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:

Oncolysis without viruses — inducing systemic anticancer immune responses with local therapies

Nature Reviews Clinical Oncology volume 17, pages 49–64 (2020)Cite this article

Subjects

Abstract

Local administration of oncolytic viruses to tumours can promote anticancer immune responses that lead to the abscopal regression of distant metastases, especially in patients receiving systemic immune-checkpoint inhibitors. Growing preclinical evidence indicates that non-virally induced oncolysis, defined as chemical or physical treatment administered locally to destroy malignant lesions, can promote a similar effect owing to the release of danger-associated molecular patterns that lead to the recruitment of immune cells, thus inducing a systemic response against tumour antigens that protects against local disease relapse and also mediates distant antineoplastic effects. An accumulating body of preclinical evidence supports the implementation of therapies that combine oncolysis with local or systemic immunotherapies. In this Review, we summarize the available data on innovative non-viral oncolysis strategies, including intratumorally applied cytotoxicants, photodynamic therapy, laser therapy, microwave, radiofrequency or photothermal ablation, high-intensity focused ultrasonography and cryotherapy for the local treatment of patients with solid tumours.

Key points

  • Oncolytic viruses are beginning to enter clinical use in patients with cancer despite practical considerations precluding their widespread use, highlighting the need for non-viral methods of oncolysis.

  • Multiple distinct physical and/or chemical methods of non-viral oncolysis are available. Each type of oncolysis causes a distinct type of cell stress and tissue destruction with variable immunological outcomes.

  • Immunogenic oncolysis initiates a local antitumour immune response through the destruction of immunosuppressive cells and the release of immunoactivatory danger-associated molecular patterns, leading to the recruitment of immune effectors.

  • Various strategies for increasing the immune-mediated abscopal effects of oncolysis, including local or systemic immunotherapies, are being developed. The optimal schedule of such combination regimens must be carefully evaluated in future trials.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Schematic overview of non-viral oncolytic procedures.
Fig. 2: Immunogenic cell death in oncolysis.
Fig. 3: Direct and indirect immunostimulation by oncolytic therapy.
Fig. 4: Rationale for combination treatments.

Similar content being viewed by others

References

  1. Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunological effects of conventional chemotherapy and targeted anticancer agents. Cancer Cell 28, 690–714 (2015).

    Article  CAS  PubMed  Google Scholar 

  2. Dadi, S. et al. Cancer immunosurveillance by tissue-resident innate lymphoid cells and innate-like T cells. Cell 164, 365–377 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Fridman, W. H., Zitvogel, L., Sautes-Fridman, C. & Kroemer, G. The immune contexture in cancer prognosis and treatment. Nat. Rev. Clin. Oncol. 14, 717–734 (2017).

    Article  CAS  PubMed  Google Scholar 

  4. Fucikova, J. et al. Calreticulin expression in human non-small cell lung cancers correlates with increased accumulation of antitumor immune cells and favorable prognosis. Cancer Res. 76, 1746–1756 (2016).

    Article  CAS  PubMed  Google Scholar 

  5. Pages, F. et al. International validation of the consensus immunoscore for the classification of colon cancer: a prognostic and accuracy study. Lancet 391, 2128–2139 (2018).

    Article  PubMed  Google Scholar 

  6. Weichselbaum, R. R., Liang, H., Deng, L. & Fu, Y. X. Radiotherapy and immunotherapy: a beneficial liaison? Nat. Rev. Clin. Oncol. 14, 365–379 (2017).

    Article  CAS  PubMed  Google Scholar 

  7. Postow, M. A. et al. Immunologic correlates of the abscopal effect in a patient with melanoma. N. Engl. J. Med. 366, 925–931 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. De Meerleer, G. et al. Radiotherapy for renal-cell carcinoma. Lancet Oncol. 15, e170–e177 (2014).

    Article  PubMed  Google Scholar 

  9. Mothersill, C., Rusin, A., Fernandez-Palomo, C. & Seymour, C. History of bystander effects research 1905-present; what is in a name? Int. J. Radiat. Biol. 94, 696–707 (2018).

    Article  CAS  PubMed  Google Scholar 

  10. Ngwa, W. et al. Using immunotherapy to boost the abscopal effect. Nat. Rev. Cancer 18, 313–322 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Rodriguez-Ruiz, M. E., Vanpouille-Box, C., Melero, I., Formenti, S. C. & Demaria, S. Immunological mechanisms responsible for radiation-induced abscopal effect. Trends Immunol. 39, 644–655 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Lin, A. J., Roach, M., Bradley, J. & Robinson, C. Combining stereotactic body radiation therapy with immunotherapy: current data and future directions. Transl Lung Cancer Res. 8, 107–115 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Vanpouille-Box, C. et al. DNA exonuclease Trex1 regulates radiotherapy-induced tumour immunogenicity. Nat. Commun. 8, 15618 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Formenti, S. C. et al. Radiotherapy induces responses of lung cancer to CTLA-4 blockade. Nat. Med. 24, 1845–1851 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Achard, C. et al. Lighting a fire in the tumor microenvironment using oncolytic immunotherapy. EBioMedicine 31, 17–24 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  17. Greig, S. L. Talimogene laherparepvec: first global approval. Drugs 76, 147–154 (2016).

    Article  CAS  PubMed  Google Scholar 

  18. Ribas, A. et al. Oncolytic virotherapy promotes intratumoral T cell infiltration and improves anti-PD-1 immunotherapy. Cell 170, 1109–1119.e10 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Chesney, 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. 36, 1658–1667 (2018).

    Article  CAS  PubMed  Google Scholar 

  20. Twumasi-Boateng, K., Pettigrew, J. L., Kwok, Y. Y. E., Bell, J. C. & Nelson, B. H. Oncolytic viruses as engineering platforms for combination immunotherapy. Nat. Rev. Cancer 18, 419–432 (2018).

    Article  CAS  PubMed  Google Scholar 

  21. Bommareddy, P. K., Shettigar, M. & Kaufman, H. L. Integrating oncolytic viruses in combination cancer immunotherapy. Nat. Rev. Immunol. 18, 498–513 (2018).

    Article  CAS  PubMed  Google Scholar 

  22. G Pol, J. et al. Trial watch: oncolytic viro-immunotherapy of hematologic and solid tumors. Oncoimmunology 7, e1503032 (2018).

    Article  Google Scholar 

  23. Harrington, K. J. et al. A practical guide to the handling and administration of talimogene laherparepvec in Europe. Onco Targets Ther. 10, 3867–3880 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  24. Martin, C. Oncolytic viruses: treatment and implications for patients with gliomas. Clin. J. Oncol. Nurs. 21, 60–64 (2017).

    Article  PubMed  Google Scholar 

  25. Adkins, I., Fucikova, J., Garg, A. D., Agostinis, P. & Spisek, R. Physical modalities inducing immunogenic tumor cell death for cancer immunotherapy. Oncoimmunology 3, e968434 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  26. Chu, K. F. & Dupuy, D. E. Thermal ablation of tumours: biological mechanisms and advances in therapy. Nat. Rev. Cancer 14, 199–208 (2014).

    Article  CAS  PubMed  Google Scholar 

  27. Slovak, R., Ludwig, J. M., Gettinger, S. N., Herbst, R. S. & Kim, H. S. Immuno-thermal ablations - boosting the anticancer immune response. J. Immunother. Cancer 5, 78 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  28. Schneider, T. et al. Immune response after radiofrequency ablation and surgical resection in nonsmall cell lung cancer. Semin. Thorac. Cardiovasc. Surg. 28, 585–592 (2016).

    Article  PubMed  Google Scholar 

  29. Chen, Q. et al. Photothermal therapy promotes tumor infiltration and antitumor activity of CAR T cells. Adv. Mater. 31, e1900192 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  30. den Brok, M. H. et al. Efficient loading of dendritic cells following cryo and radiofrequency ablation in combination with immune modulation induces anti-tumour immunity. Br. J. Cancer 95, 896–905 (2006).

    Article  CAS  Google Scholar 

  31. Jansen, M. C. et al. Cryoablation induces greater inflammatory and coagulative responses than radiofrequency ablation or laser induced thermotherapy in a rat liver model. Surgery 147, 686–695 (2010).

    Article  PubMed  Google Scholar 

  32. Sabel, M. S. Cryo-immunology: a review of the literature and proposed mechanisms for stimulatory versus suppressive immune responses. Cryobiology 58, 1–11 (2009).

    Article  CAS  PubMed  Google Scholar 

  33. Kato, T. et al. Characterization of the cryoablation-induced immune response in kidney cancer patients. Oncoimmunology 6, e1326441 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  34. Zhao, J. et al. Irreversible electroporation reverses resistance to immune checkpoint blockade in pancreatic cancer. Nat. Commun. 10, 899 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Pandit, H. et al. Evaluating the regulatory immunomodulation effect of irreversible electroporation (IRE) in pancreatic adenocarcinoma. Ann. Surg. Oncol. 26, 800–806 (2019).

    Article  PubMed  Google Scholar 

  36. White, S. B., Zhang, Z., Chen, J., Gogineni, V. R. & Larson, A. C. Early immunologic response of irreversible electroporation versus cryoablation in a rodent model of pancreatic cancer. J. Vasc. Interv. Radiol. 29, 1764–1769 (2018).

    Article  PubMed  Google Scholar 

  37. Calvet, C. Y., Famin, D., Andre, F. M. & Mir, L. M. Electrochemotherapy with bleomycin induces hallmarks of immunogenic cell death in murine colon cancer cells. Oncoimmunology 3, e28131 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  38. Bugaut, H. et al. Bleomycin exerts ambivalent antitumor immune effect by triggering both immunogenic cell death and proliferation of regulatory T cells. PLOS ONE 8, e65181 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Casares, N. et al. Caspase-dependent immunogenicity of doxorubicin-induced tumor cell death. J. Exp. Med. 202, 1691–1701 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Tremble, L. F., O’Brien, M. A., Soden, D. M. & Forde, P. F. Electrochemotherapy with cisplatin increases survival and induces immunogenic responses in murine models of lung cancer and colorectal cancer. Cancer Lett. 442, 475–482 (2019).

    Article  CAS  PubMed  Google Scholar 

  41. Garg, A. D. et al. A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J. 31, 1062–1079 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Gomes-da-Silva, L. C. et al. Photodynamic therapy with redaporfin targets the endoplasmic reticulum and Golgi apparatus. EMBO J. 37, e98354 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  43. Preise, D. et al. Systemic antitumor protection by vascular-targeted photodynamic therapy involves cellular and humoral immunity. Cancer Immunol. Immunother. 58, 71–84 (2009).

    Article  CAS  PubMed  Google Scholar 

  44. Kleinovink, J. W., Fransen, M. F., Lowik, C. W. & Ossendorp, F. Photodynamic-immune checkpoint therapy eradicates local and distant tumors by CD8+ T cells. Cancer Immunol. Res. 5, 832–838 (2017).

    Article  CAS  PubMed  Google Scholar 

  45. Cho, A., Jantschitsch, C. & Knobler, R. Extracorporeal photopheresis-an overview. Front. Med. 5, 236 (2018).

    Article  Google Scholar 

  46. Edelson, R. et al. Treatment of cutaneous T-cell lymphoma by extracorporeal photochemotherapy. Preliminary results. N. Engl. J. Med. 316, 297–303 (1987).

    Article  CAS  PubMed  Google Scholar 

  47. Ventura, A. et al. Extracorporeal photochemotherapy drives monocyte-to-dendritic cell maturation to induce anticancer immunity. Cancer Res. 78, 4045–4058 (2018).

    Article  CAS  PubMed  Google Scholar 

  48. Habib, A. et al. Transarterial approaches to primary and secondary hepatic malignancies. Nat. Rev. Clin. Oncol. 12, 481–489 (2015).

    Article  PubMed  Google Scholar 

  49. Lee, H. L. et al. Inflammatory cytokines and change of Th1/Th2 balance as prognostic indicators for hepatocellular carcinoma in patients treated with transarterial chemoembolization. Sci. Rep. 9, 3260 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Obeid, M. et al. Calreticulin exposure is required for the immunogenicity of gamma-irradiation and UVC light-induced apoptosis. Cell Death Differ. 14, 1848–1850 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Chew, V. et al. Immune activation underlies a sustained clinical response to Yttrium-90 radioembolisation in hepatocellular carcinoma. Gut 68, 335–346 (2019).

    Article  CAS  PubMed  Google Scholar 

  52. Pasquereau-Kotula, E., Habault, J., Kroemer, G. & Poyet, J. L. The anticancer peptide RT53 induces immunogenic cell death. PLOS ONE 13, e0201220 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  53. Zhou, H. et al. The oncolytic peptide LTX-315 triggers immunogenic cell death. Cell Death Dis. 7, e2134 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Zhou, H. et al. The oncolytic compound LTX-401 targets the Golgi apparatus. Cell Death Differ. 23, 2031–2041 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Zhou, H. et al. Oncolysis with DTT-205 and DTT-304 generates immunological memory in cured animals. Cell Death Dis. 9, 1086 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Nestvold, J. et al. Oncolytic peptide LTX-315 induces an immune-mediated abscopal effect in a rat sarcoma model. Oncoimmunology 6, e1338236 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  57. Camilio, K. A. et al. Combining the oncolytic peptide LTX-315 with doxorubicin demonstrates therapeutic potential in a triple-negative breast cancer model. Breast Cancer Res. 21, 9 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  58. Zitvogel, L., Tesniere, A. & Kroemer, G. Cancer despite immunosurveillance: immunoselection and immunosubversion. Nat. Rev. Immunol. 6, 715–727 (2006).

    Article  CAS  PubMed  Google Scholar 

  59. Schreiber, R. D., Old, L. J. & Smyth, M. J. Cancer immunoediting: integrating immunity’s roles in cancer suppression and promotion. Science 331, 1565–1570 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Palucka, A. K. & Coussens, L. M. The basis of oncoimmunology. Cell 164, 1233–1247 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Chaurasiya, S., Chen, N. G. & Fong, Y. Oncolytic viruses and immunity. Curr. Opin. Immunol. 51, 83–90 (2018).

    Article  CAS  PubMed  Google Scholar 

  62. Dvorak, H. F. Tumors: wounds that do not heal. Similarities between tumor stroma generation and wound healing. N. Engl. J. Med. 315, 1650–1659 (1986).

    Article  CAS  PubMed  Google Scholar 

  63. Bloy, N. et al. Immunogenic stress and death of cancer cells: contribution of antigenicity vs adjuvanticity to immunosurveillance. Immunol. Rev. 280, 165–174 (2017).

    Article  CAS  PubMed  Google Scholar 

  64. Obeid, M. et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat. Med. 13, 54–61 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Michaud, M. et al. Autophagy-dependent anticancer immune responses induced by chemotherapeutic agents in mice. Science 334, 1573–1577 (2011).

    Article  CAS  PubMed  Google Scholar 

  66. Martins, I. et al. Molecular mechanisms of ATP secretion during immunogenic cell death. Cell Death Differ. 21, 79–91 (2014).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Blander, J. M. & Medzhitov, R. Toll-dependent selection of microbial antigens for presentation by dendritic cells. Nature 440, 808–812 (2006).

    Article  CAS  PubMed  Google Scholar 

  69. Ali, M. Y. et al. Activation of dendritic cells by local ablation of hepatocellular carcinoma. J. Hepatol. 43, 817–822 (2005).

    Article  CAS  PubMed  Google Scholar 

  70. Fietta, A. M. et al. Systemic inflammatory response and downmodulation of peripheral CD25+Foxp3+T-regulatory cells in patients undergoing radiofrequency thermal ablation for lung cancer. Hum. Immunol. 70, 477–486 (2009).

    Article  CAS  PubMed  Google Scholar 

  71. Chen, T., Guo, J., Han, C., Yang, M. & Cao, X. Heat shock protein 70, released from heat-stressed tumor cells, initiates antitumor immunity by inducing tumor cell chemokine production and activating dendritic cells via TLR4 pathway. J. Immunol. 182, 1449–1459 (2009).

    Article  CAS  PubMed  Google Scholar 

  72. Sabel, M. S. et al. Immunologic response to cryoablation of breast cancer. Breast Cancer Res. Treat 90, 97–104 (2005).

    Article  CAS  PubMed  Google Scholar 

  73. Zitvogel, L., Galluzzi, L., Kepp, O., Smyth, M. J. & Kroemer, G. Type I interferons in anticancer immunity. Nat. Rev. Immunol. 15, 405–414 (2015).

    Article  CAS  PubMed  Google Scholar 

  74. Galluzzi, L., Buque, A., Kepp, O., Zitvogel, L. & Kroemer, G. Immunogenic cell death in cancer and infectious disease. Nat. Rev. Immunol. 17, 97–111 (2017).

    Article  CAS  PubMed  Google Scholar 

  75. Masopust, D. & Soerens, A. G. Tissue-resident T cells and other resident leukocytes. Annu. Rev. Immunol. 37, 521–546 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Tang, J. et al. Trial watch: the clinical trial landscape for PD1/PDL1 immune checkpoint inhibitors. Nat. Rev. Drug Discov. 17, 854–855 (2018).

    Article  CAS  PubMed  Google Scholar 

  77. Schmid, P. et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379, 2108–2121 (2018).

    Article  CAS  PubMed  Google Scholar 

  78. Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288–2301 (2018).

    Article  CAS  PubMed  Google Scholar 

  79. Pfirschke, C. et al. Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity 44, 343–354 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Liu, P. et al. Crizotinib-induced immunogenic cell death in non-small cell lung cancer. Nat. Commun. 10, 1486 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Rios-Doria, J. et al. Antibody-drug conjugates bearing pyrrolobenzodiazepine or tubulysin payloads are immunomodulatory and synergize with multiple immunotherapies. Cancer Res. 77, 2686–2698 (2017).

    Article  CAS  PubMed  Google Scholar 

  82. Yamazaki, T. et al. The oncolytic peptide LTX-315 overcomes resistance of cancers to immunotherapy with CTLA4 checkpoint blockade. Cell Death Differ. 23, 1004–1015 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Zhu, J. et al. Enhanced antitumor efficacy through microwave ablation in combination with immune checkpoints blockade in breast cancer: a pre-clinical study in a murine model. Diagn. Interv. Imaging 99, 135–142 (2018).

    Article  CAS  PubMed  Google Scholar 

  84. Shi, L. et al. PD-1 blockade boosts radiofrequency ablation-elicited adaptive immune responses against tumor. Clin. Cancer Res. 22, 1173–1184 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. O’Shaughnessy, M. J. et al. Systemic antitumor immunity by PD-1/PD-L1 inhibition is potentiated by vascular-targeted photodynamic therapy of primary tumors. Clin. Cancer Res. 24, 592–599 (2018).

    Article  PubMed  CAS  Google Scholar 

  86. Adashek, J. J., Salgia, M., Dizman, N., Kessler, J. & Pal, S. K. Concomitant radioembolization and immune checkpoint inhibition in metastatic renal cell carcinoma. Case Rep. Oncol. 11, 276–280 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Wehrenberg-Klee, E., Goyal, L., Dugan, M., Zhu, A. X. & Ganguli, S. Y-90 radioembolization combined with a PD-1 inhibitor for advanced hepatocellular carcinoma. Cardiovasc. Intervent. Radiol. 41, 1799–1802 (2018).

    Article  PubMed  Google Scholar 

  88. Zheng, J., Irani, Z., Lawrence, D., Flaherty, K. & Arellano, R. S. Combined effects of yttrium-90 transarterial radioembolization around immunotherapy for hepatic metastases from uveal melanoma: a preliminary retrospective case series. J. Vasc. Interv. Radiol. 29, 1369–1375 (2018).

    Article  PubMed  Google Scholar 

  89. Waitz, R. et al. Potent induction of tumor immunity by combining tumor cryoablation with anti-CTLA-4 therapy. Cancer Res. 72, 430–439 (2012).

    Article  CAS  PubMed  Google Scholar 

  90. Mozzillo, N. et al. Assessing a novel immuno-oncology-based combination therapy: Ipilimumab plus electrochemotherapy. Oncoimmunology 4, e1008842 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Theurich, S. et al. Local tumor treatment in combination with systemic ipilimumab immunotherapy prolongs overall survival in patients with advanced malignant melanoma. Cancer Immunol. Res. 4, 744–754 (2016).

    Article  CAS  PubMed  Google Scholar 

  92. Xie, C. et al. Tremelimumab in combination with microwave ablation in patients with refractory biliary tract cancer. Hepatology 69, 2048–2060 (2019).

    Article  CAS  PubMed  Google Scholar 

  93. Behm, B. et al. Additive antitumour response to the rabbit VX2 hepatoma by combined radio frequency ablation and toll like receptor 9 stimulation. Gut 65, 134–143 (2016).

    Article  CAS  PubMed  Google Scholar 

  94. Lin, M. et al. An important discovery on combination of irreversible electroporation and allogeneic natural killer cell immunotherapy for unresectable pancreatic cancer. Oncotarget 8, 101795–101807 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  95. Yang, Y. et al. Safety and short-term efficacy of irreversible electroporation and allogenic natural killer cell immunotherapy combination in the treatment of patients with unresectable primary liver cancer. Cardiovasc. Intervent. Radiol. 42, 48–59 (2019).

    Article  PubMed  Google Scholar 

  96. Bear, A. S. et al. Elimination of metastatic melanoma using gold nanoshell-enabled photothermal therapy and adoptive T cell transfer. PLOS ONE 8, e69073 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Marabelle, A. et al. Depleting tumor-specific Tregs at a single site eradicates disseminated tumors. J. Clin. Invest. 123, 2447–2463 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Marabelle, A., Tselikas, L., de Baere, T. & Houot, R. Intratumoral immunotherapy: using the tumor as the remedy. Ann. Oncol. 28, xii33–xii43 (2017).

    Article  CAS  PubMed  Google Scholar 

  99. Frank, M. J. et al. In situ vaccination with a TLR9 agonist and local low-dose radiation induces systemic responses in untreated indolent lymphoma. Cancer Discov. 8, 1258–1269 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Sagiv-Barfi, I. et al. Eradication of spontaneous malignancy by local immunotherapy. Sci. Transl Med. 10, eaan4488 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Hammerich, L. et al. Systemic clinical tumor regressions and potentiation of PD1 blockade with in situ vaccination. Nat. Med. 25, 814–824 (2019).

    Article  CAS  PubMed  Google Scholar 

  102. Li, L. et al. Microwave ablation combined with OK-432 induces Th1-type response and specific antitumor immunity in a murine model of breast cancer. J. Transl Med. 15, 23 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Lemdani, K. et al. Local immunomodulation combined to radiofrequency ablation results in a complete cure of local and distant colorectal carcinoma. Oncoimmunology 8, 1550342 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Veenstra, J. J. et al. Cryotherapy with concurrent CpG oligonucleotide treatment controls local tumor recurrence and modulates HER2/neu immunity. Cancer Res. 74, 5409–5420 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Machlenkin, A. et al. Combined dendritic cell cryotherapy of tumor induces systemic antimetastatic immunity. Clin. Cancer Res. 11, 4955–4961 (2005).

    Article  CAS  PubMed  Google Scholar 

  106. Alteber, Z. et al. Cryoimmunotherapy with local co-administration of ex vivo generated dendritic cells and CpG-ODN immune adjuvant, elicits a specific antitumor immunity. Cancer Immunol. Immunother. 63, 369–380 (2014).

    Article  CAS  PubMed  Google Scholar 

  107. Chua, C. Y. X. et al. Nanofluidic drug-eluting seed for sustained intratumoral immunotherapy in triple negative breast cancer. J. Control. Release 285, 23–34 (2018).

    Article  CAS  PubMed  Google Scholar 

  108. Luo, L. et al. Sustained release of anti-PD-1 peptide for perdurable immunotherapy together with photothermal ablation against primary and distant tumors. J. Control. Release 278, 87–99 (2018).

    Article  CAS  PubMed  Google Scholar 

  109. Chen, Q. et al. Photothermal therapy with immune-adjuvant nanoparticles together with checkpoint blockade for effective cancer immunotherapy. Nat. Commun. 7, 13193 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Andtbacka, R. H. et al. Patterns of clinical response with talimogene laherparepvec (T-VEC) in patients with melanoma treated in the optim phase III clinical trial. Ann. Surg. Oncol. 23, 4169–4177 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  111. Chao, Y. et al. Combined local immunostimulatory radioisotope therapy and systemic immune checkpoint blockade imparts potent antitumour responses. Nat. Biomed. Eng. 2, 611–621 (2018).

    Article  CAS  PubMed  Google Scholar 

  112. Chen, Q. et al. In situ sprayed bioresponsive immunotherapeutic gel for post-surgical cancer treatment. Nat. Nanotechnol. 14, 89–97 (2019).

    Article  CAS  PubMed  Google Scholar 

  113. Abdo, J., Cornell, D. L., Mittal, S. K. & Agrawal, D. K. Immunotherapy plus cryotherapy: potential augmented abscopal effect for advanced cancers. Front. Oncol. 8, 85 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Fu, J. et al. STING agonist formulated cancer vaccines can cure established tumors resistant to PD-1 blockade. Sci. Transl Med. 7, 283ra52 (2015).

    PubMed  PubMed Central  Google Scholar 

  115. Zamarin, D. et al. Localized oncolytic virotherapy overcomes systemic tumor resistance to immune checkpoint blockade immunotherapy. Sci. Transl Med. 6, 226ra32 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Postel-Vinay, S. et al. Challenges of phase 1 clinical trials evaluating immune checkpoint-targeted antibodies. Ann. Oncol. 27, 214–224 (2016).

    Article  CAS  PubMed  Google Scholar 

  117. Skolnik, J. M., Barrett, J. S., Jayaraman, B., Patel, D. & Adamson, P. C. Shortening the timeline of pediatric phase I trials: the rolling six design. J. Clin. Oncol. 26, 190–195 (2008).

    Article  PubMed  Google Scholar 

  118. Turajlic, S., Sottoriva, A., Graham, T. & Swanton, C. Resolving genetic heterogeneity in cancer. Nat. Rev. Genet. 20, 404–416 (2019).

    Article  CAS  PubMed  Google Scholar 

  119. Angelova, M. et al. Evolution of metastases in space and time under immune selection. Cell 175, 751–765.e16 (2018).

    Article  CAS  PubMed  Google Scholar 

  120. Rosenthal, R. et al. Neoantigen-directed immune escape in lung cancer evolution. Nature 567, 479–485 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Galluzzi, L., Chan, T. A., Kroemer, G., Wolchok, J. D. & Lopez-Soto, A. The hallmarks of successful anticancer immunotherapy. Sci. Transl Med. 10, eaat7807 (2018).

    Article  PubMed  CAS  Google Scholar 

  122. Engelhard, V. H. et al. Immune cell infiltration and tertiary lymphoid structures as determinants of antitumor immunity. J. Immunol. 200, 432–442 (2018).

    Article  CAS  PubMed  Google Scholar 

  123. Lavin, Y. et al. Tissue-resident macrophage enhancer landscapes are shaped by the local microenvironment. Cell 159, 1312–1326 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Lavin, Y. et al. Innate immune landscape in early lung adenocarcinoma by paired single-cell analyses. Cell 169, 750–765.e17 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Lewis, K. L. et al. Notch2 receptor signaling controls functional differentiation of dendritic cells in the spleen and intestine. Immunity 35, 780–791 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Zitvogel, L., Ma, Y., Raoult, D., Kroemer, G. & Gajewski, T. F. The microbiome in cancer immunotherapy: diagnostic tools and therapeutic strategies. Science 359, 1366–1370 (2018).

    Article  CAS  PubMed  Google Scholar 

  127. Fend, L. et al. Immune checkpoint blockade, immunogenic chemotherapy or IFN-α blockade boost the local and abscopal effects of oncolytic virotherapy. Cancer Res. 77, 4146–4157 (2017).

    Article  CAS  PubMed  Google Scholar 

  128. Seremet, T. et al. Successful treatment with intralesional talimogene laherparepvec in two patients with immune checkpoint inhibitor-refractory, advanced-stage melanoma. Melanoma Res. 29, 85–88 (2019).

    Article  CAS  PubMed  Google Scholar 

  129. Woodland, D. L. Jump-starting the immune system: prime-boosting comes of age. Trends Immunol. 25, 98–104 (2004).

    Article  CAS  PubMed  Google Scholar 

  130. Vrankar, M. & Unk, M. Immune RECIST criteria and symptomatic pseudoprogression in non-small cell lung cancer patients treated with immunotherapy. Radiol. Oncol. 52, 365–369 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  132. Marabelle, A. et al. Starting the fight in the tumor: expert recommendations for the development of human intratumoral immunotherapy (HIT-IT). Ann. Oncol. 29, 2163–2174 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Gujar, S., Pol, J. G., Kim, Y., Lee, P. W. & Kroemer, G. Antitumor benefits of antiviral immunity: an underappreciated aspect of oncolytic virotherapies. Trends Immunol. 39, 209–221 (2018).

    Article  CAS  PubMed  Google Scholar 

  134. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/results?cond=&term=Cryosurgery%2C+Fuda+Cancer+Hospital%2C+Guangzhou.&cntry=CN&state=&city=&dist= (2019)

Download references

Acknowledgements

We thank E. Deutsch (GRCC) for critical reading. A.M. gratefully acknowledges financial support from BMS, Fondation MSD Avenir, INSERM CIC 1428 Biotherapies, the Institut National du Cancer (INCa) and the SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE). G.K. gratefully acknowledges financial support from the Agence National de la Recherche (ANR) – Projets blancs, ANR under the frame of E-Rare-2, the ERA-Net for Research on Rare Diseases, the Association pour la recherche sur le cancer (ARC), Cancéropôle Ile-de-France, Chancellerie des universités de Paris (Legs Poix), a donation from Elior, the European Research Area Network on Cardiovascular Diseases (ERA-CVD, MINOTAUR), the European Union Horizon 2020 Project Oncobiome, Fondation Carrefour; High-end Foreign Expert Program in China (GDW20171100085 and GDW20181100051), Fondation pour la Recherche Médicale (FRM), Gustave Roussy Odyssea, Inserm (HTE), the Institut National du Cancer (INCa), the Institut Universitaire de France, LabEx Immuno-Oncology, the LeDucq Foundation, the Ligue contre le Cancer (équipe labellisée), the RHU Torino Lumière, the Seerave Foundation, the SIRIC Cancer Research and Personalized Medicine (CARPEM), and the SIRIC Stratified Oncology Cell DNA Repair and Tumour Immune Elimination (SOCRATE).

Author information

Authors and Affiliations

  1. Equipe labellisée par la Ligue contre le cancer, Université de Paris, Sorbonne Université, INSERM U1138, Centre de Recherche des Cordeliers, Paris, France

    Oliver Kepp & Guido Kroemer

  2. Metabolomics and Cell Biology Platforms, Gustave Roussy, Villejuif, France

    Oliver Kepp & Guido Kroemer

  3. Department of Medical Oncology, Gustave Roussy Cancer Campus (GRCC), Villejuif, France

    Aurelien Marabelle & Laurence Zitvogel

  4. INSERM U1015, Villejuif, France

    Aurelien Marabelle & Laurence Zitvogel

  5. University Paris-Sud, University Paris-Saclay, GRCC, Villejuif, France

    Aurelien Marabelle & Laurence Zitvogel

  6. Center of Clinical Investigations in Biotherapies of Cancer (CICBT) 1428, Villejuif, France

    Aurelien Marabelle & Laurence Zitvogel

  7. Suzhou Institute for Systems Medicine, Chinese Academy of Medical Sciences, Suzhou, China

    Laurence Zitvogel & Guido Kroemer

  8. Pôle de Biologie, Hôpital Européen Georges Pompidou, AP-HP, Paris, France

    Guido Kroemer

  9. Karolinska Institutet, Department of Women’s and Children’s Health, Karolinska University Hospital, Stockholm, Sweden

    Guido Kroemer

Authors
  1. Oliver Kepp
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Aurelien Marabelle
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Laurence Zitvogel
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Guido Kroemer
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

O.K. and G.K. researched data for the manuscript, all authors made a substantial contribution to discussions of content and wrote the manuscript, and O.K., L.Z. and G.K. reviewed and/or edited the manuscript prior to submission.

Corresponding author

Correspondence to Guido Kroemer.

Ethics declarations

Competing interests

G.K. and L.Z. have received research funding (contracts) from Lytix Ltd. A.M. has received funding from BMS, Roche and Transgene for academic sponsored clinical trials involving intratumoural immunotherapies (NCT02857569, NCT02977156 and NCT03892525) and has received honoraria and/or consulting fees from Amgen, AstraZeneca/Medimmune, Bioncotech, Boehringer Ingelheim, EISAI, Lytix pharma, MSD, Pillar Partners and Sanofi.

Additional information

Publisher’s note

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

Glossary

Oncolysis

The lysis of malignant cells using locally applied physical or chemical methods.

Oncolytic virus

A virus designed to infect and kill cancer cells.

Dendritic cells

(DCs). A specialized subset of myeloid cells with the capacity to process and present antigens to cells that mediate the adaptive immune response. Such cells engulf proportions of tumour cells, digest their proteins and present the resulting peptides in the context of MHC class I molecules to CD8+ T lymphocytes.

Necrosis

An unregulated form of cell death accompanied by early rupture of the plasma membrane.

Coagulation

Denaturation of proteins that clot together. This effect is usually induced by heat.

Apoptosis

The best characterized form of regulated cell death, involving activation of caspases, shrinkage of cells and the generation of apoptotic bodies.

CD8:FOXP3 ratio

The ratio of CD8 (mostly expressed by cytotoxic T lymphocytes) to FOXP3 (mostly expressed by regulatory T cells) expression, which indicates the local immune tonus. A high ratio suggests the presence of an active immune response, whereas a low ratio is suggestive of immunosuppression.

Immunogenic cell death

(ICD). A form of cell death occurring in virally infected or cancer cells that stimulates an immune response against antigens released by dead or dying cells.

Immunogenicity

The capacity to elicit a protective immune response.

Necroptosis

A regulated form of cell death that is distinctly different to apoptosis and involves the activation of specific effector molecules such as RIPK3 and MLKL.

Antigenicity

The presence of antigenic determinants that are absent in non-malignant cells and tissues and can be recognized by specific B and T lymphocytes.

Adjuvanticity

The presence of danger-associated molecules that activate the effector cells of the innate immune system.

Penumbra

The area of the tumour surrounding the region of central necrosis.

Tumour-associated antigens

(TAAs). Proteins that are either structurally different (often owing to mutations) to those present in non-malignant cells or expressed by malignant but not by non-malignant cells.

Toll-like receptor

(TLR). A pattern-recognition receptor that recognizes bacterial or viral motifs located within or on the surface of cells.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Kepp, O., Marabelle, A., Zitvogel, L. et al. Oncolysis without viruses — inducing systemic anticancer immune responses with local therapies. Nat Rev Clin Oncol 17, 49–64 (2020). https://doi.org/10.1038/s41571-019-0272-7

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41571-019-0272-7

This article is cited by

Search

Advanced search

Quick links

Nature Briefing: Cancer

Sign up for the Nature Briefing: Cancer newsletter — what matters in cancer research, free to your inbox weekly.

Get what matters in cancer research, free to your inbox weekly. Sign up for Nature Briefing: Cancer