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Updated: Apr 5, 2026
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Armed oncolytic adenovirus elicits a "self-feeder" effect to supercharge NK cells for solid tumor control
Qibin Liao1, Siqiang Lai2, Zhongyi Fan3
1Biotherapy Clinical Research Center, Shenzhen Third People's Hospital, The Second Affiliated Hospital, Southern University of Science and Technology, Shenzhen 518112, Guangdong Province, China; State Key Laboratory of Respiratory Disease, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou Medical University, Guangzhou 510182, Guangdong Province, China.
Background:
Natural killer (NK) cells are pivotal effectors in innate anti-tumor immunity, but their efficacy against solid tumors is constrained by inadequate tumor infiltration and functional suppression within the tumor microenvironment (TME). Although ex vivo expansion increases NK cell numbers, poor tumor homing and transient post-infusion activity persist as major limitations. This work aims to develop a combinatorial approach integrating ex vivo NK cell expansion with localized immunomodulation via engineered oncolytic adenoviruses (oAds) to address these challenges.
Methods:
K562 feeder cells were engineered to stably express IL-2, membrane-bound IL-21 (mbIL-21), and 4-1BBL to activate and expand NK cells ex vivo. Following irradiation, these cells were used to expand NK cells ex vivo. Armed oAds (oAd-IL-2/mbIL-21/4-1BBL) were designed to express IL-2, mbIL-21, and 4-1BBL. In vitro assays were used to evaluate the impact of oAd-IL-2/mbIL-21/4-1BBL on tumor cell lysis, as well as NK cell proliferation, activation, and migration. A HCT116 subcutaneous tumor-bearing mouse model was used to assess the combined anti-tumor effects of ex vivo-expanded NK cells and oAd-IL-2/mbIL-21/4-1BBL, focusing on tumor growth inhibition and NK cell infiltration in tumor lesions.
Results:
We firstly constructed K562 feeder cells stably co-express IL-2, mbIL-21, and 4-1BBL, enabling 100-fold NK cell expansion (>85% purity) within 14 days. Concurrently, armed oAds were engineered to deliver these immunomodulators. oAd-IL-2/mbIL-21/4-1BBL enhanced NK cell proliferation, activation, migration, and tumor cell lysis in vitro. In HCT116 colorectal xenograft models, combing ex vivo-expanded NK cells with oAd-IL-2/mbIL-21/4-1BBL synergistically suppressed tumor growth and increased tumor-infiltrating NK cells. Mechanistically, oAds elicited a "self-feeder" effect through localized immunomodulator production, sustaining NK cell activity within the TME.
Conclusions:
These findings define a dual-phase strategy that integrate scalable ex vivo expansion with in situ activation to overcome key barriers in NK cell therapy for solid tumors.
Insights
This study combines ex vivo expanded natural killer (NK) cells with engineered oncolytic adenoviruses (oAds) for enhanced anti-tumor immunity. The dual-phase strategy improves NK cell infiltration and activity in solid tumors.
Area of Science:
- Immunology
- Oncology
- Gene Therapy
Background:
- Natural killer (NK) cells are crucial for innate anti-tumor immunity but face limitations in solid tumors due to poor infiltration and suppression within the tumor microenvironment (TME).
- Ex vivo expansion of NK cells increases their numbers but does not fully overcome challenges of tumor homing and sustained activity post-infusion.
- Engineered oncolytic adenoviruses (oAds) offer a potential strategy for localized immunomodulation to enhance NK cell-based cancer therapies.
Purpose of the Study:
- To develop a combinatorial approach integrating ex vivo NK cell expansion with localized immunomodulation using engineered oAds.
- To address the challenges of inadequate tumor infiltration and functional suppression of NK cells in the TME.
- To enhance the efficacy of NK cell therapy against solid tumors.
Main Methods:
- Engineered K562 feeder cells to express IL-2, membrane-bound IL-21 (mbIL-21), and 4-1BBL for ex vivo NK cell expansion.
- Developed armed oAds (oAd-IL-2/mbIL-21/4-1BBL) to express the same immunomodulators for localized delivery.
- Evaluated the combined effects in vitro and in a HCT116 subcutaneous tumor-bearing mouse model, assessing tumor growth, NK cell infiltration, proliferation, activation, and migration.
Main Results:
- Achieved 100-fold NK cell expansion with >85% purity using engineered feeder cells within 14 days.
- oAd-IL-2/mbIL-21/4-1BBL enhanced NK cell proliferation, activation, migration, and tumor cell lysis in vitro.
- The combination therapy synergistically suppressed tumor growth and increased tumor-infiltrating NK cells in vivo, with oAds creating a 'self-feeder' effect within the TME.
Conclusions:
- A dual-phase strategy integrating scalable ex vivo expansion with in situ activation effectively overcomes key barriers in NK cell therapy for solid tumors.
- This approach enhances NK cell homing, persistence, and anti-tumor activity within the tumor microenvironment.
- The findings support the potential of this combinatorial therapy for improving cancer treatment outcomes.
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