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 grade gliomas. 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. We propose 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 RRV susceptible and resistant sub-populations. Our first RRV, Toca 511, delivers an optimized yeast cytosine deaminase (CD) gene. The CD enzyme converts the prodrug 5-fluorocytosine (5-FC) into the cytotoxic drug, 5-fluorouracil (5-FU) directly within the infected cancer cells. With consortium of collaborators in neurosurgery and neuro-oncology at UCLA, UCSF, UCSD, Ohio State, Cleveland Clinic, and the Henry Ford Health System, Toca 511 has entered Phase I investigational clinical trials for patients with recurrent high-grade glioma (rHGG) (www.clinicaltrials.gov: NCT01156584 and NCT01470794) in combination with Toca FC (an extended- release formulation of 5-FC). Proof of mechanism and preliminary evidence of therapeutic benefit has been observed in patients with rHGG. To more fully optimize the treatment, we propose to directly test the relationship between vector spread and dose and timing of prodrug using available PET imaging techniques. We have constructed a Herpes simplex thymidine kinase (HSV-TK) version of our platform RRV (RRV-TK). In combination with its prodrugs ganciclovir (GCV) or valacyclovir (VCV), non-invasive real-time monitoring of vector biodistribution and intratumoral spread can be performed in vivo by PET imaging methods using 18-F FHBG. HSV-TK, GCV, and VCV have established clinical safety profiles, so this work can be directly translated into clinical studies either alone or in combination with our Toca 511 investigational product. We plan to investigate the use of PET imaging as a modality to monitor RRV intratumoral spread and TK prodrug activator gene activity, and in combination with bioluminescence imaging-based methods to monitor tumor growth or recurrence, to use this information to guide the timing of pro-drug administration. The insights obtained from these studies will be used to guide the development of analogous prodrug scheduling regimens using MRI-based tumor size and PET-based vector spread criteria for use in future clinical trial protocols. We also anticipate that this technology in conjunction with conventional transcriptional array data for tumors, will allow determination of whether there are RRV resistant tumor subtypes.
We have devised a new approach, using replicating viruses to achieve highly efficient gene transfer of a prodrug converting enzyme to tumor cells in a highly selective manner (i.e., the virus is selective for cancer cells and will not infect normal cells). he infected tumor cell becomes a virus-producing cell, sustaining further infection. When a prodrug is then taken, infected cells convert the prodrug into an active chemotherapy agent resulting in tumor killing. Our first vector is being tested in two multi-center clinical trials in patients wit brain tumor. This vector is not easily measurable with existing technology. This proposal seeks to develop a noninvasive way to track the spread of vector and to use this information to appropriately time the oral administration of the prodrug to maximize tumor killing, or to identify RRV susceptible and resistant sub-populations. We have developed a second vector that has the potential to be tracked using existing PET imaging. We will compare spread, activity, and tumor growth to guide the timing of prodrug administration. If successful in these preclinical 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.
