|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 22, No 6 (March 15), 2004: pp. 1162-1163 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.235
Doomed Trials for Promising AdenovirusesA Rationale for Success
Medical Oncology Department and Molecular Oncology Unit, Hospital Universitario La Paz, Universidad Autónoma de Madrid, Madrid, Spain To the Editor: In the June 15, 2003, issue of the Journal of Clinical Oncology, Pagliaro et al [1] reported their experience with intravesical Ad5CMV-p53 in bladder cancer, reporting a safe profile and a more than doubtful antitumor effect, with discouraging results in the pathologic correlative studies. An accompanying editorial [2] emphasizes the need for additional research in the field. Repeatedly, results from gene therapy trials for human cancer have yielded similarly poor data, depicting a gloomy horizon for this treatment strategy [3]. The Pagliaro et al study merits recognition for the multidisciplinary efforts, the wisdom in the choice of a proper clinical context, and the ambition to undertake biologic evaluations. However, a number of considerations could have anticipated the negative results obtained in this and many other trials. Perhaps gene therapy is not ready to score against cancer, but recent developments in the field deserve to be tested very thoughtfully in clinical trials. Ten of 13 patients' cases were staged as invasive disease (ie, at least invasion of the bladder muscle). Thus, the vector should have been able, upfront, to target this location. At this time we know that regular replication-defective adenoviruses (Ads), as Ad5CMV-p53, are crippled to accomplish this goal [4]. Bladder cancer, like most tumors, has low levels of coxackie-adenovirus receptor, resulting in low Ads transduction efficiencies [5]. Intracavitary therapy offers the opportunity to locally overcome this natural tumor resistance, but only in the exposed neoplastic cells. The authors stated that they had previously reported high luciferase expression in mouse bladder tissues after adenoviral intravesical administration [6] and that Kubal et al [7] had shown deep viral transgene expression in human bladder cancer with the same route of delivery. However, immunohistochemistry studies—evaluation of luciferase expression from tissue grindings do not provide topological evidence of viral penetration—have shown that although defective Ads transduce the outer layers, they do not spread beyond this limit. Kuball et al [7] had previously reported strong vector-specific signal through the whole urothelium by in situ polymerase chain reaction, using an interesting approach consisting of the coadministration of a transduction-enhancing agent (eg, polyamines or BigCHAP) not used by Pagliaro et al. Amplification of the Ad effect is essential for cancer therapeutics. Other examples include the use of transductionally modified Ads that incorporate arg-gly-asp (RGD) motifs in the fiber knob, very efficiently redirecting Ad infection to secondary integrin receptors. Moreover, conditionally replicative adenoviruses (CRAds), such as ONYX-015, D24, and many others, offer excellent amplification possibilities through preferential replication in tumor cells. In addition, the incorporation of toxic transgenes can be very useful if they possess the so-called bystander effect, killing surrounding noninfected cells [8]. Perhaps higher Ad doses could be administered after premedication with drugs like clodronate [9], capable of preventing the viral particle associated acute toxicity in animal models. Concerning the antitumor effect, it seems unlikely that, even with a 100% tumor transduction, the correction of a single major genetic alteration, such as a p53 mutation, could circumvent the redundant survival pathways activated in cancer. Suicide or immunomodulatory transgenes, for example, seem to be exceedingly more attractive payload approaches. It also would have been interesting to investigate the levels of antibodies against Ads, of CAR receptors in tumor samples, and the mutational status of p53 in every patient. Immunohistochemical overexpression of p53 confers a worse prognosis in bladder cancer but does not necessarily correlate with a nonfunctional protein. Finally, although chemotherapy and radiotherapy were not administered by Pagliaro et al, we would like to emphasize that these natural partners in therapeutic combos have to be carefully integrated. A suitable time schedule and the selection of proper drugs are elements that have been largely forgotten in other studies. Gene therapy had a rocky start in the new millennium. The early 1990s were thought to be the best of times for gene therapy. But early hopes were frustrated by the many steps necessary to produce success, as with major achievements in every field, such as space exploration, with the first moon landing. In this way, we have learned many lessons and also can guess new routes. Newborn cancer gene therapy trials will not be doomed to failure if they are bred in our clinical and scientific experience—as they deserve. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest. REFERENCES
1. Pagliaro LC, Keyhani A, Williams D, 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 21:2247-2253, 2003
2. Connell PP, Weichselbaum RR: Gene therapy: The challenges of translating laboratory research into clinical practice. J Clin Oncol 21:2230-2231, 2003 3. Cusack JC Jr: Clinical trials for cancer gene therapy. Surg Oncol Clin N Am 11:717-825, 2002[Medline] 4. Gomez-Navarro J, Curiel DT, Douglas JT: Gene therapy for cancer. Eur J Cancer 35:2039-2057, 1999 5. Sachs MD, Rauen KA, Ramamurthy M, et al: Integrin alpha(v) and coxsackie adenovirus receptor expression in clinical bladder cancer. Urology 60:531-536, 2002[CrossRef][Medline] 6. Wood M, Perrotte P, Onishi E, et al: Biodistribution of an adenoviral vector carrying the luciferase reporter gene following intravesical or intravenous administration to a mouse. Cancer Gene Ther 6:367-372, 1999[CrossRef][Medline]
7. Kuball J, Wen SF, Leissner J, et al: Successful adenovirus-mediated wild-type p53 gene transfer in patients with bladder cancer by intravesical vector instillation. J Clin Oncol 20:957-965, 2002 8. Alemany R, Balague C, Curiel DT: Replicative adenoviruses for cancer therapy. Nat Biotechnol 18:723-727, 2000[CrossRef][Medline] 9. Kuzmin AI, Finegold MJ, Eisensmith RC: Macrophage depletion increases the safety, efficacy and persistence of adenovirus-mediated gene transfer in vivo. Gene Ther 4:309-316, 1997[CrossRef][Medline]
Related Article
Related Editorial
Related Reply
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
