 study of intravenous administration of the chimeric adenovirus enadenotucirev in patients undergoing primary tumor resection. J Immunother Cancer. 2017;5:71.

    Article  PubMed  PubMed Central  Google Scholar 

  133. Heinzerling L, Künzi V, Oberholzer PA, Kündig T, Naim H, Dummer R. Oncolytic measles virus in cutaneous T-cell lymphomas mounts antitumor immune responses in vivo and targets interferon-resistant tumor cells. Blood. 2005;106:2287–94.

    Article  CAS  PubMed  Google Scholar 

  134. Turtle CJ, Hanafi L-A, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR–T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126:2123–38.

    Article  PubMed  PubMed Central  Google Scholar 

  135. Peng K-W, Myers R, Greenslade A, Mader E, Greiner S, Federspiel MJ, et al. Using clinically approved cyclophosphamide regimens to control the humoral immune response to oncolytic viruses. Gene Ther. 2013;20:255–61.

    Article  CAS  PubMed  Google Scholar 

  136. Gattinoni L, Finkelstein SE, Klebanoff CA, Antony PA, Palmer DC, Spiess PJ, et al. Removal of homeostatic cytokine sinks by lymphodepletion enhances the efficacy of adoptively transferred tumor-specific CD8+ T cells. J Exp Med. 2005;202:907–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Esmaeili Govarchin Ghaleh H, Zarei L, Mansori Motlagh B, Jabbari N. Using CuO nanoparticles and hyperthermia in radiotherapy of MCF-7 cell line: synergistic effect in cancer therapy. Artif Cells Nanomed Biotechnol. 2019;47:1396–403.

    Article  CAS  PubMed  Google Scholar 

  138. Akram A, Inman RD. Immunodominance: a pivotal principle in host response to viral infections. Clin Immunol. 2012;143:99–115.

    Article  CAS  PubMed  Google Scholar 

  139. Frahm N, DeCamp AC, Friedrich DP, Carter DK, Defawe OD, Kublin JG, et al. Human adenovirus-specific T cells modulate HIV-specific T cell responses to an Ad5-vectored HIV-1 vaccine. J Clin Invest. 2012;122:359–67.

    Article  CAS  PubMed  Google Scholar 

  140. Galivo F, Diaz RM, Thanarajasingam U, Jevremovic D, Wongthida P, Thompson J, et al. Interference of CD40L-mediated tumor immunotherapy by oncolytic vesicular stomatitis virus. Hum Gene Ther. 2010;21:439–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Rodriguez-Garcia A, Svensson E, Gil-Hoyos R, Fajardo C, Rojas L, Arias-Badia M, et al. Insertion of exogenous epitopes in the E3-19K of oncolytic adenoviruses to enhance TAP-independent presentation and immunogenicity. Gene Ther. 2015;22:596–601.

    Article  CAS  PubMed  Google Scholar 

  142. Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med. 2008;14:1264–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Melzer MK, Zeitlinger L, Mall S, Steiger K, Schmid RM, Ebert O, et al. Enhanced safety and efficacy of oncolytic VSV therapy by combination with T cell receptor transgenic T cells as carriers. Mol Ther Oncolytics. 2019;12:26–40.

    Article  CAS  PubMed  Google Scholar 

  144. Todo T, Tanaka M, Ito M, Ito H, Ino Y. Clinical trials of a third-generation recombinant oncolytic HSV-1 in recurrent glioblastoma and olfactory neuroblastoma patients. Neuro Oncol. 2014;16:iii51–iii51.

    Article  PubMed Central  Google Scholar 

  145. Markert JM, Liechty PG, Wang W, Gaston S, Braz E, Karrasch M, et al. Phase Ib trial of mutant herpes simplex virus G207 inoculated pre-and post-tumor resection for recurrent GBM. Mol Ther. 2009;17:199–207.

    Article  CAS  PubMed  Google Scholar 

  146. Breitbach CJ, Moon A, Burke J, Hwang TH, Kirn DH. A Phase 2, open-label, randomized study of Pexa-Vec (JX-594) Administered by intratumoral injection in patients with unresectable primary hepatocellular carcinoma. Methods Mol Biol. 2015;1317:343–57.

    Article  PubMed  Google Scholar 

  147. Packiam VT, Lamm DL, Barocas DA, Trainer A, Fand B, Davis RL 3rd, et al. An open label, single-arm, phase II multicenter study of the safety and efficacy of CG0070 oncolytic vector regimen in patients with BCG-unresponsive non-muscle-invasive bladder cancer: interim results. Urol Oncol. 2018;36:440–7.

    Article  CAS  PubMed  Google Scholar 

  148. Black AJ, Morris DG. Clinical trials involving the oncolytic virus, reovirus: ready for prime time? Expert Rev Clin Pharmacol. 2012;5:517–20.

    Article  CAS  PubMed  Google Scholar 

  149. Jaime-Ramirez AC, Yu JG, Caserta E, Yoo JY, Zhang J, Lee TJ, et al. Reolysin and histone deacetylase inhibition in the treatment of head and neck squamous cell carcinoma. Mol Ther Oncolytics. 2017;5:87–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Lauer U, Zimmermann M, Sturm J, Koppenhoefer U, Bitzer M, Malek NP, et al. Phase I/II clinical trial of a genetically modified and oncolytic vaccinia virus GL-ONC1 in patients with unresactable, chemotherapy-resistant peritoneal carcinomatosis. Am Soc Clin Oncol. 2013;31:127–40.

    Google Scholar 

  151. Andtbacka RHI, Curti BD, Kaufman H, Daniels GA, Nemunaitis JJ, Spitler LE, et al. Final data from CALM: A phase II study of Coxsackievirus A21(CVA21) oncolytic virus immunotherapy in patients with advanced melanoma. Am Soc Clin Oncol. 2015;33:101–10.

    Google Scholar 

  152. Merchan JR, Patel M, Cripe TP, Old MO, Strauss JF, Thomassen A, et al. Relationship of infusion duration to safety, efficacy, and pharmacodynamics(PD): Second part of a phase I-II study using VSV-IFNβ-NIS (VV1) oncolytic virus in patients with refractory solid tumors. Am Soc Clin Oncol. 2020;38:212–9.

    Google Scholar 

  153. Fueyo J, Gomez-Manzano C, Villalobos P, Rodriguez-Canales J, Wistuba I, Hess KR, et al. ATIM-08. immunomarkers in the DNX-2401 (DELTA-24-RGD) oncolytic virus phase I clinical trial. Neuro Oncol. 2017;19:vi27–vi27.

    Article  PubMed Central  Google Scholar 

  154. Desjardins A, Gromeier M, Herndon JE 2nd, Beaubier N, Bolognesi DP, Friedman AH, et al. Recurrent glioblastoma treated with recombinant poliovirus. N Engl J Med. 2018;379:150–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Foloppe J, Kempf J, Futin N, Kintz J, Cordier P, Pichon C, et al. The enhanced tumor specificity of TG6002, an armed oncolytic vaccinia virus deleted in two genes involved in nucleotide metabolism. Mol Ther Oncolytics. 2019;14:1–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Dispenzieri A, Tong C, LaPlant B, Lacy MQ, Laumann K, Dingli D, et al. Phase I trial of systemic administration of Edmonston strain of measles virus genetically engineered to express the sodium iodide symporter in patients with recurrent or refractory multiple myeloma. Leukemia. 2017;31:2791–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Louis CU, Savoldo B, Dotti G, Pule M, Yvon E, Myers GD, et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood. 2011;118:6050–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Katz SC, Burga RA, McCormack E, Wang LJ, Mooring W, Point GR, et al. Phase I hepatic immunotherapy for metastases study of intra-arterial chimeric antigen receptor–modified T-cell therapy for CEA+ liver metastases. Clin Cancer Res. 2015;21:3149–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. 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;25:1248–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Feng K, Guo Y, Dai H, Wang Y, Li X, Jia H, et al. Chimeric antigen receptor-modified T cells for the immunotherapy of patients with EGFR-expressing advanced relapsed/refractory non-small cell lung cancer. Sci China life Sci. 2016;59:468–79.

    Article  CAS  PubMed  Google Scholar 

  161. Ahmed N, Brawley V, Hegde M, Bielamowicz K, Wakefield A, Ghazi A, et al. Autologous HER2 CMV bispecific CAR T cells are safe and demonstrate clinical benefit for glioblastoma in a Phase I trial. J Immunother Cancer. 2015;3:1–1.

    Article  Google Scholar 

  162. Feng K, Liu Y, Guo Y, Qiu J, Wu Z, Dai H, et al. Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers. Protein Cell. 2018;9:838–47.

    Article  CAS  PubMed  Google Scholar 

  163. O'Rourke DM, Nasrallah M, Morrissette JJ, Melenhorst JJ, Lacey SF, Mansfield K. et al. Pilot study of T cells redirected to EGFRvIII with a chimericantigen receptor in patients with EGFRvIII+ glioblastoma. Am Soc Clin Oncol. 2016;34:183–92.

    Google Scholar 

  164. Katz SC, Hardaway J, Prince E, Guha P, Cunetta M, Moody A, et al. HITM-SIR: phase Ib trial of intraarterial chimeric antigen receptor T-cell therapy and selective internal radiation therapy for CEA+ liver metastases. Cancer Gene Ther. 2020;27:341–55.

    Article  CAS  PubMed  Google Scholar 

  165. Nishio N, Diaconu I, Liu H, Cerullo V, Caruana I, Hoyos V, et al. Armed oncolytic virus enhances immune functions of chimeric antigen receptor–modified T cells in solid tumors. Cancer Res. 2014;74:5195–205.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Shaw AR, Porter CE, Watanabe N, Tanoue K, Sikora A, Gottschalk S, et al. Adenovirotherapy delivering cytokine and checkpoint inhibitor augments CAR T cells against metastatic head and neck cancer. Mol Ther. 2017;25:2440–51.

    Article  CAS  Google Scholar 

  167. Tanoue K, Shaw AR, Watanabe N, Porter C, Rana B, Gottschalk S, et al. Armed oncolytic adenovirus–expressing PD-L1 mini-body enhances antitumor effects of chimeric antigen receptor T cells in solid tumors. Cancer Res. 2017;77:2040–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Contributions

All authors equally contribute to this study.

Corresponding author

Correspondence to Hadi Esmaeili Gouvarchin Ghaleh.

Ethics declarations

COMPETING INTERESTS

The authors declare no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Rezaei, R., Esmaeili Gouvarchin Ghaleh, H., Farzanehpour, M. et al. Combination therapy with CAR T cells and oncolytic viruses: a new era in cancer immunotherapy. Cancer Gene Ther 29, 647–660 (2022). https://doi.org/10.1038/s41417-021-00359-9

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41417-021-00359-9

This article is cited by

Search

Quick links