Novel Gene Therapy Effective for High-Grade Gliomas

Toca 511 is a retroviral replicating vector and it is being combined with oral Toca FC, which is extended-release 5-fluorocytosine (5-FC). Toca 511 (vocimagene amiretrorepvec) encodes a cytosine deaminase (CD) that is yeast-derived, codon-optimized, and heat-stabilized. Toca 511 converts 5-FC to the anticancer drug 5-fluorouracil (5-FU) in infected tumors. This phase I study is seeking to determine the highest tolerated doses and the viral pharmacokinetics of these agents in patients who have recurrent high-grade glioma.

“Toca 511 delivers the prodrug activator gene cytosine deaminase. CD converts 5-FC to 5-FU. Though 5-FU has a very short half-life, it affects direct cell killing and impacts the cancer microenvironment in a localized manner,” said lead author Timothy Cloughesy, MD, director of the Neuro-Oncology Program at the University of California Los Angeles. 5-FU kills the tumor and also activates the immune system against the cancer.

In this open-label phase I study, Toca 511 was administered intravenously over 1, 3, or 5 days in 17 patients. Subsequently, tumors were resected and then Toca 511 was injected into the resection cavity walls. Then, 6 weeks later, Toca FC was administered for 7 days every 6 weeks.

Eligible patients had to have a resection of at least 80% planned, be aged 18 to 80 years old, and have a Karnofsky performance score of at least 70. The 17 enrolled patients had a median age of 52 years (range, 28-77) and 8 (47.1%) were male. Baseline Karnofsky performance scores were 70 to 80 in 3 patients (17.7%) and 90 to 100 in 14 patients (82.4%).

The initial tumor histologies of the enrolled patients were glioblastoma multiforme in 14 (82.4%), anaplastic astrocytoma in 1 (5.9%), and anaplastic oligoastrocytoma in 2 (11.8%). Their number of recurrences, including their current recurrence, was 1 recurrence in 8 patients (47.1%), 2 in 3 patients (17.6%), and 3 or more in 6 patients (35.3%).

The combination of intravenous and intracranial Toca 511 was generally well tolerated. Vasogenic edema of at least grade 3 occurred in 1 patient in the 3-day IV cohort; it was consistent with intracranial inflammation or rapid tumor progression. The patient experienced a related grade 3 cerebral cyst.

Additionally, 2 patients (11.8%) experienced grade 1/2 pyrexia, 2 patients (11.8%) experienced grade 1/2 malaise, and 1 patient (5.9%) experienced grade 1/2 vasogenic edema. No treatment-related deaths were reported.

The only dose-limiting toxicity was the grade 3 vasogenic edema, but, notably, it occurred 33 days after the surgery and intracranial Toca 511 injection and prior to the Toca FC treatment.

When the resected tumor samples were examined, viral DNA was found in 13 of 17 (76%). The amount of viral DNA was dose-dependent, as it was detected in 3 of 5 (60%) subjects who received the 1-day delivery, in 7 of 9 (78%) subjects who received the 3-day delivery, and in all 3 (100%) patients who received the 5-day delivery. Quantifiable DNA was found in 8 of 17 (47%) subjects overall, which included 1 of 5 (20%) in the 1-day, 5 of 9 (56%) in the 3-day, and 2 of 3 (67%) in the 5-day cohorts.

Transgene expression was detected by IHC, which indicated that approximately 50% of dividing cells were transduced by Toca 511. At 5 weeks after the Toca 511 injection, viral RNA could not be detected in the blood at levels above the lower quantification limit.

Independent radiology reviews of 11 subjects found 1 radiological complete response (with an unrelated stroke) and 2 patients with stable disease. Cloughesy shared scans of a patient with glioblastoma multiforme who had a complete response after 12 cycles and has remained alive for more than 2 years.

The median OS was 13.6 months (95% CI, 5.8-20.6). This compares favorably with historic data, noted Cloughesy.

“Overall survival preliminarily looks interesting when compared with historical benchmarks,” stated Cloughesy. “Preliminary overall survival data is encouraging.”

A phase Ib trial has been initiated to investigate IV Toca 511 in solid tumors (NCT02576665). This study will include brain metastases from breast cancer and NSCLC, colorectal cancer with liver metastases, metastatic renal cell carcinoma, locally advanced or recurrent melanoma, and locally advanced or metastatic pancreatic or breast cancer.

Cloughesy C, Walbert T, Bota D, et al. Successful cancer-selective gene delivery following intravenous Toca 511 delivery in patients with recurrent high grade glioma (HGG). Presented at 2016 SNO Annual Meeting; November 17-20, 2016; Scottsdale, Arizona. Abstract 4.