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Publications

Journal Article Epublish

PubMed: 40546314 DOI: 10.1016/j.omton.2025.201006

Oncolytic adeno-immunotherapy improves allogeneic adoptive HER2.CAR-NK function against pancreatic ductal adenocarcinoma.

Mol Ther Oncol 33(2):201006

Authors: Greyson Biegert, Amanda Rosewell Shaw, Daisuke Morita, Caroline Porter, Ryu Matsumoto, Lisa Jatta, Noah Crooks, Mae Woods, Qizhi Cathy Yao, Robin Parihar, Masataka Suzuki

Affiliations

  • Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
  • Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX, USA.
  • Department of Biology, Benedict College, Columbia, SC, USA.
  • Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.
  • Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan.
  • Department of Medicine, Baylor College of Medicine, Houston, TX, USA. Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX, USA.
  • Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
  • Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.
  • Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey VA Medical Center, Houston, TX, USA.
  • Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) responds poorly to conventional treatments and immunotherapy. We previously developed a binary oncolytic/helper-dependent adenovirus system (CAdTrio) that facilitated oncolysis and expressed the immunomodulatory molecule interleukin-12 and a programmed death ligand 1 (PD-L1) blocking mini-antibody. Given that CAdTrio enhanced endogenous natural killer (NK) cell anti-tumor activity in humanized mice bearing PDAC tumors and that NK cells can be adoptively transferred to patients safely in the allogeneic setting, we hypothesized that a combination of CAdTrio and allogeneic NK cells expressing a HER2-specific chimeric antigen receptor (HER2.CAR-NK) would be an effective, entirely "off-the-shelf" treatment against PDAC. We found that CAdTrio-derived immunomodulatory molecules prolonged HER2.CAR-NK persistence at tumor sites, allowing long-term tumor growth control and improved survival in both humanized mice and a heterogeneous PDAC patient-derived xenografts (PDX) model. This effect was based on CAdTrio-derived transgene support that shifted HER2.CAR-NK gene expression to that resembling an NK memory-like phenotype. Additionally, this allogeneic combination therapy was tolerated in humanized mice. Together, these data suggest that CAdTrio and HER2.CAR-NK cell combination immunotherapy may be a novel and effective option for the treatment for immunologically "cold" PDAC tumors.

MeSH

Cells, Genes, Killer Cells, Natural, Neoplasms, Adenocarcinoma, Immunotherapy, Therapeutics