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Problems, Side Effects, and Disappointments in Clinical Cancer Gene Therapy

  • Chapter
Gene Therapy for Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

Abstract

Genetic therapeutic agents have been tested in cancer patients for over 10 yr. Five major approaches have been tested in clinical trials: tumor suppressor gene replacement, prodrug-activating enzyme delivery, oncolytic virotherapy, antisense oligonucleotide delivery, and cytokine immuno-gene therapy. Proof-of-principle demonstrations of transgene expression, as well as certain biological activities, have been shown; serious toxicity has been rare. However, the field faces several challenges, including limited efficacy, side effects, and lack of proper response indicators. Inefficient tumor delivery and/or transfection, and rapid clearance mediated by host immune responses result in inadequate transgene expression and limited efficacy. Major side effects include vector-/transgene-specific toxicities and disease-/host-specific idiosyncrasy. Discrepancies between certain biomarkers and imaging studies also increase the difficulties in interpretation. Future cancer gene therapy agents need to incorporate mechanisms that allow us to further understand the biodistribution, expression, and function of the vector/transgene. Immune responses toward vectors and transgenes should be reduced, whereas antitumoral immune responses should be enhanced. Vectors and transgenes that offer more than one mechanisms-of-action need to be explored and combined. Finally, our understanding of tumor biology, vectorology and immunology needs to be strengthened in order to improve efficacy and minimizing toxicity.

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References

  1. Gottesman MM. Cancer gene therapy: an awkward adolescence. Cancer Gene Ther 2003;10:501–508.

    Article  PubMed  CAS  Google Scholar 

  2. Nielsen LL, Maneval DC. P53 tumor suppressor gene therapy for cancer. Cancer Gene Ther 1998;5:52–63.

    PubMed  CAS  Google Scholar 

  3. Klatzmann D, et al. A phase I/II study of herpes simplex virus type 1 thymidine kinase “suicide” gene therapy for recurrent glioblastoma. Study Group on Gene Therapy for Glioblastoma. Hum Gene Ther 1998;9:2595–2604.

    Article  PubMed  CAS  Google Scholar 

  4. Pandha HS, et al. Genetic prodrug activation therapy for breast cancer: A phase I clinical trial of erbB-2-directed suicide gene expression. J Clin Oncol 1999; 17:2180–2189.

    PubMed  CAS  Google Scholar 

  5. DeWeese TL, et al. A phase I trial of CV706, a replication-competent, PSA selective oncolytic adenovirus, for the treatment of locally recurrent prostate cancer following radiation therapy. Cancer Res 2001;61:7464–7472.

    Google Scholar 

  6. Hortobagyi GN, Hung M, Lopez-Berestein G. A Phase I multicenter study of E1A gene therapy for patients with metastatic breast cancer and epithelial ovarian cancer that overexpresses HER-2/neu or epithelial ovarian cancer. Hum Gene Ther 1998;9:1775–1798.

    PubMed  CAS  Google Scholar 

  7. Tartour E, et al. Phase I clinical trial with IL-2-transfected xenogeneic cells administered in subcutaneous metastatic tumours: clinical and immunological findings. Br J Cancer 2000;83:1454–1461.

    Article  PubMed  CAS  Google Scholar 

  8. Mastrangelo MJ, et al. Intratumoral recombinant GM-CSF-encoding virus as gene therapy in patients with cutaneous melanoma. Cancer Gene Ther 1999;6:409–422.

    Article  PubMed  CAS  Google Scholar 

  9. Rubin J, et al. Phase I study of immunotherapy of hepatic metastases of colorectal carcinoma by direct gene transfer of an allogeneic histocompatibility antigen, HLA-B7. Gene Ther 1997;4:419–425.

    Article  PubMed  CAS  Google Scholar 

  10. Okada H, et al. Gene therapy of malignant gliomas: a pilot study of vaccination with irradiated autologous glioma and dendritic cells admixed with IL-4 transduced fibroblasts to elicit an immune response. Hum Gene Ther 2001; 12:575–595.

    Article  PubMed  CAS  Google Scholar 

  11. Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol 2002;29:15–18.

    PubMed  CAS  Google Scholar 

  12. Yang JC, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427–434.

    Article  PubMed  CAS  Google Scholar 

  13. Willett CG, et al. Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer. Nat Med 2004; 10:145–147.

    Article  PubMed  CAS  Google Scholar 

  14. Kong HL, Crystal RG. Gene therapy strategies for tumor antiangiogenesis. J Natl Cancer Inst 1998;90:273–286.

    Article  PubMed  CAS  Google Scholar 

  15. Hesdorffer C, et al. Phase I trial of retroviral-mediated transfer of the human MDR1 gene as marrow chemoprotection in patients undergoing high-dose chemotherapy and autologous stem-cell trans-plantation. J Clin Oncol 1998;16:165–172.

    PubMed  CAS  Google Scholar 

  16. Wu N, Ataai MM. Production of viral vectors for gene therapy applications. Curr Opin Biotechnol 2000;11:205–208.

    Article  PubMed  CAS  Google Scholar 

  17. Kay MA, Glorioso JC, Naldini L. Viral vectors for gene therapy: the art of turning infectious agents into vehicles of therapeutics. Nat Med 2001;7:33–40.

    Article  PubMed  CAS  Google Scholar 

  18. Kootstra NA, Verma IM. Gene therapy with viral vectors. Annu Rev Pharmacol Toxicol 2003;43:413–439.

    Article  PubMed  CAS  Google Scholar 

  19. Lundstrom K. Latest development in viral vectors for gene therapy. Trends Biotechnol 2003;21:117–122.

    Article  PubMed  CAS  Google Scholar 

  20. Nabel GJ, et al. Direct gene transfer with DNA-liposome complexes in melanoma: expression, biologic activity, and lack of toxicity in humans. Proc Natl Acad Sci U S A 1993;90:11,307–11,311.

    CAS  Google Scholar 

  21. Bermudes D, Low B, Pawelek J. Tumor-targeted Salmonella. Highly selective delivery vectors. Adv Exp Med Biol 2000;465:57–63.

    PubMed  CAS  Google Scholar 

  22. Jain KK. Use of bacteria as anticancer agents. Expert Opin Biol Ther 2001;l:291–300.

    Article  Google Scholar 

  23. Galanis E, et al. Immunotherapy of advanced malignancy by direct gene transfer of an interleukin-2 DNA/DMRIE/DOPE lipid complex: phase I/II experience. J Clin Oncol 1999;17:3313–3323.

    PubMed  CAS  Google Scholar 

  24. Harrington K, et al. Cells as vehicles for cancer gene therapy: the missing link between targeted vectors and systemic delivery? Hum Gene Ther 2002;13:1263–1280.

    Article  PubMed  CAS  Google Scholar 

  25. Anklesaria P. Gene therapy: a molecular approach to cancer treatment. Curr Opin Mol Ther 2000;2:426–432.

    PubMed  CAS  Google Scholar 

  26. Kirn D. Oncolytic virotherapy for cancer with the adenovirus dll520 (Onyx-015): results of phase I and II trials. Expert Opin Biol Ther 2001;l:525–538.

    Article  Google Scholar 

  27. Rainov NG, Ren H. Gene therapy for human malignant brain tumors. Cancer J 2003;9:180–188.

    PubMed  CAS  Google Scholar 

  28. Tait DL, Obermiller PS, Hatmaker AR, Redlin-Frazier S, Holt JT. Ovarian cancer BRCA1 gene therapy: Phase I and II trial differences in immune response and vector stability. Clin Cancer Res 1999;5:1708–1714.

    PubMed  CAS  Google Scholar 

  29. Schuler M, et al. Adenovirus-mediated wild-type p53 gene transfer in patients receiving chemotherapy for advanced non-small-cell lung cancer: results of a multicenter phase II study. J Clin Oncol 2001;19:1750–1758.

    PubMed  CAS  Google Scholar 

  30. Harvey BG, et al. Variability of human systemic humoral immune responses to adenovirus gene transfer vectors administered to different organs. J Virol 1999;73:6729–6742

    PubMed  CAS  Google Scholar 

  31. Gahery-Segard H, et al. Phase I trial of recombinant adenovirus gene transfer in lung cancer. Longitudinal study of the immune responses to transgene and viral products. J Clin Invest 1997;100:2218–2226.

    PubMed  CAS  Google Scholar 

  32. Molnar-Kimber KL, et al. Impact of preexisting and induced humoral and cellular immune responses in an adenovirus-based gene therapy phase I clinical trial for localized mesothelioma. Hum Gene Ther 1998;9:2121–2133.

    PubMed  CAS  Google Scholar 

  33. Zeimet AG, Marth C. Why did p53 gene therapy fail in ovarian cancer? Lancet Oncol 2003;4:415–422.

    Article  PubMed  CAS  Google Scholar 

  34. Raper SE, et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab 2003;80:148–158.

    Article  PubMed  CAS  Google Scholar 

  35. Reid T, Warren R, Kirn D. Intravascular adenoviral agents in cancer patients: lessons from clinical trials. Cancer Gene Ther 2002;9:979–986.

    Article  PubMed  CAS  Google Scholar 

  36. Cavazzana-Calvo M, et al. Gene therapy of human severe combined immunodeficiency (SCID)-Xl disease. Science 2000;288:669–672.

    Article  PubMed  CAS  Google Scholar 

  37. Hacein-Bey-Abina S, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science 2003;302:415–419.

    Article  PubMed  CAS  Google Scholar 

  38. Kohn DB, Sadelain M, Glorioso JC. Occurrence of leukaemia following gene therapy of X-linked SCID. Nat Rev Cancer 2003;3:477–488.

    Article  PubMed  CAS  Google Scholar 

  39. Whitwam T, et al. Retroviral marking of canine bone marrow: long-term, high-level expression of human interleukin-2 receptor common gamma chain in canine lymphocytes. Blood 1998;92:1565–1575.

    PubMed  CAS  Google Scholar 

  40. Hacein-Bey S, Basile GD, Lemerle J, Fischer A, Cavazzana-Calvo M. gammac gene transfer in the presence of stem cell factor, FLT-3L, interleukin-7 (IL-7), IL-1, and IL-15 cytokines restores T-cell differentiation from gammac(-) X-linked severe combined immunodeficiency hematopoietic progenitor cells in murine fetal thymic organ cultures. Blood 1998;92:4090–4097.

    PubMed  CAS  Google Scholar 

  41. Insertional mutagenesis and oncogenesis: update from non-clinical and clinical studies. Gene Therapy Expert Group of the Committee for Proprietary Medical Products (CPMP), European Agency for the Evaluation of Medical Products — June 2003 meeting. J Gene Med 2004;6:127–129.

    Article  Google Scholar 

  42. Baum C, et al. Chance or necessity? Insertional mutagenesis in gene therapy and its consequences. Mol Ther 2004;9:5–13.

    Article  PubMed  CAS  Google Scholar 

  43. Dave UP, Jenkins NA, Copeland NG. Gene therapy insertional mutagenesis insights. Science 2004;303:333.

    Article  PubMed  Google Scholar 

  44. Kirn D, Martuza RL, Zwiebel J. Replication-selective virotherapy for cancer: Biological principles, risk management and future directions. Nat Med 2001;7:781–787.

    Article  PubMed  CAS  Google Scholar 

  45. Smith JS, Tian J, Muller J, Byrnes AR Unexpected pulmonary uptake of adenovirus vectors in animals with chronic liver disease. Gene Ther 2004;l 1:431–438.

    Article  CAS  Google Scholar 

  46. Crystal RG, et al. Analysis of risk factors for local delivery of low-and intermediate-dose adenovirus gene transfer vectors to individuals with a spectrum of comorbid conditions. Hum Gene Ther 2002;13:65–100.

    Article  PubMed  CAS  Google Scholar 

  47. Buller R, et al. A phase I/II trial of rAd/p53 (SCH 58500) gene replacement in recurrent ovarian cancer. Cancer Gene Ther 2002;9:553–566.

    Article  PubMed  CAS  Google Scholar 

  48. Jacobs A, et al. Positron-emission tomography of vector-mediated gene expression in gene therapy for gliomas. Lancet 2001;358:727–729.

    Article  PubMed  CAS  Google Scholar 

  49. Vansteenkiste JF, Stroobants SG. Positron emission tomography in the management of non-small cell lung cancer. Hematol Oncol Clin North Am 2004; 18:269–288.

    Article  PubMed  Google Scholar 

  50. Vassaux G, Groot-Wassink T. In Vivo Noninvasive Imaging for Gene Therapy. J Biomed Biotechnol 2003;2003:92–101.

    Article  PubMed  Google Scholar 

  51. Groot-Wassink T, et al. Quantitative imaging of Na/I symporter transgene expression using positron emission tomography in the living animal. Mol Ther 2004;9:436–442.

    Article  PubMed  CAS  Google Scholar 

  52. McCaffrey A, Kay MA, Contag CH. Advancing molecular therapies through in vivo bioluminescent imaging. Mol Imaging 2003;2:75–86.

    Article  PubMed  CAS  Google Scholar 

  53. Schellingerhout D, Bogdanov AA, Jr. Viral imaging in gene therapy noninvasive demonstration of gene delivery and expression. Neuroimaging Clin N Am 2002;12:571–581, vi-vii.

    Article  PubMed  Google Scholar 

  54. Zinn KR, et al. Noninvasive monitoring of gene transfer using a reporter receptor imaged with a high-affinity peptide radiolabeled with 99mTc or 188Re. J Nucl Med 2000;41:887–895.

    PubMed  CAS  Google Scholar 

  55. Ray P, et al. Monitoring gene therapy with reporter gene imaging. Semin Nucl Med 2001;31:312–320.

    Article  PubMed  CAS  Google Scholar 

  56. Shah K, Jacobs A, Breakefield XO, Weissleder R. Molecular imaging of gene therapy for cancer. Gene Ther 2004; 11:1175–1187.

    Article  PubMed  CAS  Google Scholar 

  57. Peng KW, et al. IntraperitO’Neal therapy of ovarian cancer using an engineered measles virus. Cancer Res 2002;62:4656–4662.

    PubMed  CAS  Google Scholar 

  58. Phuong LK, et al. Use of a vaccine strain of measles virus genetically engineered to produce carcinoembryonic antigen as a novel therapeutic agent against glioblastoma multiforme. Cancer Res 2003;63:2462–2469.

    PubMed  CAS  Google Scholar 

  59. Reid T, et al. Hepatic arterial infusion of a replication-selective oncolytic adenovirus (d11520): phase II viral, immunologic, and clinical endpoints. Cancer Res 2002;62:6070–6079.

    PubMed  CAS  Google Scholar 

  60. Kirn D. Virotherapy for cancer: current status, hurdles, and future directions. Cancer Gene Ther 2002;9:959–960.

    Article  PubMed  CAS  Google Scholar 

  61. Hermiston TW, Kuhn I. Armed therapeutic viruses: strategies and challenges to arming oncolytic viruses with therapeutic genes. Cancer Gene Ther 2002;9:1022–1035.

    Article  PubMed  CAS  Google Scholar 

  62. Chillon M, Lee JH, Fasbender A, Welsh MJ. Adenovirus complexed with polyethylene glycol and cationic lipid is shielded from neutralizing antibodies in vitro. Gene Ther 1998;5:995–1002.

    Article  PubMed  CAS  Google Scholar 

  63. O’Riordan CR, et al. PEGylation of adenovirus with retention of infectivity and protection from neutralizing antibody in vitro and in vivo. Hum Gene Ther 1999;10:1349–1358.

    Article  PubMed  CAS  Google Scholar 

  64. Croyle MA, Chirmule N, Zhang Y, Wilson JM. PEGylation of El-deleted adenovirus vectors allows significant gene expression on readministration to liver. Hum Gene Ther 2002; 13:1887–1900.

    Article  PubMed  CAS  Google Scholar 

  65. Monck MA, et al. Stabilized plasmid-lipid particles: pharmacokinetics and plasmid delivery to distal tumors following intravenous injection. J Drug Target 2000;7:439–452.

    PubMed  CAS  Google Scholar 

  66. Shi L, et al. Repeated intrathecal administration of plasmid DNA complexed with polyethylene glycol-grafted polyethylenimine led to prolonged transgene expression in the spinal cord. Gene Ther 2003;10:1179–1188.

    Article  PubMed  CAS  Google Scholar 

  67. Bruckheimer E, et al. In vivo efficacy of fol ate-targeted lipid-protamine-DNA (LPD-PEG-Folate) complexes in an immunocompetent syngeneic model for breast adenocarcinoma. Cancer Gene Ther 2004;l 1:128–134.

    Article  CAS  Google Scholar 

  68. Fisher KD, et al. Polymer-coated adenovirus permits efficient retargeting and evades neutralising antibodies. Gene Ther 2001;8:341–348.

    Article  PubMed  CAS  Google Scholar 

  69. Green NK, et al. Extended plasma circulation time and decreased toxicity of polymer-coated adenovirus. Gene Ther 2004;11:1256–1263.

    Article  PubMed  CAS  Google Scholar 

  70. Sun JY, Chatterjee S, Wong KK, Jr. Immunogenic issues concerning recombinant adeno-associated virus vectors for gene therapy. Curr Gene Ther 2002;2:485–500.

    Article  PubMed  CAS  Google Scholar 

  71. Sterman DH, et al. A pilot study of systemic corticosteroid administration in conjunction with intrapleural adenoviral vector administration in patients with malignant pleural mesothelioma. Cancer Gene Ther 2000;7:1511–1518.

    Article  PubMed  CAS  Google Scholar 

  72. Burgert HG, et al. Subversion of host defense mechanisms by adenoviruses. Curr Top Microbiol Immunol 2002;269:273–318.

    PubMed  CAS  Google Scholar 

  73. Fessier SP, Delgado-Lopez F, Horwitz MS. Mechanisms of E3 modulation of immune and inflammatory responses. Curr Top Microbiol Immunol 2004;273:113–135.

    Google Scholar 

  74. Windheim M, Hilgendorf A, Burgert HG. Immune evasion by adenovirus E3 proteins: exploitation of intracellular trafficking pathways. Curr Top Microbiol Immunol 2004;273:29–85.

    PubMed  CAS  Google Scholar 

  75. Wang Y, et al. E3 gene manipulations affect oncolytic adenovirus activity in immunocompetent tumor models. Nat Biotechnol 2003;21:1328–1335.

    Article  PubMed  CAS  Google Scholar 

  76. 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 U S A 2001;98:6396–6401.

    Article  PubMed  CAS  Google Scholar 

  77. Nickiin SA, Baker AH. Tropism-modified adenoviral and adeno-associated viral vectors for gene therapy. Curr Gene Ther 2002;2:273–293.

    Article  Google Scholar 

  78. Einfeld DA, Roelvink PW. Advances towards targetable adenovirus vectors for gene therapy. Curr Opin Mol Ther 4:444–451.

    Google Scholar 

  79. Doronin K, et al. Overexpression of the ADP (E3-11.6K) protein increases cell lysis and spread of adenovirus. Virology 2003;305:378–387.

    Article  PubMed  CAS  Google Scholar 

  80. Liu TC, et al. An E1B-19 kDa gene deletion mutant adenovirus demonstrates tumor necrosis factorenhanced cancer selectivity and enhanced oncolytic potency. Mol Ther 2004;9:786–803.

    Article  PubMed  CAS  Google Scholar 

  81. Khuri FR, 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  PubMed  CAS  Google Scholar 

  82. Sandalon Z, Fusenig NE, McCutcheon J, Taichman LB, Garlick JA. Suicide gene therapy for premalignant disease: a new strategy for the treatment of intraepithelial neoplasia. Gene Ther 2001;8:232–238.

    Article  PubMed  CAS  Google Scholar 

  83. Rudin CM, et al. An attenuated adenovirus, ONYX-015, as mouthwash therapy for premalignant oral dysplasia. J Clin Oncol 2003;21:4546–4552.

    Article  PubMed  CAS  Google Scholar 

  84. Lang FF, et al. Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. J Clin Oncol 2003;21:2508–2518.

    Article  PubMed  CAS  Google Scholar 

  85. dayman GL, Frank DK, Bruso PA, Goepfert H. Adenovirus-mediated wild-type p53 gene transfer as a surgical adjuvant in advanced head and neck cancers. Clin Cancer Res 1999;5:1715–1722.

    PubMed  CAS  Google Scholar 

  86. Han DM, et al. Effectiveness of recombinant adenovirus p53 injection on laryngeal cancer: phase I clinical trial and follow up. Zhonghua Yi Xue Za Zhi 2003;83:2029–2032.

    PubMed  CAS  Google Scholar 

  87. Dummer R, et al. Biological activity and safety of adenoviral vector-expressed wild-type p53 after intratumoral injection in melanoma and breast cancer patients with p53-overexpressing tumors. Cancer Gene Ther 2000;7:1069–1076.

    Article  PubMed  CAS  Google Scholar 

  88. Roth JA, et al. Retrovirus-mediated wild-type p53 gene transfer to tumors of patients with lung cancer. Nat Med 1996;2:985–991.

    Article  PubMed  CAS  Google Scholar 

  89. Schuler M, et al. A phase I study of adenovirus-mediated wild-type p53 gene transfer in patients with advanced non-small cell lung cancer. Hum Gene Ther 1998;9:2075–2082.

    PubMed  CAS  Google Scholar 

  90. Swisher SG, et al. Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer. J Natl Cancer Inst 1999;91:763–771.

    Article  PubMed  CAS  Google Scholar 

  91. Kuball J, et al. Successful adenovirus-mediated wild-type p53 gene transfer in patients with bladder cancer by intravesical vector instillation. J Clin Oncol 2002;20:957–965.

    Article  PubMed  CAS  Google Scholar 

  92. Pagliaro LC, et al. Repeated intravesical instillations of an adenoviral vector in patients with locally advanced bladder cancer: a phase I study of p53 gene therapy. J Clin Oncol 2003;21:2247–2253.

    Article  PubMed  CAS  Google Scholar 

  93. Nemunaitis J, et al. Adenovirus-mediated p53 gene transfer in sequence with cisplatin to tumors of patients with non-small-cell lung cancer. J Clin Oncol 2000;18:609–622.

    PubMed  CAS  Google Scholar 

  94. Swisher SG, et al. Induction of p53-regulated genes and tumor regression in lung cancer patients after intratumoral delivery of adenoviral p53 (INGN 201) and radiation therapy. Clin Cancer Res 2003;9:93–101.

    PubMed  CAS  Google Scholar 

  95. Zhang SW, et al. Treatment of head and neck squamous cell carcinoma by recombinant adenovirus-p53 combined with radiotherapy: a phase II clinical trial of 42 cases. Zhonghua Yi Xue Za Zhi 2003;83:2023–2028.

    PubMed  CAS  Google Scholar 

  96. Chen CB, Pan JJ, Xu LY Recombinant adenovirus p53 agent injection combined with radiotherapy in treatment of nasopharyngeal carcinoma: a phase II clinical trial. Zhonghua Yi Xue Za Zhi 2003;83:2033–2035.

    PubMed  CAS  Google Scholar 

  97. Klatzmann D, et al. A phase I/II dose-escalation study of herpes simplex virus type 1 thymidine kinase „suicide” gene therapy for metastatic melanoma. Study Group on Gene Therapy of Metastatic Melanoma. Hum Gene Ther 1998;9:2585–2594.

    Article  PubMed  CAS  Google Scholar 

  98. Izquierdo M, et al. Human malignant brain tumor response to herpes simplex thymidine kinase (HSVtk)/ganciclovir gene therapy. Gene Ther 1996;3:491–495.

    PubMed  CAS  Google Scholar 

  99. Trask TW, et al. Phase I study of adenoviral delivery of the HSV-tk gene and ganciclovir administration in patients with current malignant brain tumors. Mol Ther 2000;l:195–203.

    Article  CAS  Google Scholar 

  100. Ram, Z, et al. Therapy of malignant brain tumors by intratumoral implantation of retroviral vectorproducing cells. Nat Med 1997;3:1354–1361.

    Article  PubMed  CAS  Google Scholar 

  101. Singh S, Cunningham C, Buchanan A, Jolly DJ, Nemunaitis J. Toxicity assessment of intratumoral injection of the herpes simplex type I thymidine kinase gene delivered by retrovirus in patients with refractory cancer. Mol Ther 2001;4:157–160.

    Article  PubMed  CAS  Google Scholar 

  102. Sterman DH, et al. Adenovirus-mediated herpes simplex virus thymidine kinase/ganciclovir gene therapy in patients with localized malignancy: results of a phase I clinical trial in malignant mesothelioma. Hum Gene Ther 1998;9:1083–1092.

    Article  PubMed  CAS  Google Scholar 

  103. Sung MW, et al. Intratumoral adenovirus-mediated suicide gene transfer for hepatic metastases from colorectal adenocarcinoma: results of a phase I clinical trial. Mol Ther 2001;4:182–191.

    Article  PubMed  CAS  Google Scholar 

  104. Miles BJ, et al. Prostate-specific antigen response and systemic T cell activation after in situ gene therapy in prostate cancer patients failing radiotherapy. Hum Gene Ther 2001;12:1955–1967.

    Article  PubMed  CAS  Google Scholar 

  105. Freytag SO, et al. Phase I study of replication-competent adenovirus-mediated double suicide gene therapy for the treatment of locally recurrent prostate cancer. Cancer Res 2002;62:4968–4976.

    PubMed  CAS  Google Scholar 

  106. Herman JR, et al. In situ gene therapy for adenocarcinoma of the prostate: a phase I clinical trial. Hum Gene Ther 1999;10:1239–1249.

    Article  PubMed  CAS  Google Scholar 

  107. Kubo H, et al. Phase I dose escalation clinical trial of adenovirus vector carrying osteocalcin promoter-driven herpes simplex virus thymidine kinase in localized and metastatic hormone-refractory prostate cancer. Hum Gene Ther 2003; 14:227–241.

    Article  PubMed  CAS  Google Scholar 

  108. Prados MD, et al. Treatment of progressive or recurrent glioblastoma multiforme in adults with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration: a phase I/II multi-institutional trial. J Neurooncol 2003;65:269–278.

    Article  PubMed  Google Scholar 

  109. Germano IM, Fable J, Gultekin SH, Silvers A. Adenovirus/herpes simplex-thymidine kinase/-ganciclovir complex: preliminary results of a phase I trial in patients with recurrent malignant gliomas. J Neurooncol 2003;65:279–289.

    Article  PubMed  Google Scholar 

  110. Shand N, et al. A phase 1-2 clinical trial of gene therapy for recurrent glioblastoma multiforme by tumor transduction with the herpes simplex thymidine kinase gene followed by ganciclovir. GLI328 European-Canadian Study Group. Hum Gene Ther 1999;10:2325–2335.

    Article  PubMed  CAS  Google Scholar 

  111. Smitt PS, Driesse M, Wolbers J, Kros M, Avezaat C. Treatment of relapsed malignant glioma with an adenoviral vector containing the herpes simplex thymidine kinase gene followed by ganciclovir. Mol Ther 2003;7:851–858.

    Article  PubMed  CAS  Google Scholar 

  112. Packer RJ, et al. Treatment of progressive or recurrent pediatric malignant supratentorial brain tumors with herpes simplex virus thymidine kinase gene vector-producer cells followed by intravenous ganciclovir administration. J Neurosurg 2000;92:249–254.

    Article  PubMed  CAS  Google Scholar 

  113. Sandmair AM, et al. Thymidine kinase gene therapy for human malignant glioma, using replicationdeficient retroviruses or adenoviruses. Hum Gene Ther 2000;11:2197–2205.

    Article  PubMed  CAS  Google Scholar 

  114. Immonen A, et al. AdvHSV-tk gene therapy with intravenous ganciclovir improves survival in human malignant glioma: a randomised, controlled study. Mol Ther 2004; 10:967–972.

    Article  PubMed  CAS  Google Scholar 

  115. Alvarez RD, et al. Adenoviral-mediated suicide gene therapy for ovarian cancer. Mol Ther 2000;2:524–530.

    Article  PubMed  CAS  Google Scholar 

  116. Teh BS, et al. Phase I/II trial evaluating combined radiotherapy and in situ gene therapy with or without hormonal therapy in the treatment of prostate cancer—a preliminary report. Int J Radiat Oncol Biol Phys 2001;51:605–613.

    Article  PubMed  CAS  Google Scholar 

  117. Teh BS, et al. Phase I-II trial evaluating combined intensity-modulated radiotherapy and in situ gene therapy with or without hormonal therapy in treatment of prostate cancer-interim report on PSA response and biopsy data. Int J Radiat Oncol Biol Phys 2004;58:1520–1529.

    Article  PubMed  CAS  Google Scholar 

  118. Satoh T, et al. Enhanced systemic T-cell activation after in situ gene therapy with radiotherapy in prostate cancer patients. Int J Radiat Oncol Biol Phys 2004;59:562–571.

    Article  PubMed  CAS  Google Scholar 

  119. Freytag SO, et al. Phase I study of replication-competent adenovirus-mediated double-suicide gene therapy in combination with conventional-dose three-dimensional conformai radiation therapy for the treatment of newly diagnosed, intermediate-to high-risk prostate cancer. Cancer Res 2003;63:7497–7506.

    PubMed  CAS  Google Scholar 

  120. Rainov NG. A phase III clinical evaluation of herpes simplex virus type 1 thymidine kinase and ganciclovir gene therapy as an adjuvant to surgical resection and radiation in adults with previously untreated glioblastoma multiforme. Hum Gene Ther 2000; 11:2389–2401.

    Article  PubMed  CAS  Google Scholar 

  121. Hasenburg A, et al. Thymidine kinase gene therapy with concomitant topotecan chemotherapy for recurrent ovarian cancer. Cancer Gene Ther 2000;7:839–844.

    Article  PubMed  CAS  Google Scholar 

  122. Hasenburg A, et al. Adenovirus-mediated thymidine kinase gene therapy in combination with topotecan for patients with recurrent ovarian cancer: 2.5-year follow-up. Gynecol Oncol 2001;83:549–554.

    Article  PubMed  CAS  Google Scholar 

  123. Ganly I, et al. A phase I study of Onyx-015, an E1B attenuated adenovirus, administered intratumorally to patients with recurrent head and neck cancer. Clin Cancer Res 2000;6:798–806.

    PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  125. Nemunaitis J, et al. Phase II trial of intratumoral administration of ONYX-015, a replication-selective adenovirus, in patients with refractory head and neck cancer. J Clin Oncol 2001; 19:289–298.

    PubMed  CAS  Google Scholar 

  126. Morley S, et al. The dl 1520 virus is found preferentially in tumor tissue after direct intratumoral injection in oral carcinoma. Clin Cancer Res 2004;10:4357–4362.

    Article  PubMed  CAS  Google Scholar 

  127. Mulvihill S, et al. Safety and feasibility of injection with an E1B-55 kDa gene-deleted, replicationselective adenovirus (ONYX-015) into primary carcinomas of the pancreas: a phase I trial. Gene Ther 2001;8:308–315.

    Article  PubMed  CAS  Google Scholar 

  128. Chiocca EA, et al. A Phase I Open-Label, Dose-Escalation, Multi-Institutional Trial of Injection with an ElB-Attenuated Adenovirus, ONYX-015, into the Peritumoral Region of Recurrent Malignant Gliomas, in the Adjuvant Setting. Mol Ther 2004; 10:958–966.

    Article  PubMed  CAS  Google Scholar 

  129. Makower D, et al. Phase II clinical trial of intralesional administration of the oncolytic adenovirus ONYX-015 in patients with hepatobiliary tumors with correlative p53 studies. Clin Cancer Res 2003;9:693–702.

    PubMed  Google Scholar 

  130. Vasey PA, et al. Phase I trial of intraperitO’Neal injection of the ElB-55-kd-gene-deleted adenovirus ONYX-015 (d11520) given on days 1 through 5 every 3 weeks in patients with recurrent/refractory epithelial ovarian cancer. J Clin Oncol 2002;20:1562–1569.

    Article  PubMed  CAS  Google Scholar 

  131. Habib N, et al. Clinical trial of ElB-deleted adenovirus (dll520) gene therapy for hepatocellular carcinoma. Cancer Gene Ther 2002;9:254–259.

    Article  PubMed  CAS  Google Scholar 

  132. Hamid O, et al. Phase II trial of intravenous CI-1042 in patients with metastatic colorectal cancer. J Clin Oncol 2003;21:1498–1504.

    Article  PubMed  CAS  Google Scholar 

  133. Hecht JR, et al. A phase I/II trial of intratumoral endoscopie ultrasound injection of ONYX-015 with intravenous gemcitabine in unresectable pancreatic carcinoma. Clin Cancer Res 2003;9:555–561.

    PubMed  CAS  Google Scholar 

  134. Galanis E, et al. Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas. Gene Ther 2005;12:437–445.

    Article  PubMed  CAS  Google Scholar 

  135. Habib NA, et al. ElB-deleted adenovirus (d11520) gene therapy for patients with primary and secondary liver tumors. Hum Gene Ther 2001;12:219–226.

    Article  PubMed  CAS  Google Scholar 

  136. Reid T, et al. Intra-arterial administration of a replication-selective adenovirus (d11520) in patients with colorectal carcinoma metastatic to the liver: a phase I trial. Gene Ther 2001;8:1618–1626.

    Article  PubMed  CAS  Google Scholar 

  137. Nemunaitis J, et al. Pilot trial of intravenous infusion of a replication-selective adenovirus (ONYX-015) in combination with chemotherapy or IL-2 treatment in refractory cancer patients. Cancer Gene Ther 2003;10:341–352.

    Article  PubMed  CAS  Google Scholar 

  138. Nemunaitis J, et al. Intravenous infusion of a replication-selective adenovirus (ONYX-015) in cancer patients: safety, feasibility and biological activity. Gene Ther 2001;8:746–759.

    Article  PubMed  CAS  Google Scholar 

  139. Webb A, et al. BCL-2 antisense therapy in patients with non-Hodgkin lymphoma. Lancet 1997;349:1137–1141.

    Article  PubMed  CAS  Google Scholar 

  140. Waters JS, et al. Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin’s lymphoma. J Clin Oncol 2000;18:1812–1823.

    PubMed  CAS  Google Scholar 

  141. Morris MJ, et al. Phase I trial of BCL-2 antisense oligonucleotide (G3139) administered by continuous intravenous infusion in patients with advanced cancer. Clin Cancer Res 2002;8:679–683.

    PubMed  CAS  Google Scholar 

  142. Rudin CM, et al. A pilot trial of G3139, a bcl-2 antisense oligonucleotide, and paclitaxel in patients with chemorefractory small-cell lung cancer. Ann Oncol 2002;13:539–545.

    Article  PubMed  CAS  Google Scholar 

  143. Rudin CM, et al. Phase I study of G3139, a bcl-2 antisense oligonucleotide, combined with carboplatin and etoposide in patients with small-cell lung cancer. J Clin Oncol 2004;22:1110–1117.

    Article  PubMed  CAS  Google Scholar 

  144. Chi KN, et al. A phase I dose-finding study of combined treatment with an antisense Bcl-2 oligonucleotide (Genasense) and mitoxantrone in patients with metastatic hormone-refractory prostate cancer. Clin Cancer Res 2001;7:3920–3927.

    PubMed  CAS  Google Scholar 

  145. Tolcher AW, et al. A Phase I pharmacokinetic and biological correlative study of oblimersen sodium (genasense, g3139), an antisense oligonucleotide to the bcl-2 mRNA, and of docetaxel in patients with hormone-refractory prostate cancer. Clin Cancer Res 2004; 10:5048–5057.

    Article  PubMed  CAS  Google Scholar 

  146. Tolcher AW, et al. A phase II, pharmacokinetic, and biological correlative study of oblimersen sodium and docetaxel in patients with hormone-refractory prostate cancer. Clin Cancer Res 2005;11:3854–3861.

    Article  PubMed  CAS  Google Scholar 

  147. Jansen B, et al. Chemosensitisation of malignant melanoma by BCL2 antisense therapy. Lancet 2000;356:1728–1733.

    Article  PubMed  CAS  Google Scholar 

  148. Marshall J, et al. A phase I trial of a Bcl-2 antisense (G3139) and weekly docetaxel in patients with advanced breast cancer and other solid tumors. Ann Oncol 2004; 15:1274–1283.

    Article  PubMed  CAS  Google Scholar 

  149. Morris MJ, et al. Safety and biologic activity of intravenous BCL-2 antisense oligonucleotide (G3139) and taxane chemotherapy in patients with advanced cancer. Appl Immunohistochem Mol Morphol 2005;13:6–13.

    Article  PubMed  CAS  Google Scholar 

  150. van de Donk NW, et al. G3139, a Bcl-2 antisense oligodeoxynucleotide, induces clinical responses in VAD refractory myeloma. Leukemia 2004; 18:1078–1084.

    Article  PubMed  CAS  Google Scholar 

  151. Badros AZ, et al. Phase II study of G3139, a Bcl-2 antisense oligonucleotide, in combination with dexamethasone and thalidomide in relapsed multiple myeloma patients. J Clin Oncol 2005;23:4089–4099.

    Article  PubMed  CAS  Google Scholar 

  152. Marcucci G, et al. Phase 1 and pharmacodynamic studies of G3139, a Bcl-2 antisense oligonucleotide, in combination with chemotherapy in refractory or relapsed acute leukemia. Blood 2003;101:425–432.

    Article  PubMed  CAS  Google Scholar 

  153. Marcucci G, et al. Phase I study of oblimersen sodium, an antisense to Bcl-2, in untreated older patients with acute myeloid leukemia: pharmacokinetics, pharmacodynamics, and clinical activity. J Clin Oncol 2005;23:3404–3411.

    Article  PubMed  CAS  Google Scholar 

  154. Rousseau RF, et al. Local and systemic effects of an allogeneic tumor cell vaccine combining transgenic human lymphotactin with interleukin-2 in patients with advanced or refractory neuroblastoma. Blood 2003;101:1718–1726.

    Article  PubMed  CAS  Google Scholar 

  155. Sobol RE, et al. Interleukin 2 gene therapy of colorectal carcinoma with autologous irradiated tumor cells and genetically engineered fibroblasts: a Phase I study. Clin Cancer Res 1999;5:2359–2365.

    PubMed  CAS  Google Scholar 

  156. Belli F, et al. Active immunization of metastatic melanoma patients with interleukin-2-transduced allogeneic melanoma cells: evaluation of efficacy and tolerability. Cancer Immunol Immunother 1997;44:197–203.

    Article  PubMed  CAS  Google Scholar 

  157. Palmer K, et al. Gene therapy with autologous, interleukin 2-secreting tumor cells in patients with malignant melanoma. Hum Gene Ther 1999;10:1261–1268.

    Article  PubMed  CAS  Google Scholar 

  158. Osanto S, et al. Vaccination of melanoma patients with an allogeneic, genetically modified interleukin 2-producing melanoma cell line. Hum Gene Ther 2000; 11:739–750.

    Article  PubMed  CAS  Google Scholar 

  159. Sun Y, et al. Vaccination with IL-12 gene-modified autologous melanoma cells: preclinical results and a first clinical phase I study. Gene Ther 1998;5:481–490.

    Article  PubMed  CAS  Google Scholar 

  160. Trudel S, et al. Adenovector engineered interleukin-2 expressing autologous plasma cell vaccination after high-dose chemotherapy for multiple myeloma—a phase 1 study. Leukemia 2001; 15:846–854.

    Article  PubMed  CAS  Google Scholar 

  161. Stewart AK. et al. Adenovector-mediated gene delivery of interleukin-2 in metastatic breast cancer and melanoma: results of a phase 1 clinical trial. Gene Ther 1999;6:350–363.

    Article  PubMed  CAS  Google Scholar 

  162. Schreiber S, et al. Immunotherapy of metastatic malignant melanoma by a vaccine consisting of autologous interleukin 2-transfected cancer cells: outcome of a phase I study. Hum Gene Ther 1999; 10:983–993.

    Article  PubMed  CAS  Google Scholar 

  163. Veelken H, et al. A phase-I clinical study of autologous tumor cells plus interleukin-2-gene-transfected allogeneic fibroblasts as a vaccine in patients with cancer. Int J Cancer 1997;70:269–277.

    Article  PubMed  CAS  Google Scholar 

  164. Belldegrun A, et al. Interleukin 2 gene therapy for prostate cancer: phase I clinical trial and basic biology. Hum Gene Ther 2001; 12:883–892.

    Article  PubMed  CAS  Google Scholar 

  165. Trudel S, et al. A phase I trial of adenovector-mediated delivery of interleukin-2 (AdIL-2) in highrisk localized prostate cancer. Cancer Gene Ther 2003; 10:755–763.

    Article  PubMed  CAS  Google Scholar 

  166. Jantscheff P, et al. Gene therapy with cytokine-transfected xenogenic cells (Vero-IL-2) in patients with metastatic solid tumors: mechanism(s) of elimination of the transgene-carrying cells. Cancer Immunol Immunother 1999;48:321–330.

    Article  PubMed  CAS  Google Scholar 

  167. Rochlitz C, et al. Gene therapy study of cytokine-transfected xenogeneic cells (Vero-interleukin-2) in patients with metastatic solid tumors. Cancer Gene Ther 1999;6:271–281.

    Article  PubMed  CAS  Google Scholar 

  168. Rochlitz C, et al. Phase I immunotherapy with a modified vaccinia virus (MVA) expressing human MUC1 as antigen-specific immunotherapy in patients with MUCl-positive advanced cancer. J Gene Med 2003;5:690–699.

    Article  PubMed  CAS  Google Scholar 

  169. Schmidt-Wolf IG, et al. Phase I clinical study applying autologous immunological effector cells transfected with the interleukin-2 gene in patients with metastatic renal cancer, colorectal cancer and lymphoma. Br J Cancer 1999;81:1009–1016.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Molecular Neurosurgery Laboratory, Massachusetts General Hospital, Harvard Medical School, Boston, MA

    Ta-Chiang Liu MD, PhD

  2. Department of Clinical Pharmacology, University of Oxford Medical School, Oxford, UK

    David H. Kirn MD

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  1. Ta-Chiang Liu MD, PhD
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  2. David H. Kirn MD
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Editors and Affiliations

  1. The University of Texas M. D. Anderson Cancer Center, Houston, TX

    Kelly K. Hunt MD  & Stephen G. Swisher MD  & 

  2. Inselspital Bern, University of Bern, Bern, Switzerland

    Stephan A. Vorburger MD, MCR

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Liu, TC., Kirn, D.H. (2007). Problems, Side Effects, and Disappointments in Clinical Cancer Gene Therapy. In: Hunt, K.K., Vorburger, S.A., Swisher, S.G. (eds) Gene Therapy for Cancer. Cancer Drug Discovery and Development. Humana Press. https://doi.org/10.1007/978-1-59745-222-9_20

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  • DOI: https://doi.org/10.1007/978-1-59745-222-9_20

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