Replacing Defective p53 Gene May Slow Progression of NSCLC
SAN DIEGO--A therapy for advanced lung cancer patients who have not responded to other treatments is showing promise in studies at M.D. Anderson Cancer Center. In this phase I trial, 18 patients with non-small-cell lung cancer (NSCLC) and missing or defective copies of the tumor-suppressor p53 gene have received injections directly into their tumors of an adenovirus containing the p53 wildtype gene.
SAN DIEGO--A therapy for advanced lung cancer patients who have notresponded to other treatments is showing promise in studies at M.D. AndersonCancer Center. In this phase I trial, 18 patients with non-small-cell lungcancer (NSCLC) and missing or defective copies of the tumor-suppressorp53 gene have received injections directly into their tumors of an adenoviruscontaining the p53 wildtype gene.
Most of the patients had previously failed almost all traditional therapies,including chemotherapy and radiation therapy. "It was a difficultpopulation to look at," Stephen G. Swisher, MD, said at the AmericanAssociation for Cancer Research annual meeting.
Patients received varying dosages once a month for up to six months."We were especially interested in later gene deliveries," Dr.Swisher said, to look not only for late responses but also for the possibleneutralizing effects of viral-induced antibodies that may develop withsubsequent injections.
Indeed, the study showed a definite rise in antibody levels after thefirst treatment. "The average serum antibody level rose from 1:700before treatment to approximately 1:25,000 following treatment. This wasa dramatic rise, and it was maintained throughout the treatment period,"he said. Despite the high antibody levels, the researchers saw minimaltoxicity associated with injection of the disabled cold virus.
"We saw maybe a transient fever that would occur after the injectionand last about 24 hours," Dr. Swisher said. He speculated that themild toxicity could be explained, in part, because the treatment was alocal, regional delivery into the tumor rather than systemic.
The high antibody levels also did not appear to interfere with expressionof the wildtype p53 gene. Biopsies of the lung tumors, before and aftertreatment, were analyzed for vector DNA by polymerase chain reaction (PCR)and for gene expression by RT (reverse transcriptase)-PCR and immunohistochemistry.
"We clearly saw evidence of the adenoviral vector within the tumortissue in the majority of patients with evaluable samples, even with subsequentserial dosages," Dr. Swisher said. "We were also able to seetrans gene expression both with immunohistochemistry and RT-PCR. .. . The tumor cells were able to express this wildtype p53 even in theface of high antibodies."
Dosages were escalated from 106 pfu (plaque forming units)in log increments to 109 pfu, and there did appear to be a dose-responseeffect. Four of the six patients who received the highest doses experienceddisease stabilization and another had a partial response.
"The numbers at this time are too small to look at response correlations,"warned study head Jack A. Roth, MD. "We don't want to emphasize responserates in a phase I study."
Dr. Roth said he was especially encouraged by the finding that "replacementof a single genetic defect is able to drive the apoptotic process in cancercells. While further research is required, we believe this may prove tobe an advantage in our ability to fine tune or control p53-mediated apoptosis."
The Texas researchers are currently in the late planning stage for aphase II trial, expected to include about 100 patients.
Eric Ko on Combining Radiation Therapy With Immunotherapy to Treat Non–Small-Cell Lung Cancer
September 18th 2018ONCOLOGY spoke with Eric Ko, MD, PhD, who recently published a review article with his colleagues on strategies for combining radiation therapy with immunotherapy for the treatment of non–small-cell lung cancer.
