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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Comparison of Clinically Relevant Oncolytic Virus Platforms for Enhancing T Cell Therapy of Solid Tumors
Victor Cervera-Carrascon1,2, Dafne C A Quixabeira1, Riikka Havunen1,2
1Cancer Gene Therapy Group, Translational Immunology Research Program, University of Helsinki, 00290 Helsinki, Finland.
Abstract:
Despite some promising results, the majority of patients do not benefit from T cell therapies, as tumors prevent T cells from entering the tumor, shut down their activity, or downregulate key antigens. Due to their nature and mechanism of action, oncolytic viruses have features that can help overcome many of the barriers currently facing T cell therapies of solid tumors. This study aims to understand how four different oncolytic viruses (adenovirus, vaccinia virus, herpes simplex virus, and reovirus) perform in that task. For that purpose, an immunocompetent in vivo tumor model featuring adoptive tumor-infiltrating lymphocyte (TIL) therapy was used. Tumor growth control (p < 0.001) and survival analyses suggest that adenovirus was most effective in enabling T cell therapy. The complete response rate was 62% for TILs + adenovirus versus 17.5% for TILs + PBS. Of note, TIL biodistribution did not explain efficacy differences between viruses. Instead, immunostimulatory shifts in the tumor microenvironment mirrored efficacy results. Overall, the use of oncolytic viruses can improve the utility of T cell therapies, and additional virus engineering by arming with transgenes can provide further antitumor effects. This phenomenon was seen when an unarmed oncolytic adenovirus was compared to Ad5/3-E2F-d24-hTNFa-IRES-hIL2 (TILT-123). A clinical trial is ongoing, where patients receiving TIL treatment also receive TILT-123 (ClinicalTrials.gov: NCT04217473).
Insights
Oncolytic viruses enhance T-cell therapy effectiveness against solid tumors. Adenovirus demonstrated the greatest efficacy, significantly improving tumor control and survival rates in preclinical models.
Area of Science:
- Immunology
- Virology
- Oncology
Background:
- T-cell therapies face challenges in solid tumors, including tumor infiltration barriers and immune suppression.
- Oncolytic viruses possess inherent properties that can potentially overcome these limitations.
Purpose of the Study:
- To evaluate the efficacy of four oncolytic viruses (adenovirus, vaccinia virus, herpes simplex virus, reovirus) in combination with adoptive T-cell therapy.
- To investigate the impact of oncolytic viruses on the tumor microenvironment and T-cell infiltration.
Main Methods:
- An immunocompetent in vivo tumor model was utilized to assess adoptive tumor-infiltrating lymphocyte (TIL) therapy combined with different oncolytic viruses.
- Tumor growth, survival, and TIL biodistribution were analyzed. Changes in the tumor microenvironment were also assessed.
Main Results:
- Adenovirus significantly enhanced TIL therapy, leading to improved tumor growth control (p < 0.001) and survival compared to control (PBS).
- Complete response rates were 62% for TILs + adenovirus versus 17.5% for TILs + PBS.
- Efficacy was correlated with immunostimulatory shifts in the tumor microenvironment, not TIL biodistribution.
Conclusions:
- Oncolytic viruses, particularly adenovirus, can improve the efficacy of T-cell therapies for solid tumors.
- Virus engineering, such as arming with transgenes (e.g., TILT-123), may further enhance antitumor effects.
- A clinical trial is underway to evaluate TILT-123 in combination with TIL therapy (NCT04217473).
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