Publication Date
6-18-2025
Journal
Molecular Therapy Oncology
DOI
10.1016/j.omton.2025.201006
PMID
40546314
PMCID
PMC12179663
PubMedCentral® Posted Date
5-26-2025
PubMedCentral® Full Text Version
Post-print
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.
Keywords
MT: Regular Issue, pancreatic ductal adenocarcinoma, oncolytic viro-immuno therapy, CAR-NK cell, humanized mouse model, PDX model
Published Open-Access
yes
Recommended Citation
Biegert, Greyson; Shaw, Amanda Rosewell; Morita, Daisuke; et al., "Oncolytic Adeno-Immunotherapy Improves Allogeneic Adoptive HER2CAR-NK Function Against Pancreatic Ductal Adenocarcinoma" (2025). Faculty, Staff and Students Publications. 6346.
https://digitalcommons.library.tmc.edu/baylor_docs/6346