Retriev Technologies (United States)

Toca 511, a tumor-selective retroviral replicating vector encoding the yeast cytosine deaminase (yCD) gene, exerts direct antitumor effects through intratumoral prodrug 5-fluorocytosine (5-FC) conversion to active drug 5-fluorouracil by yCD, and has demonstrated therapeutic efficacy in preclinical and clinical trials of various cancers. Toca 511/5-FC treatment may also induce antitumor immunity. Here, we first examined antitumor immune responses activated by Toca 511/5-FC treatment in an immunocompetent murine pancreatic cancer model. We then evaluated the therapeutic effects achieved in combination with anti-programmed cell death protein 1 antibody. In the bilateral subcutaneous tumor model, as compared with the control group, enhanced CD8+ T-cell-mediated cytotoxicity and increased T-cell infiltration in Toca 511-untransduced contralateral tumors were observed. Furthermore, the expression levels of T-cell co-inhibitory receptors on CD8+ T-cells increased during treatment. In the bilateral subcutaneous tumor model, combination therapy showed significantly stronger tumor growth inhibition than that achieved with either monotherapy. In an orthotopic tumor and peritoneal dissemination model, the combination therapy resulted in complete regression in both transduced orthotopic tumors and untransduced peritoneal dissemination. Thus, Toca 511/5-FC treatment induced a systemic antitumor immune response, and the combination therapy could be a promising clinical strategy for treating metastatic pancreatic cancer.

Introducción. Los músculos que interaccionan en el complejo glabelar y, por extensión, la frente y las cejas conforman muchas expresiones, entre las que destacan las que sugiere el ceño fruncido. El objetivo del presente trabajo es identificar patrones generales de contracción para realizar tratamientos de relajación muscular de forma precisa con dosis ajustadas de toxina botulínica (TB) a cada uno de ellos para obtener mejores resultados. Material y método. Se ha realizado un estudio clínico sobre 664 pacientes, 583 mujeres y 81 varones, identificando 5 patrones que, en orden de frecuencia, fueron: “V”, “U”, “convergente”, “omega” y “omega invertida”. Todos se han tratado con Abobotulinumtoxin A, ajustando dosis y sitios de inyección a cada patrón. Resultados. Las inyecciones de TB, realizadas de acuerdo con el patrón asignado, han alcanzado resultados más naturales, durante más tiempo y con un alto grado de satisfacción para los pacientes. No se registraron efectos adversos, salvo los habituales, escasas equimosis y leves asimetrías. Conclusiones. El tratamiento con TB tipo A es más eficaz y preciso cuando se identifican bien los patrones musculares de expresión, requiriendo menos puntos de inyección y con menores posibilidades de difusión hacia músculos adyacentes.

Abstract BACKGROUND Toca 511 (vocimagene amiretrorepvec) is a cancer-selective, retroviral replicating vector encoding a codon optimized, heat stabilized cytosine deaminase that converts Toca FC (extended-release 5-fluorocytosine, 5-FC) into the anticancer agent 5-fluorouracil. Three Ph1 studies in patients with recurrent high grade glioma have demonstrated a tolerable safety profile and encouraging efficacy. METHODS Toca 5 is a multi-national, randomized, open-label Ph3 trial (NCT02414165) of Toca 511 & Toca FC versus standard of care (SOC) options that comprises Investigator’s choice of single agent chemotherapy (lomustine, temozolomide) or bevacizumab in patients who have undergone resection for first or second recurrence of glioblastoma or anaplastic astrocytoma. 403 patients were randomized 1:1 to the Toca arm or the SOC arm and stratified by IDH1 status, KPS, and geographic region. Primary endpoint was overall survival (OS), and secondary endpoints were durable response rate, durable clinical benefit rate, duration of durable response, and 12-month survival rate. The study used group sequential design including 2 interim analyses and 1 final analysis, and the stratified log-rank test are used for the analysis. RESULTS 271 events were observed for this analysis. Median follow-up was 22.8 months, and the Toca arm missed the primary endpoint (OS) compared to the SOC arm (11.1 months median compared to 12.2 months, HR=1.06, p=0.6154). All secondary endpoints showed no meaningful difference between the arms of the trial. The safety, tolerability and adverse event profile of Toca 511 and Toca FC was as expected for this patient population, with low incidences of Grade 3–4 adverse events. Pre-planned subgroup analyses showed compelling OS improvement in patients with secondary recurrence, and favorable trends in IDH1 mutant and AA population. Detailed data will be presented at the time of the conference.

April 24, 2018April 10, 2018Free AccessToca 511 & Toca FC: Evaluation of Durable Response Rate in the Post-Resection Setting and Association with Survival in Patients with Recurrent High Grade Glioma (S23.006)Timothy Cloughesy, Joseph Landolfi, Michael Vogelbaum, Derek Ostertag, Bradley Elder, Bob Carter, Clark Chen, … Show All … , Steven Kalkanis, Santosh Kesari, Albert Lai, Ian Lee, Linda Liau, Phioanh Nghiemphu, David Piccioni, William Accomando, Oscar Diago, Daniel Hogan, Douglas Jolly, Katie Wood, Thian Kheoh, Harry Gruber, Asha Das, and Tobias Walbert Show FewerAuthors Info & AffiliationsApril 10, 2018 issue90 (15_supplement)https://doi.org/10.1212/WNL.90.15_supplement.S23.006 Letters to the Editor

Investigational Toca 511, a retroviral replicating vector, and Toca FC (extended-release flucytosine) are used in combination to target recurrent high grade glioma at resection by transducing the tumor with the gene encoding cytosine deaminase, converting flucytosine to 5-FU intratumorally. Preclinically, additive efficacy with temozolomide, lomustine and radiation therapy has been observed. Patients treated on two protocols (NCT 01156584 and NCT01470794) delivering intracranial Toca 511 and Toca FC were enrolled in a continuation protocol for extended safety observations, which allows Toca FC with investigator's choice of subsequent therapy. Exploratory safety analysis of the combinability of Toca 511 and Toca FC with concurrent subsequent therapy was conducted. Five patients received Toca FC in combination with other therapies. These patients were 37-68 years old; 4 had recurrent glioblastoma and 1 recurrent anaplastic oligodendroglioma. Concurrent therapy was administered for 2 to 10 months, including Toca FC + lomustine (1), lomustine + procarbazine (1), lomustine + bevacizumab (2), sequential bevacizumab + lomustine then bevacizumab + carboplatin (1). Patients reported adverse events (AEs) ranging from Grade 1 to Grade 3. No Toca 511- or Toca FC- related serious AEs were reported. AEs related to Toca 511 occurred in 2 patients: grade 1 fatigue, generalized aching and to Toca FC in 4 patients: grade 1 fatigue, decreased appetite, nausea, constipation, diarrhea; grade 2 heartburn, nausea, vomiting, constipation. Overall survival was 11-30+ months (2 alive as of data cut-off date). Preliminary data suggest that in combination with chemotherapy and/or bevacizumab, Toca 511 and Toca FC are tolerated with a manageable safety profile. Updates with prospectively collected data on treatment with lomustine or bevacizumab will be provided. The safety of combining Toca 511 and Toca FC with multimodality treatment will be further explored in a Phase 1b in newly diagnosed glioblastoma to begin enrollment in 2016.

We developed a Moloney mouse leukemia virus (MLV)-based retroviral replicating vector (RRV), Toca 511, which has displayed tumor specificity in resected brain tumor material and blood in clinical trials. Here, we investigated the interaction between Toca 511 and human host cells, and we show that RRVs do not induce type I interferon (IFN) responses in cultured human tumor cells or cultured human primary cells. However, exogenous type I IFN inhibited RRV replication in tumor cells and induced IFN-regulated genes, albeit at a lower level than in primary cells. Unexpectedly, RRVs did not induce IFN-α production upon incubation in vitro with human plasmacytoid dendritic cells (pDCs), whereas lentivirus vector and heat-treated RRVs did. Coincubation of RRVs with heat-treated RRVs or with lentivirus vector suppressed IFN-α production in pDCs, suggesting that native RRV has a dominant inhibitory effect on type I IFN induction. This effect is sensitive to trypsin treatment. In addition, heat treatment inactivated that activity but exposed an immune-stimulatory activity. The immune-stimulating component is sensitive to deglycosidases, trypsin, and phospholipase C treatment. Experiments with retroviral nonreplicating vectors and virus-like particles demonstrated that the immunosuppressive activity is not associated with the amphotropic envelope or the glyco-Gag protein. In summary, our data provide evidence that RRVs do not directly trigger type I IFN responses in IFN-responsive tumor cells. Moreover, RRVs appear to carry a heat-labile component that actively suppresses activation of cellular innate immune responses in pDCs. Inhibition of IFN induction by RRVs and the reduced response to IFN should facilitate tumor-specific infection in vivo. RRVs have a convincing preference for replicating in tumor cells in animal models, and we observed similar preferences in the initial treatment of human glioblastoma patients. This study investigates the basis for the interaction between RRV and human host cells (tumor versus nontumor) in vitro. We found that RRVs do not trigger an IFN-α/β response in tumor cells, but the cells are capable of responding to type I IFNs and of producing them when stimulated with known agonists. Surprisingly, the data show that RRVs can actively inhibit induction of cellular innate immunity and that this inhibitory activity is heat labile and trypsin sensitive and not attributable to the envelope protein. These data partially explain the observed in vivo tumor specificity.