Atim-17. Investigation of Anti-tumor Cellular Immune Response Elicited by Toca 511 & Toca Fc Therapy in a Recurrent Hgg Phase 1 Trial
Year: 2016
Type: conference-abstract
Abstract: A dose-escalation clinical study (NCT01470794) using a retroviral replicating vector (RRV), Toca 511, in combination with oral Toca FC (extended-release 5-fluorocytosine [5-FC]) is ongoing to evaluate safety and preliminary efficacy of this investigational therapy in patients with recurrent HGG. Toca 511 (vocimagene amiretrorepvec) encodes a yeast-derived, codon-optimized, heat-stabilized cytosine deaminase (CD) that converts 5-FC to the anti-cancer drug 5-FU in infected tumors. This virus replicates preferentially in malignant tissue and may have wide application in cancer therapies. When Toca FC is administered, the infected cells are killed by the 5-FU metabolized from 5-FC by the cytosine deaminase protein. In animal tumor models, as infected cancer cells are killed, the diffusible 5-FU also kills neighboring susceptible cells, including myeloid immune suppressor cells that the cancer has attracted to set up an immune-suppressed tumor microenvironment. The killed cancer cells release molecules, such as DAMPs, PAMPs and TLRs that activate antigen presenting cells against released tumor-specific antigens. These tumor antigens are presented to the otherwise intact immune system in the absence of local tumor immune suppression, leading to a robust anti-tumor immune response that targets tumor specific antigens. In the clinical study presented here, Toca 511 is injected into resection cavity walls at time of tumor resection, and followed with multiple courses of Toca FC. Temporal changes in PBMC populations during treatment were measured. Assays included: subtyping of effector, memory, Treg, and myeloid derived suppressor cell panels by flow cytometry; and specific antitumor activity by assays for tumor reactive peripheral blood monocyte (PBMC). Tumor and blood exome sequencing was performed to assess immunogenic potential of the tumor. Measurement of tumor infiltrating lymphocytes was also performed. A multivariate analysis using immune data and clinical factors will be presented. Clinical data are consistent with the induction of anti-tumor immune responses after Toca-FC administration.
Source: Neuro-Oncology
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
OpenAlex ID: W2586113155