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Updated: Dec 9, 2025
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Tumor microenvironment remodeling by an engineered oncolytic adenovirus results in improved outcome from PD-L1
Victor Cervera-Carrascon1,2, Dafne C A Quixabeira1, Joao Manuel Santos1,2
1Cancer Gene Therapy Group, Translational Immunology Research Program and Department of Oncology, University of Helsinki, Helsinki, Finland.
Abstract:
Checkpoint inhibitors have revolutionized cancer therapy and validated immunotherapy as an approach. Unfortunately, responses are seen in a minority of patients. Our objective is to use engineered adenoviruses designed to increase lymphocyte trafficking and cytokine production at the tumor, to assess if they increase the response rate to checkpoint inhibition, as these features have been regarded as predictive for the responses. When Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (an oncolytic adenovirus coding for TNFa and IL-2, also known as TILT-123) and checkpoint inhibitors were used together in fresh urological tumor histocultures, a significant shift toward immune activity (not only tumor necrosis alpha and interleukin-2 but also interferon gamma and granzyme B) and increased T-cell trafficking signals (CXCL10) was observed. In vivo, our viruses enabled an anti-PD-L1 (a checkpoint inhibitor) delivering complete responses in all the treated animals (hazard ratios versus anti-PD-L1 alone 0.057 [0.007; 0.451] or virotherapy alone 0.067 [0.011; 0.415]). To conclude, when an engineered oncolytic adenovirus was utilized to modify the tumor microenvironment towards what meta-analyses have pointed as predictive markers for checkpoint inhibitory therapy, the response to them increased synergistically. Of note, key findings were confirmed in fresh patient-derived tumor explants.
Insights
Engineered oncolytic adenoviruses enhance cancer immunotherapy responses. Combining these viruses with checkpoint inhibitors significantly boosted anti-tumor immune activity and led to complete responses in animal models.
Area of Science:
- Oncology
- Immunotherapy
- Virology
Background:
- Checkpoint inhibitors have transformed cancer treatment but benefit only a subset of patients.
- Enhancing anti-tumor immune responses is crucial for improving immunotherapy efficacy.
- Specific immune markers in the tumor microenvironment predict response to checkpoint inhibitors.
Purpose of the Study:
- To evaluate if engineered adenoviruses can improve response rates to checkpoint inhibitors.
- To assess the impact of oncolytic adenoviruses on lymphocyte trafficking and cytokine production within tumors.
- To determine if adenovirus-mediated modification of the tumor microenvironment synergizes with checkpoint blockade.
Main Methods:
- Utilized an engineered oncolytic adenovirus (Ad5/3-E2F-d24-hTNFa-IRES-hIL2, TILT-123) designed to increase immune cell activity and trafficking.
- Tested the combination of TILT-123 and checkpoint inhibitors in fresh human urological tumor histocultures and in vivo animal models.
- Measured immune cell activation (cytokines like IFN-γ, Granzyme B) and T-cell trafficking (CXCL10) in tumor samples.
- Assessed complete response rates in animals treated with the combination therapy versus monotherapy.
Main Results:
- Combined therapy significantly increased immune activity, including tumor necrosis factor alpha (TNFa), interleukin-2 (IL-2), interferon gamma (IFN-γ), and granzyme B.
- Observed enhanced T-cell trafficking signals (CXCL10) in tumor histocultures.
- In vivo studies showed that anti-PD-L1 combined with the oncolytic adenovirus resulted in complete responses in all treated animals.
- Hazard ratios indicated a significant survival benefit for the combination therapy compared to monotherapies.
Conclusions:
- Engineered oncolytic adenoviruses can effectively modify the tumor microenvironment to enhance immune responses.
- The combination of oncolytic adenovirus and checkpoint inhibitors demonstrates synergistic efficacy, leading to significantly improved anti-tumor activity.
- Findings suggest that targeting the tumor microenvironment with engineered viruses is a promising strategy to overcome resistance to checkpoint inhibitors, with validation in patient-derived explants.
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