University of Pittsburgh Cancer Institute (UPCI)

Viral Vectors and Gene Therapy (VVGT)

DNA StrandThe CVP has a long-standing research interest in viruses as delivery vectors for cancer-specific antigens to enhance immunologic therapies, and to develop novel oncolytic viral therapeutics. VVGT researchers extensively collaborate and interact with faculty in other CVP research areas such as the ARM group, as well as other UPCI programs such as the Cancer Immunology Program (CIP).

Selected Publications

  • Here we demonstrate that the cross-talk between cancer-associated fibroblasts (CAFs) and cancer cells leads to enhanced growth of oncolytic virus (OV)-based therapeutics. Transforming growth factor-β (TGF-β) produced by tumor cells reprogrammed CAFs, dampened their steady-state level of antiviral transcripts and rendered them sensitive to virus infection. In turn, CAFs produced high levels of fibroblast growth factor 2 (FGF2), initiating a signaling cascade in cancer cells that reduced retinoic acid-inducible gene I (RIG-I) expression and impeded the ability of malignant cells to detect and respond to virus. In xenografts derived from individuals with pancreatic cancer, the expression of FGF2 correlated with the susceptibility of the cancer cells to OV infection, and local application of FGF2 to resistant tumor samples sensitized them to virotherapy both in vitro and in vivo. An OV engineered to express FGF2 was safe in tumor-bearing mice, showed improved therapeutic efficacy compared to parental virus and merits consideration for clinical testing. (Nat Med. 2015 May;21(5):530-6.)
  • Oncolytic HSV vectors (oHSVs) are attenuated lytic viruses that have shown promise in the treatment of human glioblastoma multiforme (GBM) models in animals, but their efficacy in early phase patient trials has been limited. We engineered four copies of the recognition sequence for miR-124 into the 3'UTR of the essential ICP4 gene to protect healthy tissue against lytic virus replication; miR-124 is expressed in neurons but not in glioblastoma cells. Following intracranial inoculation into nude mice, the miR-124-sensitive vector failed to replicate or show overt signs of pathogenesis. To address the concern that this safety feature may reduce oncolytic activity, we inserted the miR-124 response elements into an unattenuated, human receptor (EGFR/EGFRvIII)-specific HSV vector. We found that miR-124 sensitivity did not cause a loss of treatment efficiency in an orthotopic model of primary human GBM in nude mice. These results demonstrate that engineered miR-124 responsiveness can eliminate off-target replication by unattenuated oHSV without compromising oncolytic activity, thereby providing increased safety. (Mazzacurati et. al., Mol Ther. 2015 Jan;23(1):99-107.)

Members

Section Leader: Stephen Thorne, PhD

Gambotto, Andrea, MD
Surgery
Grandi, Paola, PhD
Neurological Surgery
Glorioso, Joseph, PhD
Microbiology and Molecular Genetics
Thorne, Stephen, PhD
Surgery