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Neoadjuvant treatment of hepatic malignancy: an oncolytic herpes simplex virus expressing IL-12 effectively treats the parent tumor and protects against recurrence-after resection

Cancer Gene Therapy volume 10, pages 215–223 (2003)Cite this article

Abstract

The objective of the study was to evaluate the utility of NV1042, a replication competent, oncolytic herpes simplex virus (HSV) containing the interleukin-12 (IL-12) gene, as primary treatment for hepatic tumors and to further assess its ability to reduce tumor recurrence following resection. Resection is the most effective therapy for hepatic malignancies, but is not possible in the majority of the patients. Furthermore, recurrence is common after resection, most often in the remnant liver and likely because of microscopic residual disease in the setting of postoperative host cellular immune dysfunction. We hypothesize that, unlike other gene transfer approaches, direct injection of liver tumors with replication competent, oncolytic HSV expressing IL-12 will not only provide effective control of the parent tumor, but will also elicit an immune response directed at residual tumor cells, thus decreasing the risk of cancer recurrence after resection. Solitary Morris hepatomas, established in Buffalo rat livers, were injected directly with 107 particles of NV1042, NV1023, an oncolytic HSV identical to NV1042 but without the IL-12 gene, or with saline. Following tumor injection, the parent tumors were resected and measured and the animals were challenged with an intraportal injection of 105 tumor cells, recreating the clinical scenario of residual microscopic cancer. In vitro cytotoxicity against Morris hepatoma cells was similar for both viruses at a multiplicity of infection of 1 (MOI, ratio of viral particles to target cells), with >90% tumor cell kill by day 6. NV1042 induced high-level expression of IL-12 in vitro, peaking after 4 days in culture. Furthermore, a single intratumoral injection of NV1042, but not NV1023, induced marked IL-12 and interferon-γ (IFN-γ) expression. Both viruses induced a significant local immune response as evidenced by an increase in the number of intratumoral CD4(+) and CD8(+) lymphocytes, although the peak of CD8(+) infiltration was later with NV1042 compared with NV1023. NV1042 and NV1023 reduced parent tumor volume by 74% (P<.003) and 52% (P<.03), respectively, compared to control animals. Treatment of established tumors with NV1042, but not with NV1023, significantly reduced the number of hepatic tumors after resection of the parent tumor and rechallenge (16.8±11 (median=4) vs. 65.9±15 (median=66) in control animals, P<.025). In conclusion, oncolytic HSV therapy combined with local immune stimulation with IL-12 offers effective control of parent hepatic tumors and also protects against microscopic residual disease after resection. The ease of use of this combined modality approach, which appears to be superior to either approach alone, suggests that it may have clinical relevance, both as primary treatment for patients with unresectable tumors and also as a neoadjuvant strategy for reducing recurrence after resection.

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References

  1. Fan ST, Lo CM, Liu CL, et al. Hepatectomy for hepatocellular carcinoma: toward zero hospital deaths. Ann Surg. 1999;229:322–330.

    Article  CAS  Google Scholar 

  2. Fong Y, Fortner JG, Sun R, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230:309–321.

    Article  CAS  Google Scholar 

  3. Fong Y, Sun RL, Jarnagin W, et al. An analysis of 412 cases of hepatocellular carcinoma at a Western center. Ann Surg. 1999;229:790–799.

    Article  CAS  Google Scholar 

  4. Nordlinger B, Vaillant JC, Guiguet M, et al. Survival benefit of repeat liver resections for recurrent colorectal metastases: 143 cases. J Clin Oncol. 1994;12:1491–1496.

    Article  CAS  Google Scholar 

  5. Scheele J, Stang R, Altendorf-Hofmann A, et al. Resection of colorectal liver metastases. World J Surg. 1995;19:59–71.

    Article  CAS  Google Scholar 

  6. Fan ST . Problems of hepatectomy in cirrhosis. Hepato–Gastro 1998;45(Suppl 3):1288–1290.

    Google Scholar 

  7. Karpoff HM, Tung C, Ng B, et al. Interferon gamma protects against hepatic tumor growth in rats by increasing kupffer cell tumoricidal activity. Hepatology 1996;24:374–379.

    Article  CAS  Google Scholar 

  8. Kemeny N, Huang Y, Cohen AM, et al. Hepatic arterial infusion of chemotherapy after resection of hepatic metastases from colorectal cancer. N Eng J Med. 1999;341:2039–2048.

    Article  CAS  Google Scholar 

  9. Kemeny N, Gonen M, Sullivan D, et al. Phase I study of hepatic arterial infusion of floxuridine and dexamethasone with systemic irinotecan for unresectable hepatic metastases from colorectal cancer. J Clin Oncol. 2001;19:2687–2695.

    Article  CAS  Google Scholar 

  10. Fidler IJ . Systemic macrophage activation with liposome-entrapped immunomodulators for therapy of cancer metastasis. Res Immunol. 1996;143:199–204.

    Article  Google Scholar 

  11. Kawata A, Une Y, Hosokawa M, et al. Adjuvant chemoimmunotherapy for hepatocellular carcinoma patients. Adriamycin, interleukin-2, and lymphokine-activated killer cells versus adriamycin alone. Am J Clin Oncol. 1995;18:257–262.

    Article  CAS  Google Scholar 

  12. Connor J, Bannerji R, Saito S, et al. Regression of bladder tumors in mice treated with interleukin-2 gene-modified tumor cells. J Exp Med. 1993;177:1127–1134.

    Article  CAS  Google Scholar 

  13. Allione A, Consalvo M, Nanni P, et al. Immunizing and curative potential of replicating and nonreplicating murine mammary adenocarcinoma cells engineered with interleukin (IL)-2, IL-4, IL-6, IL-7, IL-10, tumor necrosis factor alpha, granulocyte-macrophage colony stimulating factor, and gamma-interferon gene or admixed with conventional adjuvants. Cancer Res. 1994;54:6022–6026.

    CAS  PubMed  Google Scholar 

  14. Saito S, Bannerji R, Gansbacher B et al. Immunotherapy of bladder cancer with cytokine gene-modified tumor vaccines. Cancer Res. 1994;54:3516–3520.

    CAS  PubMed  Google Scholar 

  15. Porgador A, Tzehoval E, Vadai E, et al. Immunotherapy via gene therapy: comparison of the effects of tumor cells transduced with the interleukin-2, interleukin-6, or interferon-lambda genes. J Immunother. 1993;14:191–201.

    Article  CAS  Google Scholar 

  16. Vieweg J, Rosenthal FM, Bannerji R, et al. Immunotherapy of prostate cancer in the dunning rat model: use of cytokine gene modified tumor vaccines. Cancer Res 1994;54:1760–1765.

    CAS  PubMed  Google Scholar 

  17. Golumbek PT, Lazenby AJ, Levitsky HI, et al. Treatment of established renal cancer by tumor cells engineered to secrete interleukin-4. Science 1991;254:713–716.

    Article  CAS  Google Scholar 

  18. Porgador A, Tzehoval E, Katz A, et al. Interleukin 6 gene transfection into Lewis lung carcinoma tumor cells suppresses the malignant phenotype and confers immunotherapeutic competence against parental metastatic cells. Cancer Res. 1992;52:3679–3686.

    CAS  PubMed  Google Scholar 

  19. Dranoff G, Jaffee E, Lazenby A, et al. Vaccination with irradiated tumor cells engineered to secrete murine granulocyte-macrophage colony-stimulating factor stimulates potent, specific, and long-lasting anti-tumor immunity. Proc Natl Acad Sci USA. 1993;90:3539–3543.

    Article  CAS  Google Scholar 

  20. D'Angelica M, Tumg C, Alien P, et al. HSV-mediated ICAM-1 gene transfer abrogates tumorigenicity and induces anti-tumor immunity. Mol Med. 1999;5:606–616.

    Article  CAS  Google Scholar 

  21. Colombo MP, Ferrari G, Stoppacciaro A, et al. Granulocyte colony-stimulating factor gene transfer suppresses tumorigenicity of a murine adenocarcinoma in vivo. J Exp Med. 1991;173:889–897.

    Article  CAS  Google Scholar 

  22. Gansbacher B, Zier K, Daniels B, et al. Interleukin-2 gene transfer into tumor cells abrogates tumorigenicity and induces protective immunity. J Exp Med. 1990;172:1217–1224.

    Article  CAS  Google Scholar 

  23. Jarnagin WR, Delman K, Kooby D, et al. Neoadjuvant interluekin-12 immunogene therapy protects against cancer recurrence after liver resection in an animal model. Ann Surg. 2000;231:762–771.

    Article  CAS  Google Scholar 

  24. Kooby DA, Carew JF, Halterman MW, et al. Oncolytic viral therapy for human colorectal cancer and liver metastases using a multimutated herpes simplex virus type-1 (G207). FASEB J. 1999;15:1306–1308.

    Google Scholar 

  25. Mineta T, Rabkin SD, Yazaki T, et al. Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas. Nat Med. 1995;1:938–943.

    Article  CAS  Google Scholar 

  26. Pyles RB, Thompson RL . Evidence that the herpes simplex virus type 1 uracil DNA glycosylace is required for efficient viral replication and latency in the murine nervous system. J Virol. 2002;68:4963–4972.

    Google Scholar 

  27. Bennett JJ, Kooby D, Delman K, et al. Antitumor efficacy of regional oncolytic viral therapy for peritoneally disseminated cancer. J Mol Med. 2002;78:166–174.

    Article  Google Scholar 

  28. Carew JF, Kooby D, Halterman MW, et al. Selective infection and cytolysis of human head and neck squamous cell carcinoma with sparing of normal mucosa by a cytolytic herpes simplex virus type 1 (G207). Human Gene Therapy. 1999;10:1599–1606.

    Article  CAS  Google Scholar 

  29. Karpoff HM, D'Angelica M, Blair S, et al. Prevention of hepatic tumor metastases in rats with herpes viral vaccines and gamma-interferon. J Clin Invest. 1997;99:799–804.

    Article  CAS  Google Scholar 

  30. Tahara H, Zeh, III HJ, Storkus WJ, et al. Fibroblasts genetically engineered to secrete interleukin 12 can suppress tumor growth and induce antitumor immunity to a murine melanoma in vivo. Cancer Res. 1994;54:182–189.

    CAS  PubMed  Google Scholar 

  31. Rao JB, Chamberlain RS, Bronte V, et al. IL-12 is an effective adjuvant to recombinant vaccinia virus-based tumor vaccines: enhancement by simultaneous B7-1 expression. J Immunol. 1996;156:3357–3365.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Federoff HJ . Replication-defective herpesvirus amplicon vectors and their use for gene transfer. In: Spector DL, Leinwand L, Goldman R, eds. Cells. A Laboratory Manual. Plainview, NY: Cold Spring Harbor Laboratory Press, 1998:19.1–91.10.

    Google Scholar 

  33. Bennett JJ, Malhotra S, Wong RJ, et al. Interleukin 12 secretion enhances antitumor efficacy of oncolytic herpes simplex viral therapy for colorectal cancer. Ann Surg 2002;233:819–826.

    Article  Google Scholar 

  34. Brunda MJ, Luistro L, Warrier RR, et al. Antitumor and antimetastatic activity of interleukin 12 against murine tumors. J Exp Med. 1993;178:1223–1230.

    Article  CAS  Google Scholar 

  35. Vagliani M, Rodolfo M, Cavallo F, et al. Interleukin 12 potentiates the curative effect of a vaccine based on Interleukin 2-transduced tumor cells. Cancer Res. 1996;56:467–470.

    CAS  PubMed  Google Scholar 

  36. Meignier B, Longnecker R, Roizman B . In vivo behavior of genetically engineered herpes simplex viruses R7017 and R7020: construction and evaluation in rodents. J Inf Dis. 1988;158:602–614.

    Article  CAS  Google Scholar 

  37. Meignier B, Martin B, Whitley RJ, et al. In vivo behavior of genetically engineered herpes simplex viruses R7017 and R7020. II. Studies in immunocompetent and immunosuppressed owl monkeys (Aotus trivirgatus). J Inf Dis. 1990;162:313–321.

    Article  CAS  Google Scholar 

  38. Wong RJ, Patel SG, Kirn S, et al. Cytokine gene transfer enhances herpes oncolytic therapy in murine squamous cell carcinoma. Hum Gene Ther. 2001;12:253–265.

    Article  CAS  Google Scholar 

  39. Sung MW, Yeh HC, Thung SN, et al. Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases from colorectal adenocarcinoma: results of a phase I clinical trial. Mol Ther: J Am Soc Gene Ther. 2001;4:182–191.

    Article  CAS  Google Scholar 

  40. Habib N, Salama H, Abd El Latif Abu Median, et al. Clinical trial of EIB-deleted adenovirus (dl1520) gene therapy for hepatocellular carcinoma. Cancer Gene Ther. 2002;9:254–259.

    Article  CAS  Google Scholar 

  41. Reid T, Galanis E, Abbruzzese J, et al. Intra-arterial administration of a replication-selective adenovirus (dl1520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial. Gene Therapy. 2001;8:1618–1626.

    Article  CAS  Google Scholar 

  42. Breakefield XO, DeLuca NA . Herpes simplex virus for gene delivery to neurons. New Biol. 1991;3:203–218.

    CAS  PubMed  Google Scholar 

  43. D'Angelica M, Karpoff H, Brownlee M, et al. In vivo IL-2 gene transduction of implanted tumors induces a systemic anti-tumor response. Cancer, Immunology and Immunotherpay. 1999;47 (5):265–271.

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, USA

    W R Jarnagin, J S Zager, K A Delman, S Malhotra, M Ebright, S Little, B DeRubertis, S F Stanziale, M Hezel & Y Fong

  2. Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, USA

    D Klimstra

  3. Department of Neurology, University of Rochester School of Medicine, Rochester, New York, USA

    H Federoff

  4. Department of Medicine, University of Rochester School of Medicine, Rochester, New York, USA

    H Federoff

  5. Department of Microbiology and Immunology, University of Rochester School of Medicine, Rochester, New York, USA

    H Federoff

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  1. W R Jarnagin
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Correspondence to W R Jarnagin.

Additional information

Supported in part by training Grant T32 CA 09501 (ME) and US Public Health Service grants RO1CA75416, RO1CA72632, and RO1CA61524 from the National Institutes of Health and MBC-99366 from the American Cancer Society (YF).

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Jarnagin, W., Zager, J., Klimstra, D. et al. Neoadjuvant treatment of hepatic malignancy: an oncolytic herpes simplex virus expressing IL-12 effectively treats the parent tumor and protects against recurrence-after resection. Cancer Gene Ther 10, 215–223 (2003). https://doi.org/10.1038/sj.cgt.7700558

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