Armed oncolytic parvoviral vectors for modulating the tumor microenvironment

Abstract public domain (NIH RePORTER)

Abstract:  Armed  oncolytic  viruses  are  an  emerging  therapeutic  strategy  for  many  cancers.  The  parvoviruses  are  the  smallest  viruses  currently  being  developed  as  oncotherapeutic  agents,  and  are  non-­enveloped  and  extremely  rugged,  simplifying  their  production,  purification  and  storage,  as  well  as  enhancing  their  tissue  penetration  properties.    Rodent  protoparvoviruses  can  infect  human  cells  only  if  neoplastically  transformed,  and  thus  are  intrinsically  oncotropic  -­  the  rodent  protoparvovirus  H-­1  is  currently  in  Phase  I/IIA  clinical  trials  against  glioblastoma and pancreatic cancer.  We have developed a replicating, but non-­propagating, parvoviral vector  system,  which  can  be  packaged  into  tumor  cell  target-­enhanced  capsid  selected  in  vitro.    These  dual  transgene  vectors  express  secreted,  soluble  versions  of  murine  or  human  PD-­1  (sPD-­1),  or  an  anti-­CTLA-­4  camelid nanobody, coordinately with the murine co-­stimulatory molecules CD80 or CD48, to render the tumor  cell itself an effective antigen presenting cell.  We will test the hypothesis that the secreted transgene products  will  effectively  block  the  two  major  immune  checkpoint  pathways  when  secreted  directly  within  the  tumor  microenvironment,  potentially  avoiding  the  side-­effects  associated  with  systemic  administration  of  immune  checkpoint inhibitors.

Public health relevance public domain (NIH RePORTER)

Narrative - Public Health Relevance Statement Melanoma is a prevalent, deadly disease with poor outcomes following metastasis. Recently developed monoclonal antibody treatments have been dramatically effective in treating metastatic melanoma by blocking inhibitory immune signals such as the CTLA-4:CD80 and/or PD-1:PDL-1 axes. To be effective, these biologics have to be administered systemically at high doses, and therefore carry the risk of inducing severe side-effects due to disruption of immune homeostasis in non-tumor tissues. To overcome these problems, we have developed replicating, but non-propagating vectors based on non-pathogenic rodent parvovirus genomes, that are capable of targeting tumor cells and delivering locally high doses of these immune checkpoint inhibitors within the tumor microenvironment. In addition, these vectors have been engineered to directly activate naive CD8+ T cells cognate for tumor-associated antigens, thus enhancing the overall anti-tumor immune response.