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

  • Despite promising preclinical studies using oncolytic herpes simplex virus (oHSV) vectors, efficacy in glioblastoma multiforme (GBM) patients has been limited by inefficient virus replication in tumor cells. An HSV retargeting system has now been established that relies on the combination of two engineered viral glycoproteins, gD and gB, to mediate highly efficient HSV infection exclusively through recognition of the abundantly expressed epidermal growth factor receptor (EGFR) on glioblastoma cells. Treatment of orthotopic primary human GBM xenografts demonstrated prolonged survival with up to 73% of animals showing a complete response as confirmed by magnetic resonance imaging. (Uchida et. al., Mol Ther. 2013 Mar;21(3):561-9.)
  • Oncolytic poxviruses have demonstrated initial promising results in patients with cancer in clinical trials, yet further improvements are needed. A new oncolytic poxvirus (designated vA34R) has been genetically engineered by incorporating a mutated A34R gene into a viral backbone (vvDD), which was designed for tumor-selective replication. This rationally designed virus can evade neutralization from antipoxvirus antibodies and is highly cytotoxic to cancer cells. It demonstrates improved spread and increased replication within the peritoneal cavity resulting in improved antitumor effects in a peritoneal carcinomatosis (PC) model of MC38 colon cancer. Impressively, after carrier cell-mediated delivery in the preimmunized host, vA34R displayed high replication in tumor nodules yet low accumulation in normal tissues thus enhancing the therapeutic index leading to 70% long-term cures. (Thirunavukarasu et al., Mol Ther. 2013 May;21(5):1024-33.)
  • The combination of an oncolytic virus, that directly destroys tumor cells and mediates an acute immune response, with an immune cell therapy, capable of further enlisting and enhancing the host immune response, has the potential to create a potent therapeutic effect. A novel therapeutic was created, consisting of an immune cell (cytokine-induced killer, CIK) preloaded with an oncolytic virus that is extracellular enveloped viral (EEV)-enhanced, and therefore better adapted to spreading within a host. Direct interactions between the viral and immune cell components enabled cooperative homing to the tumor and enhanced antitumor effects. (Sampath et. al., Mol Ther. 2013 Mar;21(3):620-8.)

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