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Journal of Clinical Oncology, Vol 22, No 6 (March 15), 2004: pp. 1163-1164 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.99.325
In Reply:Department of Genitourinary Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Casado et al comment on the need to anticipate obstacles when designing cancer gene therapy trials and suggest that maybe gene therapy is not ready to score against cancer. We agree that our recent report [1] of a phase I clinical trial of intravesical Ad5CMV-p53 gene therapy sheds light on some significant challenges, but it also points to opportunities that are not so gloomy. We succeeded in demonstrating the safety of repeated intravesical gene therapy at all of the planned dose levels. We also obtained sufficient data from tissue studies to conclude that a replication-defective adenoviral vector does not accomplish efficient gene transfer in this setting. Where do we go from here?
We observed a clinical response in a patient who had evidence of p53 transduction by reverse transcriptase polymerase chain reaction, but did not show changes in p53 or p21 immunostain. He had only superficial bladder cancer (stage Strategies listed by Casado et al (and in our report) for enhancing adenoviral gene therapy for bladder cancer include coadministration of a transfection-enhancing agent, modification of the fiber knob, conditionally replicative adenoviruses, different payload genes, and concomitant treatment with chemotherapy or radiotherapy. We would add to this list the use of nonviral delivery systems [4,5], and each of these strategies should be pursued. For superficial bladder cancer, however, the use of a replication-defective adenoviral vector to deliver immunomodulatory genes, aimed at inducing a large bystander effect, is a rational way to proceed. Most of the patients in our study had muscle-invasive or metastatic tumor. Eligible patients were not surgical candidates and had recurrence after BCG, or had invasive/metastatic disease previously treated with chemotherapy. We targeted patients for whom there was no established curative therapy, as was appropriate for an exploratory trial. In their editorial that accompanied our paper, Connell and Weichselbaum [6] commented that some of the patients could have received chemoradiotherapy [7]. Indeed, our eligibility criteria did not exclude prior radiotherapy, nor were patients discouraged from receiving radiotherapy after gene therapy. We also recognized that bulky tumors, although more amenable to biopsy, were less likely to show clinical benefit from gene therapy than were low-volume tumors. Accordingly, our eligibility criteria required that there be at least one measurable lesion in the bladder, which could be as little as a "patch" of erythema in a bladder with carcinoma in situ. Understandably, however, there were also patients with deeply invasive tumors that would not be fully penetrated by an adenoviral vector. Our study demonstrates that success in this and other phase I clinical trials, for gene therapy and otherwise, does not depend on a "home run" in terms of efficacy but does require careful analysis of biologic end points and the clinical experience to learn from unanticipated outcomes. Author's Disclosures of Potential Conflicts of Interest The author indicated no potential conflicts of interst. 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. Herr HW, Wartinger DD, Fair WR, et al: Bacillus Calmette-Guerin therapy for superficial bladder cancer: A 10-year follow-up. J Urol 147:1020-1023, 1992[Medline] 3. Alexandroff AB, Jackson AM, O'Donnell MA, et al: BCG immunotherapy of bladder cancer: 20 years on. Lancet 353:1689-1694, 1999[CrossRef][Medline]
4. Wu Q, Mahendran R, Esuvaranathan K: Nonviral cytokine gene therapy on an orthotopic bladder cancer model. Clin Cancer Res 9:4522-4528, 2003
5. Sweeney P, Karashima T, Ishikura H, et al: Efficient therapeutic gene delivery after systemic administration of a novel polyethylenimine/DNA vector in an orthotopic bladder cancer model. Cancer Res 63:4017-4020, 2003
6. Connell PP, Weichselbaum RR: Gene therapy: The challenges of translating laboratory research into clinical practice. J Clin Oncol 21:2230-2231, 2003 7. Shipley WU, Kaufman DS, Zehr E, et al: Selective bladder preservation by combined modality protocol treatment: Long-term outcomes of 190 patients with invasive bladder cancer. Urology 60:62-67, 2002[Medline]
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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T1) while on study, although a muscle-invasive tumor had been previously resected (and he was not a candidate for cystectomy). He was clinically disease-free when he died of an unrelated cause, and we attributed his cancer remission to a Bacillus Calmette-Guerin (BCG)–like effect of the adenovirus. This was an unexpected result, and should not be dismissed as negative simply because the level of gene transduction was low. Our data suggest that a replication-defective adenoviral vector is well suited for the delivery of immunomodulatory genes. Indeed, BCG is currently the standard therapy for superficial bladder cancer, exerting a nonspecific immunostimulatory effect through repeated exposure and a low level of infection [
