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Updated: Jan 30, 2026
Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Targeting the tumor stroma with an oncolytic adenovirus secreting a fibroblast activation protein-targeted bispecific
Jana de Sostoa1, Carlos Alberto Fajardo1, Rafael Moreno1
1ProCure Program, IDIBELL-Institut Català d'Oncologia, l'Hospitalet de Llobregat, El Prat de Llobregat, Spain.
Background:
Oncolytic virus (OV)-based therapies have an emerging role in the treatment of solid tumors, involving both direct cell lysis and immunogenic cell death. Nonetheless, tumor-associated stroma limits the efficacy of oncolytic viruses by forming a barrier that blocks efficient viral penetration and spread. The stroma also plays a critical role in progression, immunosuppression and invasiveness of cancer. Fibroblast activation protein-α (FAP) is highly overexpressed in cancer-associated fibroblasts (CAFs), the main cellular component of tumor stroma, and in this study we assessed whether arming oncolytic adenovirus (OAd) with a FAP-targeting Bispecific T-cell Engager (FBiTE) could retarget infiltrated lymphocytes towards CAFs, enhancing viral spread and T cell-mediated cytotoxicity against the tumor stroma to improve therapeutic activity.
Methods:
The bispecific T-cell Engager against FAP was constructed using an anti-human CD3 single-chain variable fragment (scFv) linked to an anti-murine and human FAP scFv. This FBiTE was inserted in the oncolytic adenovirus ICOVIR15K under the control of the major late promoter, generating the ICO15K-FBiTE. ICO15K-FBiTE replication and potency were assessed in HT1080 and A549 tumor cell lines. The expression of the FBiTE and the activation and proliferation of T cells that induced along with the T cell-mediated cytotoxicity of CAFs were evaluated by flow cytometry in vitro. In vivo, T-cell biodistribution and antitumor efficacy studies were conducted in NOD/scid/IL2rg-/- (NSG) mice.
Results:
FBiTE expression did not decrease the infectivity and replication potency of the armed virus. FBiTE-mediated binding of CD3+ effector T cells and FAP+ target cells led to T-cell activation, proliferation, and cytotoxicity of FAP-positive cells in vitro. In vivo, FBiTE expression increased intratumoral accumulation of T cells and decreased the level of FAP, a marker of CAFs, in tumors. The antitumor activity of the FBiTE-armed adenovirus was superior to the parental virus.
Conclusions:
Combination of viral oncolysis of cancer cells and FBiTE-mediated cytotoxicity of FAP-expressing CAFs might be an effective strategy to overcome a key limitation of oncolytic virotherapy, encouraging its further clinical development.
Insights
This study armed oncolytic adenovirus with a FAP-targeting Bispecific T-cell Engager (FBiTE) to enhance T-cell activity against cancer-associated fibroblasts. The modified virus improved T-cell accumulation and demonstrated superior antitumor efficacy, suggesting a promising strategy for oncolytic virotherapy.
Area of Science:
- Oncolytic virotherapy
- Cancer immunology
- Tumor microenvironment targeting
Background:
- Oncolytic viruses (OVs) offer direct tumor cell lysis and immunogenic cell death for cancer treatment.
- Tumor stroma, rich in cancer-associated fibroblasts (CAFs) expressing fibroblast activation protein-α (FAP), impedes OV efficacy by creating a barrier and promoting immunosuppression.
- Targeting FAP+ CAFs is crucial for enhancing OV penetration, spread, and overall therapeutic activity.
Purpose of the Study:
- To assess if arming an oncolytic adenovirus (OAd) with a FAP-targeting Bispecific T-cell Engager (FBiTE) can redirect lymphocytes to CAFs.
- To enhance viral spread and T cell-mediated cytotoxicity against the tumor stroma.
- To improve the therapeutic efficacy of oncolytic virotherapy.
Main Methods:
- Constructed a FAP-targeting FBiTE using anti-CD3 and anti-FAP single-chain variable fragments.
- Engineered an oncolytic adenovirus (ICOVIR15K) to express the FBiTE (ICO15K-FBiTE).
- Evaluated FBiTE expression, T-cell activation, proliferation, and cytotoxicity in vitro, and assessed T-cell biodistribution and antitumor efficacy in vivo using NSG mice.
Main Results:
- FBiTE expression did not compromise the infectivity or replication of the oncolytic adenovirus.
- In vitro studies confirmed FBiTE-mediated T-cell activation, proliferation, and cytotoxicity against FAP+ cells.
- In vivo studies showed increased intratumoral T-cell accumulation, reduced FAP levels, and superior antitumor activity compared to the parental virus.
Conclusions:
- Combining viral oncolysis with FBiTE-mediated CAF targeting presents a potent strategy to overcome OV limitations.
- This approach enhances T-cell engagement with the tumor stroma, improving therapeutic outcomes.
- Further clinical development of FBiTE-armed oncolytic adenovirus is warranted for improved cancer treatment.
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