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Ultrasound-Guided Orthotopic Implantation of Murine Pancreatic Ductal Adenocarcinoma
Published on: November 19, 2019
Oncolytic adeno-immunotherapy improves allogeneic adoptive HER2.CAR-NK function against pancreatic ductal
Greyson Biegert1,2, Amanda Rosewell Shaw1,2,3, Daisuke Morita1,2,4,5
1Department of Medicine, 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.
Insights
Combining CAdTrio oncolytic virus with HER2.CAR-NK cells offers a novel immunotherapy for pancreatic cancer. This "off-the-shelf" treatment enhances NK cell persistence and controls tumor growth in preclinical models.
Area of Science:
- Oncology
- Immunotherapy
- Virology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) exhibits resistance to standard therapies and immunotherapy.
- Previous development of CAdTrio, an oncolytic adenovirus expressing interleukin-12 and a PD-L1 blocking mini-antibody.
- Natural Killer (NK) cells show potential for adoptive cell therapy, with allogeneic NK cells offering an
- Purpose_of_the_Study: [
- To evaluate the efficacy of combining CAdTrio with allogeneic HER2-specific chimeric antigen receptor NK (HER2.CAR-NK) cells as an
- Main_Methods: [
- Utilized humanized mice models bearing PDAC tumors and patient-derived xenografts (PDX).
- Administered combination therapy of CAdTrio and HER2.CAR-NK cells.
- Assessed NK cell persistence, tumor growth, survival, and NK cell phenotype.
Purpose of the Study:
- To evaluate the efficacy of combining CAdTrio with allogeneic HER2-specific chimeric antigen receptor NK (HER2.CAR-NK) cells as an
- To investigate the underlying mechanisms of enhanced anti-tumor activity.
- To assess the safety and tolerability of the combination therapy.
Main Methods:
- Utilized humanized mice models bearing PDAC tumors and patient-derived xenografts (PDX).
- Administered combination therapy of CAdTrio and HER2.CAR-NK cells.
- Assessed NK cell persistence, tumor growth, survival, and NK cell phenotype.
Main Results:
- CAdTrio prolonged HER2.CAR-NK cell persistence at tumor sites.
- Combination therapy achieved long-term tumor growth control and improved survival in PDAC models.
- CAdTrio supported a memory-like phenotype in HER2.CAR-NK cells.
Conclusions:
- CAdTrio and HER2.CAR-NK cell combination therapy demonstrates significant anti-tumor activity against PDAC.
- This allogeneic, "off-the-shelf" approach offers a novel treatment strategy for PDAC.
- The combination therapy was well-tolerated in preclinical models.
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