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In situ cancer vaccination with a replication-conditional HSV for the treatment of liver metastasis of colon cancer

Cancer Gene Therapy volume 9, pages 142–148 (2002)Cite this article

Abstract

In this study, we investigated the therapeutic efficacy of a replication-conditional mutant HSV, G207, for the treatment of liver metastasis of colon carcinoma. Three liver metastasis models in syngeneic BALB/c mice were developed: (i) splenic injection, (ii) splenic and subcutaneous (s.c.) injection, and (iii) orthotopic implantation of CT26 colon carcinoma. In the splenic injection model, G207 was injected into the established splenic tumor on day 7. In the splenic and s.c. injection model, G207 were injected into the established s.c. tumor on days 5 and 8. In the orthotopic implantation model, a piece of CT26 tumor tissue was transplanted onto the wall of the cecum and G207 was injected in the established cecum tumor on day 7. On day 21 or 28, animals were sacrificed and liver metastases were evaluated. In all three models in immunocompetent mice, liver metastases were significantly reduced by intratumoral inoculation with G207 compared to the control. In athymic mice, however, there was no significant therapeutic effect of intratumoral inoculation with G207 on liver metastases. Tumor-specific cytotoxic T-lymphocyte responses were induced in mice treated with G207 in the orthotopic implantation model. These results suggest that intratumoral inoculation of G207, as an in situ cancer vaccine, can be an effective approach against liver metastasis of colon cancer and the efficacy involves tumor-specific T-cell responses.

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References

  1. Brand MI, Saclarides TJ, Dobson HD et al. Liver resection for colorectal cancer: liver metastases in the aged Am Surg 2000 66: 412–416

    CAS  PubMed  Google Scholar 

  2. de Brauw LM, van de Velde CJ, Bouwhuis-Hoogerwerf ML et al. Diagnostic evaluation and survival analysis of colorectal cancer patients with liver metastases J Surg Oncol 1987 34: 81–86

    Article  CAS  PubMed  Google Scholar 

  3. Ballantyne GH, Quin J . Surgical treatment of liver metastases in patients with colorectal cancer Cancer 1993 71: 4252–4266

    Article  CAS  PubMed  Google Scholar 

  4. Stangl R, Altendorf-Hofmann A, Charnley RM et al. Factors influencing the natural history of colorectal liver metastases Lancet 1994 343: 1405–1410

    Article  CAS  PubMed  Google Scholar 

  5. Chou J, Kern ER, Whitley RJ et al. Mapping of herpes simplex virus-1 neurovirulence to gamma 134.5, a gene nonessential for growth in culture Science 1990 250: 1262–1266

    Article  CAS  PubMed  Google Scholar 

  6. 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  PubMed  Google Scholar 

  7. Goldstein DJ, Weller SK . Factor(s) present in herpes simplex virus type 1–infected cells can compensate for the loss of the large subunit of the viral ribonucleotide reductase: characterization of an ICP6 deletion mutant Virology 1988 166: 41–51

    Article  CAS  PubMed  Google Scholar 

  8. Toda M, Rabkin SD, Martuza RL . Treatment of human breast cancer in a brain metastatic model by G207, a replication-competent multimutated herpes simplex virus 1 Hum Gene Ther 1998b 9: 2177–2185

    Article  CAS  PubMed  Google Scholar 

  9. Toda M, Rabkin SD, Kojima H et al. Herpes simplex virus as an in situ cancer vaccine for the induction of specific anti-tumor immunity Hum Gene Ther 1999 10: 385–393

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  11. Kooby DA, Carew JF, Halterman MW et al. Oncolytic viral therapy for human colorectal cancer and liver metastasis using a multi-mutated herpes simplex virus type-1 (G207) FASEB J 1999 13: 1325–1334

    Article  CAS  PubMed  Google Scholar 

  12. Lee JH, Federoff HJ, Schoeniger LO . G207, modified herpes simplex virus type 1, kills human pancreatic cancer cells in vitro J Gastrointest Surg 1999 3: 127–133

    Article  CAS  PubMed  Google Scholar 

  13. Walker JR, McGeagh KG, Sundaresan P et al. Local and systemic therapy of human prostate adenocarcinoma with the conditionally replicating herpes simplex virus vector G207 Hum Gene Ther 1999 10: 2237–2243

    Article  CAS  PubMed  Google Scholar 

  14. Todo T, Rabkin SD, Sundaresan P et al. Systemic antitumor immunity in experimental brain tumor therapy using a multimutated, replication-competent herpes simplex virus Hum Gene Ther 1999 10: 2741–2755

    Article  CAS  PubMed  Google Scholar 

  15. Toda M, Martuza RL, Kojima H et al. In situ cancer vaccination: an IL-12 defective vector/replication-competent herpes simplex virus combination induces local and systemic antitumor activity J Immunol 1998 160: 4457–4464

    CAS  PubMed  Google Scholar 

  16. Fearon ER, Itaya T, Hunt B et al. Induction in a murine tumor of immunogenic tumor variants by transfection with a foreign gene Cancer Res 1988 48: 2975–2980

    CAS  PubMed  Google Scholar 

  17. Wang M, Bronte V, Chen PW et al. Active immunotherapy of cancer with a nonreplicating recombinant fowlpox virus encoding a model tumor-associated antigen J Immunol 1995 154: 4685–4692

    CAS  PubMed  Google Scholar 

  18. Huang AYC, Gulden PH, Woods AS et al. The immunodominant major histocompatibility complex class I–restricted antigen of a murine colon tumor derives from an endogenous retroviral gene product Proc Natl Acad Sci USA 1996 93: 9730–9735

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Roth C, Rochlitz C, Kourilsky P . Immune response against tumors Adv Immunol 1994 57: 281–351

    Article  CAS  PubMed  Google Scholar 

  20. Brattain MG, Strobel-Stevens J, Fine D et al. Establishment of mouse colonic carcinoma cell lines with different metastatic properties Cancer Res 1980 40: 2142–2146

    CAS  PubMed  Google Scholar 

  21. Alfieri AA, Hahn EW . An in situ method for estimating cell survival in a solid tumor Cancer Res 1978 38: 3006–3011

    CAS  PubMed  Google Scholar 

  22. Kozlowski JM, Fidler IJ, Campbell D et al. Metastatic behavior of human tumor cell lines grown in the nude mouse Cancer Res 1984 44: 3522–3529

    CAS  PubMed  Google Scholar 

  23. Fu XY, Besterman JM, Monosov A et al. Models of human metastatic colon cancer in nude mice orthotopically constructed by using histologically intact patient specimens Proc Natl Acad Sci USA 1991 88: 9345–9349

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Markert JM, Medlock MD, Rabkin SD et al. Conditionally replicating herpes simplex virus mutant, G207 for the treatment of malignant glioma: results of a phase I trial Gene Ther 2000 7: 867–874

    Article  CAS  PubMed  Google Scholar 

  25. Bischoff JR, Kirn DH, Williams A et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells Science 1996 274: 373–376

    Article  CAS  PubMed  Google Scholar 

  26. Khuri FR, 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 2000 6: 879–885

    Article  CAS  PubMed  Google Scholar 

  27. Nemunaitis J, Ganly I, Khuri F et al. Selective replication and oncolysis in p53 mutant tumors with ONYX-015, an E1B-55kD gene–deleted adenovirus, in patients with advanced head and neck cancer: a phase II trial Cancer Res 2000 60: 6359–6366

    CAS  PubMed  Google Scholar 

  28. Yazaki T, Manz HJ, Rabkin SD et al. Treatment of human malignant meningiomas by G207, a replication-competent multimutated herpes simplex virus 1 Cancer Res 1995 55: 4752–4756

    CAS  PubMed  Google Scholar 

  29. Hunter WD, Martuza RL, Feigenbaum F et al. Attenuated, replication-competent herpes simplex virus type 1 mutant G207: safety evaluation of intracerebral injection in nonhuman primates J Virol 1999 73: 6319–6326

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Oyama M, Ohigashi T, Hoshi M et al. Intravesical and intravenous therapy of human bladder cancer by the herpes vector G207 Hum Gene Ther 2000 11: 1683–1693

    Article  CAS  PubMed  Google Scholar 

  31. Toda M, Martuza RL, Rabkin SD . Tumor growth inhibition by intratumoral inoculation of defective herpes simplex virus vectors expressing granulocyte–macrophage colony-stimulating factor Mol Ther 2000 2: 324–329

    Article  CAS  PubMed  Google Scholar 

  32. Toda M, Martuza RL, Rabkin SD . Combination suicide/cytokine gene therapy as adjuvants to a defective herpes simplex virus–based cancer vaccine Gene Ther 2001 8: 332–339

    Article  CAS  PubMed  Google Scholar 

  33. McLemore TL, Liu MC, Blacker PC et al. Novel intrapulmonary model for orthotopic propagation of human lung cancers in athymic nude mice Cancer Res 1987 47: 5132–5140

    CAS  PubMed  Google Scholar 

  34. Ahlering TE, Dubeau L, Jones PA . A new in vivo model to study invasion and metastasis of human bladder carcinoma Cancer Res 1987 47: 6660–6665

    CAS  PubMed  Google Scholar 

  35. Miller FR, McInerney D . Epithelial component of host–tumor interactions in the orthotopic site preference of a mouse mammary tumor Cancer Res 1988 48: 3698–3701

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Robert L Martuza and Samuel D Rabkin (Harvard Medical School) for critical comments on the manuscript and Akira Ohno for his technical assistance. This study was supported in part by grants from the Ministry of Education, Science, Sports, and Culture in Japan, the Human Science Foundation, the Mochida Memorial Foundation for Medical and Pharmaceutical Research, and the Keio Gijuku Academic Development Funds.

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Authors and Affiliations

  1. Department of Surgery, Institute for Advanced Medical Research, Keio University, School of Medicine, 160-8582, 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan

    Takashi Endo, Masahiko Watanabe, Tetsuro Kubota & Masaki Kitajima

  2. Division of Cellular Signaling, Institute for Advanced Medical Research, Keio University, School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Masahiro Toda, Yukihiko Iizuka & Yutaka Kawakami

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  1. Takashi Endo
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Correspondence to Masahiro Toda.

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Endo, T., Toda, M., Watanabe, M. et al. In situ cancer vaccination with a replication-conditional HSV for the treatment of liver metastasis of colon cancer. Cancer Gene Ther 9, 142–148 (2002). https://doi.org/10.1038/sj.cgt.7700407

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