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A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer

Abstract

ONYX-015 is an adenovirus with the E1B 55-kDa gene deleted, engineered to selectively replicate in and lyse p53-deficient cancer cells while sparing normal cells. Although ONYX-015 and chemotherapy have demonstrated anti-tumoral activity in patients with recurrent head and neck cancer, disease recurs rapidly with either therapy alone. We undertook a phase II trial of a combination of intratumoral ONYX-015 injection with cisplatin and 5-fluorouracil in patients with recurrent squamous cell cancer of the head and neck. There were substantial objective responses, including a high proportion of complete responses. By 6 months, none of the responding tumors had progressed, whereas all non-injected tumors treated with chemotherapy alone had progressed. The toxic effects that occurred were acceptable. Tumor biopsies obtained after treatment showed tumor-selective viral replication and necrosis induction.

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Figure 1: Injection of tumors with Onyx-015.
Figure 2: Efficacy of the Onyx-015/Chemotherapy Combination in Local tumor control.
Figure 3: Evidence of intratumoral replication of ONYX-015.

References

  1. Clayman, G.L., Lippman, S.M. & Laramore, G. in Cancer Medicine 4th edn.(eds. Holland, J.F., Frei, E.Jr., Kufe, D.W., Morton, D.L. & Weichselbaum, R.R.) 1645–1710 (Williams & Wilkins, Baltimore, Maryland, 1997).

    Google Scholar 

  2. Vokes, E.E., Weichselbaum, R.R., Lippman, S.M. & Hong, W.K. Head and neck cancer. N. Engl. J. Med. 328, 84–194 (1993).

    Article  Google Scholar 

  3. Greenlee, R.T., Murray, T., Bolden, S. & Wingo, P.A. Cancer statistics . CA Cancer J. Clin. 50, 7– 33 (2000).

    Article  CAS  PubMed  Google Scholar 

  4. Boyle, J.O. et al. The incidence of p53 mutations increases with progression of head and neck cancer. Cancer Res. 53, 4477–4480 (1993).

    CAS  PubMed  Google Scholar 

  5. Brennan, J.A. et al. Association between cigarette smoking and mutation of the p53 gene in squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 332,712–717 ( 1995).

    Article  CAS  PubMed  Google Scholar 

  6. Werness, B.A., Levine, A.J. & Howley, P.M. Association of human papillomavirus type 16 and 18 E6 proteins with p53. Science 248,76– 79 (1990).

    Article  CAS  PubMed  Google Scholar 

  7. Gillison, M.L. et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J. Natl. Cancer Inst. 92, 709–720 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Strong, E.W. Sites of treatment failure in head and neck cancer. Cancer Treatment Symposium 2,5–20 ( 1983).

    Google Scholar 

  9. Suit, H.D. & Westgate, S.J. Impact of improved local control on survival. Int. J. Radiat. Oncol. Biol. Phys. 12, 453–458 (1986).

    Article  CAS  PubMed  Google Scholar 

  10. Forastiere, A.A. et al. Randomized comparison of cisplatin plus fluorouracil and carboplatin plus fluorouracil versus methotrexate in advanced squamous-cell carcinoma of the head and neck: A Southwest Oncology Group study. J. Clin. Oncol. 10,1245–1251 ( 1992).

    Article  CAS  PubMed  Google Scholar 

  11. Jacobs, C. et al. A phase III randomized study comparing cisplatin and fluorouracil as single agents and in combination for advanced squamous cell carcinoma of the head and neck. J. Clin. Oncol. 10,257 –263 (1992).

    Article  CAS  PubMed  Google Scholar 

  12. Paredes, J. et al. Prospective randomized trial of high-dose cisplatin and fluorouracil infusion with or without sodium diethyldithiocarbamate in recurrent and/or metastatic squamous cell carcinoma of the head and neck. J. Clin. Oncol. 6,955–962 ( 1988).

    Article  CAS  PubMed  Google Scholar 

  13. Clavel, M. et al. Randomized comparison of cisplatin, methotrexate, bleomycin and vincristine (CABO) versus cisplatin and 5-fluorouracil (CF) versus cisplatin (C) in recurrent or metastatic squamous cell carcinoma of the head and neck. A phase III study of the EORTC Head and Neck Cancer Cooperative Group. Ann. Oncol. 5, 521–526 ( 1994).

    Article  CAS  PubMed  Google Scholar 

  14. Schrijvers, D. et al. Phase III trial of modulation of cisplatin/fluorouracil chemotherapy by interferon alpha-2b in patients with recurrent or metastatic head and neck cancer. Head and Neck Interferon Cooperative Study Group. J. Clin. Oncol. 16,1054–1059 ( 1998).

    Article  CAS  PubMed  Google Scholar 

  15. Group LHaNO. A phase III randomized trial of cisplatinum, methotrexate, cisplatinum + methotrexate and cisplatinum + 5-FU in end stage squamous carcinoma of the head and neck. Br. J. Cancer; 61, 311–315 (1990).

  16. Kish, J.A., Ensley, J.F., Jacobs, J.R., Binns, P. & Al-Sarraf, M. Evaluation of hig-dise cisplatin and 5-FU infusion as initial therapy in advanced head and neck cancer. Am. J. Clin. Oncol. 11,553–557 (1988).

    Article  CAS  PubMed  Google Scholar 

  17. Rowland, K.M. Jr. et al. Cisplatin and 5-FU infusion chemotherapy in advanced, recurrent cancer of the head and neck: an Eastern Cooperative Oncology Group Pilot Study. Cancer Treat. Rep. 70, 461–464 (1986).

    PubMed  Google Scholar 

  18. Rooney, M. et al. Improved complete response rate and survival in advanced head and neck cancer after three-course induction therapy with 120-hour 5-FU infusion and cisplatin. Cancer 55,1123– 1128 (1985).

    Article  CAS  PubMed  Google Scholar 

  19. Bischoff, J.R. et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells. Science 274,373– 376 (1996).

    Article  CAS  PubMed  Google Scholar 

  20. Heise, C. et al. Onyx-015, an E1B gene-attenuated adenovirus, causes tumor-specific cytolysis antitumoral efficacy that can be augmented by standard chemotherapeutic agents. Nature Med. 3, 639– 645 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Hall, A.R., Dix, B.R., O'Carroll, S.J. & Braithwaite, A.W. p53-dependent cell death/apoptosis is required for a productive adenovirus infection. Nature Med. 4,1068– 1072 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Kirn, D., Hermiston, T. & McCormick, F. Onyx-015: clinical data are encouraging. Nature Med. 4, 1341–1342 (1998).

    Article  CAS  PubMed  Google Scholar 

  23. Kirn, D. et al. A phase II trial of intratumoral injection with an E1B-deleted adenovirus, ONYX-015, in patients with recurrent, refractory head and neck cancer. Proc. Am. Soc. Clin. Oncol. 17, 391a (1998).

    Google Scholar 

  24. Ganly, I., et al. A phase I study of Onyx-015, an EIB attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer . Clin. Cancer Res. 6(3) 798– 806, 2000.

    CAS  PubMed  Google Scholar 

  25. Lowe, S.W., Ruley, H.E., Jacks, T. & Housman, D.E. p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74, 957–67 ( 1993).

    Article  CAS  PubMed  Google Scholar 

  26. Lowe, S.W. et al. p53 status and the efficacy of cancer therapy in vivo. Science 266, 807–10 ( 1994).

    Article  CAS  PubMed  Google Scholar 

  27. Sanchez-Prieto, R. et al. Carcinoma cells become sensitive to DNA-damaging agents by the expression of the adenovirus E1A gene. Oncogene 13, 1083–1092 (1996).

    PubMed  Google Scholar 

  28. Lowe, S.W. & Ruley, H.E. Stabilization of the p53 tumor suppressor is induced by adenovirus 5 E1A and accompanies apoptosis. Genes Dev. 7, 535–45 ( 1993).

    Article  CAS  PubMed  Google Scholar 

  29. Barker, D.D. & Berk, A.J. Adenovirus proteins from both E1B reading frames are required for transformation of rodent cells by viral infection and DNA transfection. Virology 156, 107– 121 (1987).

    Article  CAS  PubMed  Google Scholar 

  30. Wildner, O., Blaese, R.M. & Morris, J.C. Synergy between the herpes simplex virus tk/ganciclovir prodrug suicide system and the topoisomerase I inhibitor topotecan. Human Gene Ther. 10, 2679–2687 (1999).

    Article  CAS  Google Scholar 

  31. Baxter, L.T., Zhu, H., Mackensen, D.G., Butler, W.F. & Jain, R.K. Biodistribution of monoclonal antibodies: Scale-up from mouse to human using a physiologically based pharmacokinetic model. Cancer Res. 55, 4611–4622 (1995).

    CAS  PubMed  Google Scholar 

  32. Baxter, L.T., Zhu, H., Mackensen, D.G. & Jain, R.K. Physiologically based pharmacokinetic model for specific and nonspecific monoclonal antibodies and fragments in normal tissues and human tumor xenografts in nude mice. Cancer Res. 54, 1517–28 (1994).

    CAS  PubMed  Google Scholar 

  33. Shisler, J., Duerksen, H.P., Hermiston, T.M., Wold, W.S. & Gooding, L.R. Induction of susceptibility to tumor necrosis factor by E1A is dependent on binding to either p300 or p105-Rb and induction of DNA synthesis. J. Virol. 70, 68–77 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Krajcsi, P. et al. The adenovirus E3-14.7K protein and the E3-10.4K/14.5K complex of proteins, which independently inhibit tumor necrosis factor (TNF)-induced apoptosis, also independently inhibit TNF-induced release of arachidonic acid . J. Virol. 70, 4904–4913 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Krosnick, J., Mule, J., McIntosh, J. & Rosenberg, S. Augmentation of antitumor efficacy by the combination of recombinant tumor necrosis factor and chemotherapeutic agents in vivo. Cancer Res. 49, 3729–3733 (1989).

    CAS  PubMed  Google Scholar 

  36. Frei, E. & Spriggs, D. Tumor necrosis factor: still a promising agent. J. Clin. Oncol. 7, 291– 294 (1989).

    Article  PubMed  Google Scholar 

  37. Blick, M., Sherwin, S. & Rosenblum, M. Phase I study of recombinant human tumor necrosis factor in patients. Cancer Res. 47, 2986 (1987).

    CAS  PubMed  Google Scholar 

  38. Jones, A. et al. A randomized phase II study of carmustine alone or in combination with tumor necrosis factor in patients with advanced melanoma. Cancer Chemother. Pharmacol. 30, 73– 76 (1992).

    Article  CAS  PubMed  Google Scholar 

  39. Selby, P. et al. Tumor necrosis factor in man: clinical and biological observations . Br. J. Cancer 56, 803– 808 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. You, L., Yang, C-T. & Jablons, D.M. ONYX-015 works synergistically with chemotherapy in lung cancer cell lines and primary cultures freshly made from lung cancer patients. Cancer Res. 60, 1009– 1013 (2000).

    CAS  PubMed  Google Scholar 

  41. Freytag, S.O., Rogulski, K.R., Paielli, D.L., Gilbert, J.D. & Kim, J.H. A novel three-pronged approach to kill cancer cells selectively: concomitant viral, double suicide gene, and radiotherapy. Hum. Gene. Ther. 9, 1323– 1333 (1998).

    Article  CAS  PubMed  Google Scholar 

  42. Wildner, O., Blaese, R.M. & Morris, J.M. Therapy of colon cancer with oncolytic adenovirus is enhanced by the addition of herpes simplex virus-thymidine kinase. Cancer Res. 59, 410–413 (1999).

    CAS  PubMed  Google Scholar 

  43. Heise, C., Williams, A., Olesch, J. & Kirn, D. Efficacy of a replication-competent adenovirus (ONYX-015) following intratumoral injection: intratumoral spread and distribution effects. Cancer Gene Ther. 6, 499–504 (1999).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We thank the following individuals for their assistance on this clinical trial and on this manuscript: P. Coldiron, D. Davies, O. Diri, J. Kuhn, S. Landers, T. McCarty, V. Papadimitrakopoulou, M. Posner, M. Propst, P. Roo, L. Siu, J. Starr, K. Sultan, S. Toney and P. Trown.

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Correspondence to Fadlo R. Khuri.

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Khuri, F., Nemunaitis, J., Ganly, I. et al. A controlled trial of intratumoral ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer. Nat Med 6, 879–885 (2000). https://doi.org/10.1038/78638

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