This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Braybrooke, J. P. Articles by Harris, A. L. Search for Related Content PubMed PubMed Citation Articles by Braybrooke, J. P. Articles by Harris, A. L.

Phase I Study of MetXia-P450 Gene Therapy and Oral Cyclophosphamide for Patients with Advanced Breast Cancer or Melanoma

¹ Cancer Research UK Medical Oncology Unit, Churchill Hospital; ² Oxford Biomedica, Medawar Centre, Oxford Science Park, Oxford, United Kingdom and ³ Mount Vernon Hospital, Northwood, Middlesex, United Kingdom

Requests for reprints: Adrian L. Harris, Cancer Research UK Medical Oncology Unit, Churchill Hospital, Oxford OX3 7LJ, United Kingdom. Phone: 44-1865-226185; Fax: 44-1865-226179; E-mail: aharris.clin{at}cancer.org.uk.

Purpose: MetXia-P450 is a novel recombinant retroviral vector that encodes the human cytochrome P450 type 2B6 gene (CYP2B6), Escherichia coli lacZ, and neomycin resistance marker genes. Cytochrome P450 enzymes are primarily expressed in the liver and convert the prodrug cyclophosphamide to an active phosphoramide mustard and acrolein. Gene-based delivery of CYP2B6 to the tumor site leads to local prodrug activation and higher concentrations of the active metabolites at the target site.

Experimental Design: MetXia-P450 was directly injected into metastatic cutaneous tumor nodules on days 1 and 2 and nodules biopsied on day 7. Oral cyclophosphamide (100 mg/m²) was administered between days 8 and 22. Subsequent cycles of oral cyclophosphamide were repeated for 2 of 4 weeks. Gene transfer levels in biopsy samples were measured by histologic and quantitative PCR analyses. Safety assessments were made using PCR for vector dissemination to the blood after injection and using PCR and serologic analyses to detect replicating virus. Secondary end points included clinical response, toxicity, and evaluation of antitumor immune responses by measurement of carcinoembryonic antigen and 5T4 antibodies.

Results: Twelve patients with breast cancer (n = 9) and melanoma (n = 3) received three dose levels of MetXia-P450 (8 x 10⁵, 8 x 10⁶, and 8 x 10⁷ lacZ transferring units/mL). The product was safe and well tolerated. The lacZ transgene was detected in biopsy material by immunohistochemistry in 10 of 12 patients and integrated viral sequences by PCR in 3 of 6 patients. One (8%) patient with breast cancer had a partial response and received 7 months of oral cyclophosphamide. Four (33%) patients had stable disease for 3 months and the rest had progressive disease. Preliminary immunologic analyses were suggestive of an antitumor response in two patients (partial response in one patient and stable disease in one patient).

Conclusion: MetXia was safe and well tolerated. Gene transfer was detected at all dose levels, and the initial suggestion of an antitumor response indicates that MetXia-P450 should undergo further clinical assessment.

Key Words: Gene therapy • MetXia-P450 • cyclophosphamide • breast cancer

This article has been cited by other articles:

				J. A. Williams, T. Andersson, T. B. Andersson, R. Blanchard, M. O. Behm, N. Cohen, T. Edeki, M. Franc, K. M. Hillgren, K. J. Johnson, et al. PhRMA White Paper on ADME Pharmacogenomics J. Clin. Pharmacol., July 1, 2008; 48(7): 849 - 889. [Abstract] [Full Text] [PDF]

				T.-A. Nguyen, M. Tychopoulos, F. Bichat, C. Zimmermann, J.-P. Flinois, M. Diry, E. Ahlberg, M. Delaforge, L. Corcos, P. Beaune, et al. Improvement of Cyclophosphamide Activation by CYP2B6 Mutants: From in Silico to ex Vivo Mol. Pharmacol., April 1, 2008; 73(4): 1122 - 1133. [Abstract] [Full Text] [PDF]

				J. Ma and D. J. Waxman Collaboration between hepatic and intratumoral prodrug activation in a P450 prodrug-activation gene therapy model for cancer treatment Mol. Cancer Ther., November 1, 2007; 6(11): 2879 - 2890. [Abstract] [Full Text] [PDF]

				R. Harrop, N. Drury, W. Shingler, P. Chikoti, I. Redchenko, M. W. Carroll, S. M. Kingsman, S. Naylor, A. Melcher, J. Nicholls, et al. Vaccination of Colorectal Cancer Patients with Modified Vaccinia Ankara Encoding the Tumor Antigen 5T4 (TroVax) Given Alongside Chemotherapy Induces Potent Immune Responses Clin. Cancer Res., August 1, 2007; 13(15): 4487 - 4494. [Abstract] [Full Text] [PDF]

				R. Harrop, N. Connolly, I. Redchenko, J. Valle, M. Saunders, M. G. Ryan, K. A. Myers, N. Drury, S. M. Kingsman, R. E. Hawkins, et al. Vaccination of Colorectal Cancer Patients with Modified Vaccinia Ankara Delivering the Tumor Antigen 5T4 (TroVax) Induces Immune Responses which Correlate with Disease Control: A Phase I/II Trial. Clin. Cancer Res., June 1, 2006; 12(11): 3416 - 3424. [Abstract] [Full Text] [PDF]

				Y. Jounaidi, C.-S. Chen, G. J. Veal, and D. J. Waxman Enhanced antitumor activity of P450 prodrug-based gene therapy using the low Km cyclophosphamide 4-hydroxylase P450 2B11. Mol. Cancer Ther., March 1, 2006; 5(3): 541 - 555. [Abstract] [Full Text] [PDF]

				C.-S. Chen, Y. Jounaidi, and D. J. Waxman ENANTIOSELECTIVE METABOLISM AND CYTOTOXICITY OF R-IFOSFAMIDE AND S-IFOSFAMIDE BY TUMOR CELL-EXPRESSED CYTOCHROMES P450 Drug Metab. Dispos., September 1, 2005; 33(9): 1261 - 1267. [Abstract] [Full Text] [PDF]