By Debbie Strickland
Special To BioWorld Today
ATLANTA ¿ Several gene therapy approaches to cancer ¿ genes encoding tumor suppressors, immunogenic proteins and even a multidrug resistance gene ¿ were among the highlights of the American Society of Clinical Oncology¿s 35th annual meeting here, which concluded Tuesday.
¿The research here is incremental,¿ said Frank Haluska, a researcher with Massachusetts General Hospital who is investigating genetic therapy treatments for melanoma. ¿I think we¿re making progress. The techniques are becoming more refined, our delivery vehicles have been studied much more. We have reached the jumping-off point for broader application of gene therapy in cancer.¿
¿This is all solid work, making very specific points toward the potential use of these therapies in the future,¿ said Michel Sadelain, a researcher with Memorial Sloan-Kettering Cancer Center, who led a symposium on gene therapy. ¿These are mostly Phase I trials demonstrating safety and proof of concept.¿
Haluska was particularly intrigued by a pair of studies that isolated stem cells, inserted the MDR1 gene into them and reinfused them into patients. MDR1 is switched on, and used most often by kidney, colon and liver cells to help those organs excrete toxic compounds. Cancer cells, however, have learned how to turn on the gene to protect themselves against chemotherapy.
In the National Cancer Institute¿s proof-of-principle trial, the stem cells were removed from 10 breast cancer patients. The MDR1 gene was inserted in one-half of each patient¿s stem cells, and the other half received a ¿dummy¿ control gene.
In six patients for which data are available, the NCI¿s lead researcher, Kenneth Cowan, reported that the MDR1 gene had ¿become incorporated in the white blood cells¿ in all of the patients, while the control gene was detected in only three patients. There was further evidence that MDR1-altered stem cells began populating the bone marrow.
In a separate study conducted at the Indiana University School of Medicine in Indianapolis, researchers achieved ¿a high rate of gene transfer into long-term repopulating hematopoietic progenitor cells and engraftment of these cells.¿
Both studies used Nexell Therapeutics Inc.¿s Isolex CD34+ stem-cell selector, for which a marketing application is pending at the FDA.
The ex vivo work makes for good proof-of-principle studies, Haluska said, because ¿the hurdles for grafting onto those [stem cell selection] procedures are minimal.¿
Of course, he added, ¿ultimately the application we would all like to see is application to systemic disease, but we have to understand [use of gene therapy] ex vivo and in local disease first.¿ An example of the latter, he noted, is the Phase II trial of p53 gene therapy in head and neck cancer, presented at ASCO by Introgen Therapeutics Inc., of Austin, Texas, and RPR Gencell, of Collegeville, Pa. (See BioWorld Today, May 18, 1999, p. 4.)
Transgene SA, of Paris, described progress made with two trials, one a Phase I trial in prostate cancer, the other a Phase II in metastatic breast cancer. Both utilized a vaccinia virus vector to deliver genes for MUC1 (which is overexpressed in breast malignancies) and interleukin-2.
¿Because vaccinia is a big virus, we can put in MUC1 or IL-2,¿ said Michael Ross, vice president of medical and regulatory affairs. ¿It¿s an ideal vector to infect muscle cells to produce MUC1, and what we¿re hoping to do is induce immunity that can go through the body.¿
The Phase II trial has reached full enrollment at 31 patients, and while the study is not complete, Ross noted that one patient¿s hepatic metastases have regressed, while other patients¿ tumors appear to have stabilized.
Vical Inc., of San Diego, also released gene therapy news at ASCO, reporting preliminary results from a Phase II trial of Leuvectin in metastatic renal cell carcinoma.
The trial will enroll up to 80 patients who have had their primary tumor(s) removed, and for whom additional surgery would not be curative. Leuvectin, which delivers a gene encoding interleukin-2 and is injected directly into tumors, is administered on an outpatient basis.
Four of the 22 evaluable patients (18 percent) enrolled to date experienced significant tumor reductions, including one patient who experienced 90 percent and 100 percent reductions in two non-injected tumors. Twelve additional patients (55 percent) had stabilization of the injected tumor for six to 28 weeks and continuing. Six of the 22 patients (27 percent) experienced clinical stable disease for five to seven months and continuing.