Abstract
A large number of adenoviral agents are being developed for the treatment of cancer. However, the treatment-related death of a patient with ornithine transcarbamylase deficiency following adenovirus administration by hepatic artery has led to serious concerns regarding the safety of intravascular adenovirus. Both replication-incompetent (rAd.p53, e.g., SCH58500) and replication-selective (dl1520, aka Onyx-015; CG7870) oncolytic adenoviruses, by intravascular administration, are in clinical trials. We review Phases I and I/II results from these clinical trials. dl1520 and rAd.p53 were well-tolerated following hepatic artery infusion at doses of up to 2×1012 and 2.5×1013 particles, respectively. At a dose of 7.5×1013 particles, rAd.p53 was associated with dose-limiting cardiac output suppression; dl1520 dose escalation did not proceed higher than 2×1012. Intravenous (i.v.) infusions of dl1520 and CG7870 have been well tolerated by i.v. infusion at doses of 2×1013 and 6×1012, respectively, without identification of a maximally tolerated dose to date. Mild/moderate transaminitis was demonstrated in some patients on both the hepatic arterial and i.v. trials at doses ≥1012 particles. Interleukin (IL)-6 and IL-10 were induced in a dose-dependent manner in most patients, but significant interpatient and intrapatient (on repeat doses) variabilities were demonstrated. Evidence of p53 gene expression (Ad.p53) or viral replication (dl1520) was demonstrated in the majority of patients receiving ≥1012 particles. Over 100 cancer patients have been treated with intravascular adenovirus constructs to date with an acceptable toxicity profile; further clinical trial testing appears appropriate in cancer patients.
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References
McCormick F . Cancer gene therapy: fringe or cutting edge? Nat Rev Cancer 2001 1: 130–141
Kozarsky KF, Wilson JM . Gene therapy: adenovirus vectors Curr Opin Genet Dev 1993 3: 499–503
Roth J, Cristiano RJ . Gene therapy for cancer: what have we done and where are we going? J Natl Cancer Inst 1997 89: 21–39
Kirn D, Martuza RL, Zwiebel J . Replication-selective virotherapy for cancer: biological principles, risk management and future directions Nat Med 2001 7: 781–787
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
Heise C, Hermiston T, Johnson L et al. An adenovirus E1A mutant that demonstrates potent and selective antitumoral efficacy Nat Med 2000 6: 1134–1139
Fueyo J, Gomez-Manzano C, Alemany R et al. A mutant oncolytic adenovirus targeting the Rb pathway produces anti-glioma effect in vivo Oncogene 2000 19: 2–12
Hallenbeck PL, Chang YN, Hay C et al. A novel tumor-specific replication-restricted adenoviral vector for gene therapy of hepatocellular carcinoma Hum Gene Ther 1999 10: 1721–1733
Yu D, Sakamoto G, Henderson DR . Identification of the transcriptional regulatory sequences of human kallikrein 2 and their use in the construction of calydon virus 764, an attenuated replication competent adenovirus for prostate cancer therapy Cancer Res 1999 59: 1498–1504
Yu D, Chen Y, Seng M, Dilley J, Henderson DR . The addition of adenovirus region E3 enables calydon virus 787 to eliminate distant prostate tumor xenografts Cancer Res 1999 59: 4200–4203
Nemunaitis J, Ganly I, Khuri F et al. Selective replication and oncolysis in p53 mutant tumors with Onyx-015, an E1B–55 kD gene–deleted adenovirus, in patients with advanced head and neck cancer: a phase II trial Cancer Res 2000 60: 6359–6366
DeWeese T, Van der Poel H, Li S 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
Vasey P, Shulman L, Gore M, Kirn D, Kaye S . Phase I trial of intraperitoneal Onyx-015 adenovirus in patients with recurrent ovarian carcinoma Proc Am Soc Clin Oncol 2000 19: 1512 abstract
Heise C, Williams A, Xue S, Propst M, Kirn D . Intravenous administration of ONYX-015, a selectively-replicating adenovirus, induces antitumoral efficacy Cancer Res 1999 59: 2623–2628
Marshall E . Clinical trials: gene therapy death prompts review of adenovirus vector Science 1999 286: 2244–2245
Beardsley T . Gene therapy setback Sci Am 2000 282: 36–37
Jenks S . Gene therapy death — everyone has to share in the guilt J Natl Cancer Inst 2000 92: 98–100
Miller H . Letter to the editor Science 2000 287: 591
Barker DD, Berk AJ . Adenovirus proteins from both E1B reading frames are required for transformation of rodent cells by viral infection and DNA transfection Virology 1987 156: 107–121
Bischoff JR, Kirn DH, Williams A et al. An adenovirus mutant that replicates selectively in p53-deficient human tumor cells [see comments] Science 1996 274: 373–376
Heise C, Sampson JA, Williams A, McCormick F, Von HD, Kirn DH . ONYX-015, an E1B gene–attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents [see comments] Nat Med 1997 3: 639–645
Harada J, Berk A . p53-independent and -dependent requirements for E1B–55 kD in adenovirus type 5 replication J Virol 1999 73: 5333–5344
Rothmann T, Hengstermann A, Whitaker NJ, Scheffner M, zur Hausen H . Replication of ONYX-015, a potential anticancer adenovirus, is independent of p53 status in tumor cells J Virol 1998 72: 9470–9478
Goodrum FD, Ornelles DA . p53 status does not determine outcome of E1B 55-kilodalton mutant adenovirus lytic infection J Virol 1998 72: 9479–9490
Rogulski K, Freytag S, Zhang K et al. In vivo antitumor activity of ONYX-015 is influenced by p53 status and is augmented by radiotherapy Cancer Res 2000 60: 1193–1196
Ries SJ, Brandts CH, Chung AS et al. Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015) Nat Med 2000 6: 1128–1133
Kirn D, Hermiston T, McCormick F . ONYX-015: clinical data are encouraging Nat Med 1998 4: 1341–1342
Kirn D, Nemunaitis J, Ganly I 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 1998 17: 391a
Khuri F, Nemunaitis J, Ganly I et al. A controlled trial of Onyx-015, an E1B gene–deleted adenovirus, in combination with chemotherapy in patients with recurrent head and neck cancer Nat Med 2000 6: 879–885
Kirn DH, Khuri F, Ganly I et al. A phase II trial of ONYX-015, a selectively-replicating adenovirus, in combination with cisplatin and 5-fluorouracil in patients with recurrent head and neck cancer Proc Am Soc Clin Oncol 1999 18: 1505
Heise C, Sampson-Johannes A, Williams A, McCormick F, Von Hoff DD, Kirn DH . ONYX-015, an E1B gene–attenuated adenovirus, causes tumor-specific cytolysis and antitumoral efficacy that can be augmented by standard chemotherapeutic agents [see comments] Nat Med 1997 3: 639–645
Reid A, Galanis E, Abbruzzese J, Romel L, Rubin J, Kirn D . A phase I/II trial of ONYX-015 administered by hepatic artery infusion to patients with colorectal carcinoma EORTC-NCI-AACR Meeting on Molecular Therapeutics of Cancer 1999
Wills KN, Maneval DC, Menzel P et al. Development and characterization of recombinant adenoviruses encoding human p53 for gene therapy of cancer Hum Gene Ther 1994 5: 1079–1088
Mujoo K, Maneval D, Anderson S, Gutterman J . Adenoviral-mediated p53 tumor suppressor gene therapy of human ovarian carcinoma Oncogene 1996 12: 1617–1623
Nemunaitis J, Swisher SG, Timmons T 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
Rodriguez R, Schuur ER, Lim HY, Henderson GA, Simons JW, Henderson DR . Prostate attenuated replication competent adenovirus (ARCA) CN706: a selective cytotoxic for prostate-specific antigen-positive prostate cancer cells Cancer Res 1997 57: 2559–2563
Barker DD, Berk AJ . Adenovirus proteins from both E1B reading frames are required for transformation of rodent cells by viral infection and DNA transfection Virology 1987 156: 107–121
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 Ther 2001 8: 1618–1626
Reid T, Galanis E, Abbruzzese J et al. Hepatic artery infusion of Onyx-015, a replication-selective adenovirus, in combination with 5-FU/leucovorin for gastrointestinal carcinoma metastatic to the liver: a phase I/II clinical trial Proc Am Soc Clin Oncol 2000 19: 953 abstract
Nemunaitis J, Cunningham C, Buchanan A 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
Alexander HR, Bartlett DL, Libutti SK, Fraker DL, Moser T, Rosenberg SA . Isolated hepatic perfusion with tumor necrosis factor and melphalan for unresectable cancers confined to the liver J Clin Oncol 1998 16: 1479–1489
Brusilow S, Maestri N . Urea cycle disorders: diagnosis, pathophysiology and therapy Adv Pediatr 1996 43: 127–170
Yu D, Chen Y, Dilley J et al. Antitumor synergy of CN787, a prostate cancer–specific adenovirus, and paclitaxel and docetaxel Cancer Res 2001 61: 517–525
Chalavi A, Todo T, Martuza R, Rabkin S . Replication-competent herpes simplex vector G207/cisplatin combination therapy for head and neck squamous cell carcinoma Neoplasia 1999 1: 162–169
Norman K, Lee P . Reovirus as a novel oncolytic agent J Clin Invest 2000 105: 1035–1038
Pecora AL, Rizvi N, Cohen GI et al. Phase I trial of intravenous administration of PV701, an oncolytic virus, in patients with advanced solid cancers J Clin Oncol 2002 20: 2251–2266
Coffey M, Strong J, Forsyth P, Lee P . Reovirus therapy of tumors with activated ras pathway Science 1998 282: 1332–1334
Mineta T, Rabkin SD, Yazaki T, Hunter WD, Martuza RL . Attenuated multi-mutated herpes simplex virus-1 for the treatment of malignant gliomas Nat Med 1995 1: 938–943
Roelvink P, Mi G, Einfeld D, Kovesdi I, Wickham T . Identification of a conserved receptor-binding site on the fiber proteins of CAR-recognizing adenoviridae Science 1999 286: 1568–1571
Suzuki K, Fueyo J, Krasnykh VPR, Curiel D, Alemany R . A replicative adenovirus with enhanced infectivity shows improved oncolytic potency Clin Cancer Res 2001 7: 120–126
Doronin K, Toth K, Kuppuswamy M, Ward P, Tollefson A, Wold W . Tumor-specific, replication-competent adenovirus vectors overexpressing the adenovirus death protein J Virol 2000 74: 6147–6155
Hermiston T . Gene delivery from replication-selective viruses: arming guided missiles in the war against cancer J Clin Invest 2000 105: 1169–1172
Acknowledgements
We thank the following individuals for their contributions to these clinical trials: Jim Abbruzzese, Joe Rubin, Eva Galanis, and Alan Venook.
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Reid, T., Warren, R. & Kirn, D. Intravascular adenoviral agents in cancer patients: Lessons from clinical trials. Cancer Gene Ther 9, 979–986 (2002). https://doi.org/10.1038/sj.cgt.7700539
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DOI: https://doi.org/10.1038/sj.cgt.7700539
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