JCO: Gene therapy + RT safe for patients with brain tumors
Immunogene therapy is safe for treating glioblastomas, even when combined with radiation therapy, according to a report published online Aug. 15 in Journal of Clinical Oncology. The findings suggested that the therapy might also stimulate an immune response against the tumor.
Glioblastomas occur in about 18,500 Americans annually and kill nearly 13,000 of them yearly. Glioblastoma multiforme is the most common and lethal form of the malignancy, with an average survival of 15 months after diagnosis.
The tumors often recur because cancer cells typically migrate into adjacent brain tissue where they can give rise to a recurrent tumor. The study examined an immunogene therapy approach designed to kill undetected cancer cells and prevent recurrence.
The phase 1b trial was conducted at the Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus and at Methodist Hospital in Houston.
The novel treatment uses AdV-tk, an adenovirus vector, taken up by cancer cells where it activates a drug that kills the cells. The vector is applied in the operating room after removing brain tumors.
"This is the first time that a gene therapy approach was combined with radiation in patients with newly diagnosed glioblastoma," said E. Antonio Chiocca, MD, professor and chair of neurological surgery and co-director of the Dardinger Center for Neuro-oncology and Neurosciences at Ohio State.
"There had been a concern that combining these two treatments could be too toxic for patients, but this was not the case. We do not know yet if this will improve survival, but these findings are encouraging," he continued.
This clinical trial involved 10 patients with glioblastoma multiforme and two patients with anaplastic astrocytoma.
After removing the tumor, the neurosurgeon injected the tumor bed with 1 ml of a solution containing the AdV-tk vector, which carried a gene from herpes simplex virus for the thymidine kinase enzyme. Cancer cells infected with the vector began making the enzyme. Patients then took the anti-herpes virus drug valacyclovir for two weeks.
Inside the cancer cells, the herpes thymidine kinase enzyme converted valacyclovir into DNA-building blocks that the rapidly growing cancer cells cannot use to make DNA, and killed them.
Radiation therapy was initiated halfway through the course of valacyclovir. Starting radiation therapy within one week of injection overlapped the therapeutic effects, explained Chiocca et al. The radiation damaged the DNA in the cancer cells, which then tried to repair it, using the toxic valacyclovir building blocks.
The researchers did not observe dose-limiting toxicities with the treatment. However, two adverse events may have been related to AdV-tk.
Patient survival was 33 percent at two years and 25 percent at three years. In addition, patient-reported quality of life assessed with the Functional Assessment of Cancer Therapy-Brain was stable or improved after treatment, according to the authors.
In addition to improved overall survival, studies revealed a significant rise in the number of T lymphocytes in the tumors. This suggests that the gene therapy stimulated an immune response against the tumor, producing an "immunogene therapy" effect.
The study demonstrated that AdV-tk can be safely delivered intracranially and combined with surgery, radiation and chemotherapy and revealed the potential of the combined therapy, concluded the authors.
"If the results of another recently completed phase 2 efficacy trial are also encouraging, the next step will be to compare this therapy head-to-head with the current standard of care," Chiocca said.
Glioblastomas occur in about 18,500 Americans annually and kill nearly 13,000 of them yearly. Glioblastoma multiforme is the most common and lethal form of the malignancy, with an average survival of 15 months after diagnosis.
The tumors often recur because cancer cells typically migrate into adjacent brain tissue where they can give rise to a recurrent tumor. The study examined an immunogene therapy approach designed to kill undetected cancer cells and prevent recurrence.
The phase 1b trial was conducted at the Ohio State University Comprehensive Cancer Center—Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus and at Methodist Hospital in Houston.
The novel treatment uses AdV-tk, an adenovirus vector, taken up by cancer cells where it activates a drug that kills the cells. The vector is applied in the operating room after removing brain tumors.
"This is the first time that a gene therapy approach was combined with radiation in patients with newly diagnosed glioblastoma," said E. Antonio Chiocca, MD, professor and chair of neurological surgery and co-director of the Dardinger Center for Neuro-oncology and Neurosciences at Ohio State.
"There had been a concern that combining these two treatments could be too toxic for patients, but this was not the case. We do not know yet if this will improve survival, but these findings are encouraging," he continued.
This clinical trial involved 10 patients with glioblastoma multiforme and two patients with anaplastic astrocytoma.
After removing the tumor, the neurosurgeon injected the tumor bed with 1 ml of a solution containing the AdV-tk vector, which carried a gene from herpes simplex virus for the thymidine kinase enzyme. Cancer cells infected with the vector began making the enzyme. Patients then took the anti-herpes virus drug valacyclovir for two weeks.
Inside the cancer cells, the herpes thymidine kinase enzyme converted valacyclovir into DNA-building blocks that the rapidly growing cancer cells cannot use to make DNA, and killed them.
Radiation therapy was initiated halfway through the course of valacyclovir. Starting radiation therapy within one week of injection overlapped the therapeutic effects, explained Chiocca et al. The radiation damaged the DNA in the cancer cells, which then tried to repair it, using the toxic valacyclovir building blocks.
The researchers did not observe dose-limiting toxicities with the treatment. However, two adverse events may have been related to AdV-tk.
Patient survival was 33 percent at two years and 25 percent at three years. In addition, patient-reported quality of life assessed with the Functional Assessment of Cancer Therapy-Brain was stable or improved after treatment, according to the authors.
In addition to improved overall survival, studies revealed a significant rise in the number of T lymphocytes in the tumors. This suggests that the gene therapy stimulated an immune response against the tumor, producing an "immunogene therapy" effect.
The study demonstrated that AdV-tk can be safely delivered intracranially and combined with surgery, radiation and chemotherapy and revealed the potential of the combined therapy, concluded the authors.
"If the results of another recently completed phase 2 efficacy trial are also encouraging, the next step will be to compare this therapy head-to-head with the current standard of care," Chiocca said.