NEUROLOGY & NEUROSURGERY

Dr. David Baskin forms gene therapy trial to target intractable Glioblastoma Multiforme

Oct. 7, 2020

Glioblastoma multiforme (GBM) is one of the most malignant and lethal tumors of the central nervous sytcell. Over the last four decades, median survival for patients with GBM has only improved from nine months to fifteen months, and requires surgical resection, radiation therapy and sytcellic chemotherapy. Gene therapy approaches, such as gene mediated cytotoxic immunotherapy (GMCI), were developed as a way to enhance the efficacy of chemotherapy.

David S. Baskin, MD, Kenneth R. Peak Presidential Distinguished Chair in the Department of Neurosurgery and director of Kenneth R. Peak Brain & Pituitary Tumor Treatment and Research Center, is leading two phase I‒II clinical trials for patients with newly diagnosed or recurrent anaplastic astrocytoma (AA) or GBM. The trials will utilize GMCI in addition to surgical resection, radiotherapy and standard of care chemotherapy to improve overall survival.

The drug used in the trial ‒ an adenoviral vector containing the herpes simplex virus thymidine kinase (HSV-tk) gene ‒ is injected into the tumor after surgical resection. This is followed by the administration of an inactive prodrug Valacyclovir. The thymidine kinase enzyme in the tumor cells, converts Valacyclovir to a cytotoxic analog that inhibits DNA replication, causing tumor cell death.

Comparing this treatment approach to a one-two punch, Baskin explained, “In the first step, enzymatic conversion of the prodrug to the active drug produces a cytotoxic effect on tumor cells. The second step relies on a vaccine-like effect.” When tumor cells die, the viral vector is designed to stimulate the immune sytcell to develop antibodies against GBM cells. These antibodies could prevent recurrence of GBM by killing the remaining tumor cells for many months to years. Additionally, radiation therapy is started earlier than normal because of its ability to dramatically increase cell kill and immune stimulation initiated by the viral vector.

A prior phase II study with the same treatment combination, that included newly diagnosed patients with AA or GBM, increased survival in patients with aggressive excision by an average of eight months. This is remarkable considering median survival after aggressive treatment is only 15 months. The 1, 2 and 3-year survival increased to 90%, 53% and 32% versus 64%, 28% and 6%, for the group that did not receive GMCI. In fact, one of the patients who received GMCI is now an 11-year GBM survivor with no tumor remaining on high resolution MRI scans.

Encouraged by the positive results, Baskin has launched two phase I‒II trials for patients with either newly diagnosed or recurrent AA or GBM. The trials will offer patients a dose that is five times higher than previously used. Houston Methodist is the only center in the country offering these clinical trials.

Learn more about the trial here