Toca 511 is a novel retroviral replicating vector, encoding a modified yeast cytosine deaminase, administered to recurrent high grade glioma patients in Phase 1 trials by stereotactic, transcranial ...injection into the tumor or into the walls of the resection cavity. A key issue, with little published data, is vector biocompatibility with agents likely to be encountered in a neurosurgical setting. We tested biocompatibility of Toca 511 with: delivery devices; MRI contrast agents, including ProHance supporting coinjection for real time MRI-guided intratumoral delivery; hemostatic agents; biofluids (blood and cerebrospinal fluid); potential adjuvants; and a needleless vial adapter that reduces risk of accidental needle sticks. Toca 511 is stable upon thawing at ambient temperature for at least 6 hours, allowing sufficient time for administration, and its viability is not reduced in the presence of: stainless steel and silica-based delivery devices; the potential MRI contrast agent, Feraheme; ProHance at several concentrations; the hemostatic agent SURGIFOAM; blood; cerebrospinal fluid; and the needleless vial adapter. Toca 511 is not compatible with the hemostatic agent SURGICEL or with extended exposures to titanium-based biopsy needles.
Se presenta el caso clínico de un angiomixoma agresivo, de presentación en un paciente de sexo masculino, con localización presacra, el cual fue diagnosticado e intervenido en el Hospital Militar ...Central de Bogotá. Se realizó un abordaje tipo Kraske con la escisión completa de la lesión y mínimo impacto funcional y estético para el paciente. Esta clase de tumores son extremadamente infrecuentes y predominan en mujeres, con una localización pélvica. La presentación en hombres es aún más exótica, con pocos casos reportados en la literatura. Su manejo obliga a la extirpación completa de la lesión y al seguimiento clínico e imagenológico periódico, dada su alta tasa de recidiva
For many applications, human clinical therapies using retroviral vectors still require many technological improvements in key areas of vector design and production. These improvements include higher ...unprocessed manufacturing titers, complement-resistant vectors, and minimized potential to generate replication-competent retrovirus (RCR). To address these issues, we have developed a panel of human packaging cell lines (PCLs) with reduced homology between retroviral vector and packaging components. These reduced-homology PCLs allowed for the use of a novel high multiplicity of transduction (“high m.o.t.”) method to introduce multiple copies of provector within vector-producing cell lines (VPCLs), resulting in high-titer vector without the generation of RCR. In a distinct approach to increase vector yields, we integrated manufacturing parameters into screening strategies and clone selection for large-scale vector production. Collectively, these improvements have resulted in the development of diverse VPCLs with unprocessed titers exceeding 2 × 107 CFU/ml. Using this technology, human Factor VIII VPCLs yielding titers as high as 2 × 108 CFU/ml unprocessed supernatant were generated. These cell lines produce complement-resistant vector particles (N. J. DePolo et al., J. Virol. 73: 6708–6714, 1999) and provide the basis for an ongoing Factor VIII gene therapy clinical trial.
In the present study, we compared the therapeutic effect of tumor-selective retroviral replicating vectors (RRV) expressing the yeast cytosine deaminase (CD) delivered by convection-enhanced delivery ...(CED) or simple injection, followed by systemic administration of the pro-drug, 5-fluorocytosine (5-FC). Treatment with RRV-CD and systemic 5-FC significantly increased survival in rodent U87MG glioma model in comparison with controls (P<0.01). Interestingly, CED of RRV-CD followed by 5-FC further enhanced survival in this animal model in comparison with intra-tumoral injection of RRV-CD, followed by systemic 5-FC (P<0.05). High expression levels of Ki-67 were found in untreated tumors compared with treated. Untreated tumors were also much larger than treated. CED resulted in excellent distribution of RRV while only partial distribution of RRV was obtained after injection. Furthermore, RRV-CD and CD were also found in tumors from treated rats at study end points. These results demonstrated that RRV vectors may efficiently transduce and stably propagate in malignant human glioma, thereby achieving a significant in situ amplification effect after initial administration. We conclude that delivery of RRV into the glioma by CED provides much wider vector distribution than simple injection, and this correlated with better therapeutic outcomes.
Abstract
Despite advances in screening, colorectal cancer (CRC) remains the fourth most commonly diagnosed cancer and the second leading cause of cancer death for both men and women in the US. ...Approximately one half of patients with CRC develop liver metastases (mCRC). The standard treatment for mCRC is 5-fluorouracil (5-FU) based combination chemotherapy. 5-FU combination chemotherapy has extended the median survival of these patients from 6 to >20 months.
We are pursuing a unique investigational approach to treat cancer via intratumoral production of 5-FU. Patients are first administered Toca 511 (vocimagene amiretrorepvec), a retroviral replicating vector (RRV) which selectively replicates and spreads in malignant cells and encodes an optimized yeast cytosine deaminase (CD) gene. In infected cells, the CD enzyme is expressed and converts 5-FC (flucytosine, an orally available anti-fungal drug) to the anti-cancer drug 5-FU in situ.
The combination of Toca 511 with oral extended release 5-FC (Toca FC) is currently in clinical trials for recurrent High Grade Glioma (NCT01156584, NCT01470794, and NCT01985256). We tested the suitability of this approach for the treatment of mCRC in a mouse syngeneic liver metastasis model. CT-26-luciferase colon carcinoma cells were delivered via intrasplenic injection producing multiple tumor foci within the liver. Toca 511 was then delivered either by intrasplenic or intravenous injection followed by courses of 5-FC. Vector delivery to tumor was monitored by PCR. 5-FC and 5-FU were detected using LC/MS. The effect of treatment with Toca 511 and 5-FC in this mouse model of mCRC will be presented.
Citation Format: Maria E. Rodriguez-Aguirre, Fernando Lopez Espinoza, Bryan Martin, Kader Yadiz, Tiffany T. Huang, Carlos E. Ibanez, Derek G. Ostertag, Noriyuki Kasahara, Harry E. Gruber, Douglas J. Jolly, Joan M. Robbins. Toca 511 gene therapy in combination with 5-fluorocytosine for intratumoral production of 5-fluorouracil in a colon cancer metastasis model. abstract. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 708. doi:10.1158/1538-7445.AM2014-708
During the first three months of pregnancy, the parts of the palate and upper lip normally meet. When this union does not occur, the baby will present cleft lip and / or cleft palate. This type of ...malformation occurs in 1 in every 700 births. The presence of a cleft lip and cleft palate can cause various dental problems such as changes in shape, number, size, dental malposition, as well as developmental defects of enamel. Poor oral hygiene of children with cleft lip and cleft palate may contribute to the high prevalence of dental caries in these patients. We performed comprehensive dental rehabilitation of a female patient of 5 years 4 months old, diagnosed with cleft lip and cleft palate, which initially presented dental malposition, poor hygiene, and irregular shape of the arches and involvement of adjacent teeth to the slit. Strategies have been developed to prevent early childhood tooth decay, which should be considered for inclusion in the protocol of patients with cleft lip and cleft palate. We conclude that an early dental management of such patients, a periodic monitoring of bacterial plaque and instructing parents to good oral hygiene of the patients, reduce caries risk factors in this type of patients, thus favoring treatment operative success.
In this review, we describe technical advancements of retroviral vectors to address issues of safety, titer, and clinical scale manufacturing to produce high-quality retroviral vector preparations ...that have made direct intratumoral administration of cytokine encoding recombinant vectors a feasible cancer therapy in the clinic. We also review possible further advances in retroviral vector design, which may prove important in expanding these clinical applications.
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