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

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

doi:10.1016/j.omton.2025.201006

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

Mol Ther Oncol. 2025 May 26;33(2):201006. doi: 10.1016/j.omton.2025.201006. eCollection 2025 Jun 18.

Authors

Greyson Biegert^{1

2}, Amanda Rosewell Shaw^{1

2

3}, Daisuke Morita^{1

2

4

5}, Caroline Porter^{1

2}, Ryu Matsumoto^{1

2}, Lisa Jatta^{1

2}, Noah Crooks^{1

2}, Mae Woods^{1

2}, Qizhi Cathy Yao^{6

7

8}, Robin Parihar^{2

9}, Masataka Suzuki^{1

2}

Affiliations

¹ Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
² Center for Cell and Gene Therapy, Baylor College of Medicine, Texas Children's Hospital, Houston Methodist Hospital, Houston, TX, USA.
³ Department of Biology, Benedict College, Columbia, SC, USA.
⁴ Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan.
⁵ Institute for Biomedical Sciences, Interdisciplinary Cluster for Cutting Edge Research, Shinshu University, Matsumoto, Japan.
⁶ Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
⁷ Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA.
⁸ Center for Translational Research on Inflammatory Diseases, Michael E. DeBakey VA Medical Center, Houston, TX, USA.
⁹ 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.

Keywords: CAR-NK cell; MT: Regular Issue; PDX model; humanized mouse model; oncolytic viro-immuno therapy; pancreatic ductal adenocarcinoma.