12 research outputs found
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Toca 511 and Toca FC in patients with gastrointestinal tumors in the Toca 6 study
TPS880 Background: Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector (RRV). RRVs selectively infect cancer cells due to defects in innate and adaptive immune responses found in cancers that support virus replication, and the requirement for cell division for virus integration into the genome. Toca 511 spreads through tumors, stably delivering an optimized cytosine deaminase (CD) gene that converts the prodrug, Toca FC (investigational, extended-release 5-FC) into 5-FU. 5-FU kills infected dividing cancer cells and diffuses and kills surrounding cancer cells, myeloid derived suppressor cells, and tumor associated macrophages, thus reestablishing tumor immunity (Cloughesy et al. Neuro Oncol 2016). In a Phase 1 study, resected high grade glioma tumors expressed CD protein following intravenous (IV) Toca 511.1 In animal models of metastatic colorectal cancer, IV Toca 511 infected metastatic sites, and subsequent 5-FC treatment resulted in decreased tumor size and improved survival (Yagiz et al. Mol Therapy 2015). Methods: Toca 6 is a Phase 1b, multicenter, open-label study (NCT02576665) that aims to investigate changes in immune activity after treatment with Toca 511 & Toca FC in patients with solid tumors, including gastrointestinal tumors. A total of 30 patients who have advanced malignancies, including colorectal and pancreatic cancer, with molecular characteristics that may increase sensitivity to 5-FU or viral infection, or IDH1 mutated solid tumors (e.g., intrahepatic cholangiocarcinoma) will be enrolled. In these patients, Toca 511 is injected IV daily for 3 days, then intratumorally after biopsy. Oral Toca FC is started ~4 weeks later and repeated every 4-6 weeks. Changes from baseline in intratumoral immune activity (infiltrating T-cell subpopulations, B cells, monocytes) at 4 weeks after start of Toca FC are assessed. Contemporaneous peripheral blood is analyzed for effector, memory, Treg, and myeloid lineage cells. Viral RNA, DNA, and CD protein expression in tumor after IV Toca 511 are measured. Safety and efficacy will be determined. Concomitant checkpoint inhibitor therapy may be given following immune activity assessments. The study has enrolled 3 patients. Clinical trial information: NCT02576665
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Toca 6: A phase 1b study of Toca 511 and Toca FC in patients with advanced solid tumors or lymphoma
Toca 6: A phase 1b study of Toca 511 and Toca FC in patients with advanced solid tumors or lymphoma.
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ATIM-02. SUCCESSFUL CANCER-SELECTIVE GENE DELIVERY FOLLOWING INTRAVENOUS TOCA 511 DELIVERY IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA (HGG)
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ATIM-02. SUCCESSFUL CANCER-SELECTIVE GENE DELIVERY FOLLOWING INTRAVENOUS TOCA 511 DELIVERY IN PATIENTS WITH RECURRENT HIGH GRADE GLIOMA (HGG)
TMOD-15. TOCA 511 & TOCA FC: PRE-CLINICAL PROOF OF CONCEPT IN CNS METASTATIC BREAST CANCER
Toca 511, a clinical-stage retroviral replicating vector (RRV) encoding an optimized yeast cytosine deaminase (CD) prodrug activator gene, in combination with Toca FC (extended-release 5-fluorocytosine (5-FC)), is designed to produce 5-FU which kills cancer cells and immune-suppressive myeloid cells in the tumor microenvironment, leading to anti-cancer immune activation and long term survival. The combination treatment is currently under evaluation in an international Phase 2/3 trial in patients with recurrent high-grade glioma. In the present study, we investigated the feasibility of further applying Toca 511 to brain-metastatic breast cancer, which frequently arises from highly aggressive, treatment-refractory, “triple-negative” (ER(-) PR(-) HER2(-)) disease, and is associated with a dismal prognosis of 4-6 months survival. We first evaluated
in vitro
replication kinetics of RRV encoding the GFP reporter gene in MDA-MB-231-BR (human) and JC (murine) breast cancer cells. After virus inoculation at either M.O.I. of 0.01 or 0.1, high levels of transduction were achieved within 1-2 weeks as measured by flow cytometric quantitation of GFP fluorescence. Next, we tested
in vitro
cytotoxicity by MTS assay after 5-FC treatment of MDA-MB-231BR and JC cells transduced with Toca 511. In both Toca 511-transduced breast cancer lines, cell viability was reduced by approximately 70-85% after exposure to 0.1 mM 5-FC and complete cell killing was observed with 1 mM 5-FC within 4-6 days. In survival studies, animals treated with Toca 511 followed by 5-FC prodrug showed statistically significant (231-BR: p<0.0001, JC: p=0.0003) survival benefit compared to the control group. These data provide preclinical validation for a new Phase Ib trial evaluating RRV-mediated immunotherapy in various types of metastatic malignancies, including CNS-metastatic breast cancer (TOCA 6 trial: clinicaltrials.gov NCT02576665), currently recruiting at the University of Miami
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ATIM-21. INTRAVENOUS DELIVERY OF TOCA 511 IN PATIENTS WITH HIGH GRADE GLIOMA RESULTS IN QUANTIFIABLE EXPRESSION OF CYTOSINE DEAMINASE IN TUMOR TISSUE
Abstract Toca 511 (vocimagene amiretroprepvec) is an investigational, conditionally lytic, retroviral replicating vector that encodes an optimized yeast cytosine deaminase (CD) gene. The CD gene converts the prodrug, Toca FC (investigational, extended-release 5-fluorocytosine), into the chemotherapeutic, 5-FU in infected tumors. In a Phase 1 study (NCT01985256), Toca 511 was injected intravenously for 1, 3, or 5 days to patients with recurrent high grade glioma. Tumors were subsequently resected, and Toca 511 was injected into the resection cavity walls. At the time of resection, tissue from various regions of the tumor was collected and processed for quantitative PCR analysis of CD RNA and DNA. Tissue from corresponding locations was fixed for assessment of CD protein expression by immunohistochemistry (IHC). Expression of CD protein was quantified based on immunofluorescence signal and was shown to co-localize in cells with detectable levels of gag, a viral structural protein. CD protein expression by IHC was assessed in tissue from locations that corresponded with samples positive for CD by PCR and ranged from 1.16% to 10.4% area of the field. These data show that intravenous delivery of Toca 511 results in appreciable deposition of vector in the tumor. Further, we have observed an inverse correlation between T cell infiltrate in the tumor microenvironment and clinical benefit in a complementary Phase I study in which Toca 511 was solely delivered into the resection cavity. Therefore, the nature of the study design described herein, which uses IV delivery of Toca 511, provides a unique opportunity to assess the spatial relationship between CD protein expression and histological features of the tumor. Immunohistochemical assessment to determine spatial correlates between CD protein and T cells, T regulatory cells, and immunosuppressive myeloid cells will be presented. Updated clinical response data will also be presented
Abstract A018: Effects of Toca 511 and Toca FC on tumor microenvironment and peripheral blood populations in patients with advanced malignancies
Abstract Toca 511 (vocimagene amiretrorepvec) is an investigational, conditionally lytic, retroviral replicating vector that selectively infects cancer cells due to cell division requirements for virus integration into the genome, and defects in innate and adaptive immune responses found in malignant tissues that support virus replication. Toca 511 spreads through cancer cells and stably delivers optimized yeast cytosine deaminase (CD) that, upon administration of the prodrug, Toca FC (an investigational, extended-release version of 5-fluorocytosine [5-FC]), converts 5-FC into 5-fluorouracil (5-FU). 5-FU kills infected dividing cancer cells and diffuses to and kills surrounding cells in the tumor microenvironment, including immunosuppressive myeloid cells. In animal models, this depletion of immunosuppressive myeloid cells leads to therapeutically active immunity against tumors. A similarly derived antitumor response may occur in cancer patients, as local injection of Toca 511 into the tumor bed after resection of recurrent high-grade glioma followed by treatment with Toca FC has been associated with prolonged survival and durable complete responses (median duration of follow-up: 37.4+ months); responses were delayed in onset, consistent with time to response for immuno-oncology agents. The current phase 1b, multicenter, open-label study (Toca 6; NCT02576665) is designed to investigate changes in immune activity after treatment with Toca 511 and Toca FC in patients with advanced malignancies. Toca 511 is administered intravenously (IV) daily for 3 days and then as a single injection into metastatic or recurrent tumor. Oral Toca FC is started ~4 weeks later and repeated every 4-6 weeks. Biopsies are obtained prior to and following exposure to Toca 511 and Toca FC treatment to evaluate changes in immune activity, and peripheral blood is obtained contemporaneously for evaluation. The study has enrolled 19 patients to date (colorectal cancer: 15; sarcoma: 2; non-small cell lung and pancreas cancer: 1 each). Treatment has been well tolerated. Viral RNA, DNA, and CD protein expression are observed in tumor after IV delivery of Toca 511. We plan to report on tumor microenvironment remodeling that follows treatment with Toca 511 and Toca FC. Infiltrating T-cell subpopulations, B cells, and monocytes quantified by immunofluorescence from stained formalin-fixed, paraffin-embedded samples will be presented. Additionally, changes in peripheral blood, including T-cell effector, helper/memory, and regulatory populations, and myeloid lineage cells following exposure to Toca 511 alone and following subsequent exposure to Toca FC will be reported. Data from this study will inform future development of Toca 511 and Toca FC alone or in combination with other therapies in patients with solid tumors. Citation Format: Jaime Merchan, Jordi Rodon, Derek Ostertag, Shree Venkat, Arthur Donahue, Peder Horner, Dalissa Tijera, Thian Kheoh, Douglas J. Jolly, Harry E. Gruber, Jolene S. Shorr, Gerald S. Falchook. Effects of Toca 511 and Toca FC on tumor microenvironment and peripheral blood populations in patients with advanced malignancies [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A018