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“Tag Team” Glioblastoma Therapy

2016; Lippincott Williams & Wilkins; Volume: 79; Issue: 6 Linguagem: Inglês

10.1227/01.neu.0000508605.38694.fd

1524-4040

Joslyn K. Strebe, Jonathan A. Lubin, John S. Kuo,

Virus-based gene therapy research

High-grade gliomas (HGGs), including glioblastoma multiforme (GBM), are not effectively treated with current therapies. Cloughesy et al1 recently reported the results of a phase 1 clinical trial treating patients with recurrent HGG with a novel combination of Toca 511 (vocimagene amiretrorepvec) followed by Toca FC (extended release 5-fluorocytosine). Toca 511 is an investigational nonlytic, retroviral replicating vector surgically injected into the walls of tumor resection cavities to deliver a yeast cytosine deaminase gene to replicating cells. Cytosine deaminase expresses an enzyme that converts the prodrug Toca FC (extended-release version of 5-fluorocytosine) to 5-fluorouracil (5-FU). Usually, 5-FU chemotherapy is inefficient at crossing the blood-brain barrier, but the combination of Toca 511 and Toca FC solves this problem because conversion to 5-FU occurs after 5-fluorocytosine has already crossed the blood-brain barrier into Toca 511–infected cells. Because this retroviral replicating vector was designed to depend on cell division for genome integration, it preferentially infects replicating cancer and nearby immune cells; in addition, systemic side effects are minimized because of the short 5-FU half-life and direct Toca 511 injection to infect tumor cells. To test safety and efficacy, Cloughesy et al administered increasing doses of Toca 511 to 45 subjects after surgical resection, followed by Toca FC administration for 7 days every 4 to 8 weeks until radiological tumor progression or clinical progression. These subjects were compared with an external control of subjects receiving standard therapy with lomustine for recurrent HGG. Subjects were divided into cohorts receiving either higher (cohorts 4-7a) or lower (cohorts 1-3) doses of Toca 511, with overall survival (OS) also compared between the 2 groups. There was a trend observed for dose response in OS of 14.4 months for the higher-dose cohort relative to the 11.8 months OS for the lower-dose cohort (Figure, A). Likewise, the OS of subjects receiving Toca 511 and Toca FC was 13.6 months compared with 7.1 months for the lomustine control (Figure, B). OS from initial diagnosis of patients with GBM at the first or second recurrence was 29.2 months compared with 21.3 months in the control group (Figure, C). Few adverse events were reported during the course of the study, and there were no treatment-related deaths. There were also fewer treatment-emergent grade ≥ 3 adverse events relative to the lomustine control, indicating that the Toca 511/Toca FC treatment course has a more favorable safety profile.Figure: verall survival (OS) and comparison of Toca 511 and Toca FC to lomustine. A, OS Kaplan-Meier plot of subjects who have received higher (cohorts 4 to 7a [C4-7a]) vs lower (cohorts 1 to 3 [C1-3]) doses of Toca 511 and Toca FC. NR, not reached. B, OS Kaplan-Meier plot of subjects with GBM at first or second recurrence who received Toca 511 and Toca FC vs the lomustine external control. C, OS Kaplan-Meier plot from the initial diagnosis of subjects with GBM at first or second recurrence treated with Toca 511 and Toca FC vs lomustine external control. Tg 511-11-01 and Tg 11-01 are abbreviations for Toca 511 plus Toca FC treatment. From Cloughesy TF, Landolfi J, Hogan DJ, et al. Phase 1 trial of vocimagene amiretrorepvec and 5-fluorocytosine for recurrent high-grade glioma. Sci Transl Med. 2016;8(341):341ra75. Reprinted with permission from AAAS.HGGs are molecularly heterogeneous, and the different subtypes may contribute to a variation in benefits of the Toca 511/Toca FC treatment. To test for this variability, Cloughesy et al profiled tumor mRNA expression by next-generation sequencing from frozen tissue biopsies taken immediately before Toca 511 administration. Many tumor samples from subjects who survived more than a year after the Toca 511/Toca FC therapy expressed mRNA involved in neuronal functions, called survival-related neuronal subtype. The survival-related neuronal subtype identified in these patients with recurrent GBM is similar to the TCGA neural subtype identified in newly diagnosed HGG tumors, although this subtype is not associated with better survival in newly diagnosed GBM. In summary, the "tag team" therapy combination of Toca 511 and Toca FC treatment showed a favorable safety profile and better OS compared with an external lomustine control. Therefore, an international phase 2/3 trial in patients with recurrent HGG is underway to test this novel, surgically administered retroviral delivery of gene-mediated local tumor chemotherapy.