PROJECT SUMMARY/ABSTRACTHepatocellular carcinoma (HCC) is an orphan disease in the United States with an estimated incidence of 28,720 casesand prevalence of 35,557 cases in 2012. Most patients with HCC cannot undergo potentially curative treatments such assurgery or transplantation. In patients with advanced disease and for those in whom loco-regional therapy is no longerfeasible, sorafenib is the only available FDA approved therapy. No known effective therapies are available to patientsresistant/intolerant to sorafenib, and as such there is a clear unmet medical need. This proposal involves the conduct ofa first-in-human study of vesicular stomatitis virus with human interferon beta gene insert (VSV-hIFN-B) in patients withadvanced hepatocellular carcinoma (HCC) who are refractory/intolerant to sorafenib based therapies. The innovativeaspects of the proposal are to utilize a recombinant oncolytic vector that has multiple favorable characteristics. Theseinclude: 1)low prevalence of human infection in the general population to wild type vesicular stomatitis virus (VSV),2)rapid replication kinetics, 3)inability of VSV to integrate into host genome, 4)broad tropism for mammalian cells,5)differential sensitivity of tumor cells to VSV due to preponderance of defective type I interferon pathways in tumorsand 6) multifaceted mechanism of action including CD4+/CD8+, NK cell mediated anti-tumor activity and direct cytolysis.Insertion of the human interferon beta (hIFN-B) allows for attenuation of the wild type vector and subsequent reductionof risk of neurotoxicity while maintaining anti-tumor efficacy. An added feature to the transgene insert is the potentialfor CD4+/CD8+ mediated anti-tumor efficacy. Preclinical studies conducted with VSV-hIFN-B by our group and by otherswith wild type VSV and other VSV constructs, have demonstrated potent anti-tumor activity in both in vitro and in vivoHCC models. This encouraging preclinical data formed the basis for our group to conduct formal GLP toxicology studiesin rats and Rhesus macaques. A starting dose for first-in-human studies was established in this context (105 TCID50[Tissue Culture Infective Dose 50]). The current proposal entails the conduct of a first-in-human study of VSV-hIFN-Bdelivered as single as well as multiple intra-tumoral injections in sorafenib refractory/intolerant patients with advancedHCC. A '3+3' dose escalation schema will be utilized with 0.6log increments. Objectives for the study include : 1)Determination of the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), recommended phase II dose(RP2D) and observation for evidence of antitumor activity, 2) Assessment of the pharmacokinetic (PK),pharmacodynamic (PD) and biodistribution (BD) properties of the agent will be performed. PK will be assessed bymeasuring VSV-hIFN-B in PBMCs and tumor serially by RT-qPCR. PD assessments are hIFN-B and VSV antibody detection.BD will entail assessment of VSV-hIFN-B in blood, saliva, feces and urine by RT-qPCR and infectious virus recovery withVero cell assay. and 3) From a translational perspective, immunological assessments entail measuring T cell response,both CD4+ and CD8+ and also innate immune response mediated by NK cells. Given the differential between normal andtumor tissue with regards to ability to mount type I interferon response, we will also measure the transcriptionaldynamics of VSV-hIFN-B using serial assessment of whole transcriptome sequencing (RNASeq). Conduct and completionof this study will allow for further studies investigating alternate routes of delivery (intravenous and trans-arterialinfusion) and combination with existing therapies such as trans-arterial chemoembolization (TACE) andimmunotherapeutics such as anti-CTLA4/anti-PD1 antibodies.
|Effective start/end date||8/15/14 → 7/31/18|
- U.S. Food and Drug Administration: $199,522.00