San Diego, CA, United States
San Diego, CA, United States

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Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 269.02K | Year: 2012

DESCRIPTION (provided by applicant): Many strategies for gene therapy of solid tumors involve the use of replication-defective Moloney murine leukemia (MLV)-based retroviral vectors, but efficacy has been limited due to lack of adequate tumor transduction.Gene transfer using replication-competent retroviral vectors would be more efficient, as each transduced tumor cell produces more vectors capable of initiating further infection events. We have devised novel retroviral replicating vectors (RRV) capable ofhighly efficient gene delivery to solid tumor in vivo. We have demonstrated that vector spread is restricted to the tumor itself due to restriction by innate immunity in normal cells, and the intrinsic inability of the virus to infect ost-mitotic normal cells. We have enrolled 17 subjects with recurrent high grade glioma (HGG) in multi-center Phase I trials (www.clinicaltrials.gov:NCT01156584, NCT01470794). The RRV in these studies, Toca 511 (vocimagene amiretrorepvec, or RRV-CD in this proposal), expresses an optimized yeast cytosine deaminase (CD) which converts the prodrug 5-fluorocytosine (5-FC) into the classic chemotherapy drug 5-fluorouracil (5- FU). 5-FU is often used in chemotherapy combinations, but agents that directly inhibit cell proliferationinterfere with vecto spread. We propose to test combinations of different prodrug activator RRV to inhibit tumor without affecting vector spread. This is made feasible by our discovery that RRV infected tumor cells can be reinfected in vivo. We have now constructed RRV expressing an optimized Herpes simplex thymidine kinase (HSV-TK) prodrug activator gene (RRV-TK in this proposal). We propose to perform validation studies with the newly developed RRV-TK vector both in vitro and in glioma models in vivo. Wewill evaluate the potential for dual RRV gene therapy combining RRV-CD and RRV-TK. We will 1) test the transduction efficiency, transgene expression level, replicative stability, and cytotoxic potency of RRV-TK, in vitro and in vivo, and 2) determine the optimal parameters for combination therapy, using both RRV-CD and RRV-TK, in vitro and in glioma models in vivo. The information from these studies will be used to develop future clinical trial protocols and, like combination chemotherapy, offers the potential for synergistic therapeutic benefit and more efficient tumor eradication than single-agent therapy with either vector alone. Furthermore, as the infected tumor cells themselves produce their own chemotherapeutic drugs, the adverse effects of systemic chemotherapy are avoided. PUBLIC HEALTH RELEVANCE: Many researchers have used 'crippled' viruses (termed 'vectors') that can infect and modify tumor cells as cancer therapies. However such therapies have been shown to have only limited beneficialeffects, because too many tumor cells never get infected. We have devised a new approach, using replicating viruses to achieve highly efficient gene transfer to tumor cells in a highly selective manner (i.e., the virus is selective fr cancer cells and willnot infect normal cells). The infected tumor cell becomes a virus-producing cell, sustaining further infection. Our first vector is being tested in a multi-center clinical tril in patients with brain tumor. This proposal seeks to develop a second versionof this type of vector to be used in combination with the first. These two gene therapy vectors cause the cancer cells to produce their own chemotherapy drugs and the second vector potentially enables non-invasive imaging of vector infection of brain tumors. If successful in these preclincial studies, this approach can be translated into the clinic and has the potential to reduce suffering and death in brain cancer patients. It may also be applicable to brain metastases caused by other malignancies.


Grant
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 224.74K | Year: 2014

DESCRIPTION (provided by applicant): Molecular Imaging-Based Monitoring of Tumor-Selective Virus Replication Prodrug activator ('suicide') gene strategies using novel retroviral replicating vectors (RRV) have been developed for the treatment of high gradegliomas. The RRV transduced tumor cells produces more vector capable of initiating further infection events. This ability to spread has the potential to overcome one limitation previously observed with non-replicating vectors. These RRV agents are not directly cytolytic and spread specifically through the replicating cells of the tumor without direct tumor lysis. A second key limitation in the clini has been the inability to assay the extent of RVV spread in these poorly accessible, heterogeneous tumors. Wepropose to use Positron Emission Tomography (PET) as a non-invasive monitoring technique to track the spread of RRV and to use this information to appropriately time the oral administration of the prodrug to maximize tumor killing, or to identify RR


Patent
Tocagen Inc. | Date: 2015-09-02

Provided are methods and compositions useful for detecting viral infection or contamination in a biological sample.


Patent
Tocagen Inc. | Date: 2013-10-24

This disclosure provides a retroviral replicating vector for gene delivery comprising a therapeutic cassette containing at least one mini-promoter linked to a gene to be expressed.


The disclosure provides for one or more immunosuppressive components associated with retroviral replicating vectors (RRVs) that contribute to RRV tumor specificity and efficacy.


Patent
Tocagen Inc. | Date: 2014-09-04

This disclosure provides modified cytosine deaminases (CDs). The disclosure further relates to cells and vector expressing or comprising such modified CDs and methods of using such modified CDs in the treatment of disease and disorders.


Patent
Tocagen Inc. | Date: 2014-05-09

This disclosure provides modified cytosine deaminases (CDs). The disclosure further relates to cells and vector expressing or comprising such modified CDs and methods of using such modified CDs in the treatment of disease and disorders.


Patent
Tocagen Inc. | Date: 2016-02-04

The disclosure describes replication competent retroviral vectors (RCR) for gene therapy and gene delivery. The RCR includes an IRES sequence having 5-6As in A-bulge of the bifurcation region.


Patent
Tocagen Inc. | Date: 2011-03-29

This disclosure provides modified cytosine deaminases(CDs). The disclosure further relates to cells and vector expressing or comprising such modified CDs and methods of using such modified CDs in the treatment of disease and disorders. It further provides use of such modified CDs with a thymosin-alpha-1 polypeptide in the treatment of disease and disorders.


Patent
Tocagen Inc. | Date: 2013-12-20

This disclosure relates to a combination therapy of chemotherapeutics and/or radiosensitizing agents with a replication competent viral vectors for treating cell proliferative disorders and chemotherapeutic treatments. The disclosure further relates to the use of such replication competent viral vectors for delivery and expression of a heterologous nucleic acid in normal and diseased tissues and methods and compositions that facilitate such delivery and expression to tissues in vivo and in vitro. The disclosure further relates to replication competent retroviral vectors for these uses and in conjunction with methods and compositions that facilitate in vivo therapeutics.

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