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A preclinical model for the identification of therapeutically active transgenes in local cancer immunotherapy
Arne Menze1, Dmitrij Ostroumov1, Hans Heinrich Wedemeyer1
1Department of Gastroenterology, Hepatology, Infectious Diseases and Endocrinology, Hannover Medical School, Hannover, Germany.
Abstract:
The efficacy of systemic immunotherapies is limited for poorly immunogenic tumors which suppress T cell priming and tumor infiltration. Modern antigen carriers including viral vectors and messenger RNA/lipid nanoparticle (LNP) combinations have renewed the interest in local immunotherapy due to their ability to express multiple transgene constructs simultaneously. The identification of therapeutically active combinations, however, is hampered by the lack of preclinical models to rapidly express and evaluate transgenes combinations in vivo. To enable empirical testing of immunogenic transgenes, we have combined a doxycycline-inducible expression system with flow cytometry and multiplex immunohistochemistry imaging. In animal models of liver and colon cancer, we demonstrate that the impact of a single transgene on the immune milieu is limited and heavily dependent on the studied tumor entity. Compared to single transgenes, transgene combinations induced more complex and only partially predictable alterations in the tumor micromilieu but strongly enhanced therapeutic efficacy. By combining expression of transgenes with impact on antigen-presenting cells and T cells, we identified a combination of IL-12, CXCL9 and FLT3L as the most promising combinatorial approach, resulting in complete tumor remissions in mice. Taken together, we demonstrate the ability of our preclinical model to identify therapeutic transgene combinations for more efficacious locoregional immunotherapy of solid tumors.
Insights
Developing novel locoregional immunotherapies for solid tumors is crucial. This study introduces a preclinical model to identify effective transgene combinations, revealing IL-12, CXCL9, and FLT3L as a promising therapeutic strategy for enhanced tumor remission.
Area of Science:
- Oncology
- Immunology
- Biotechnology
Background:
- Systemic immunotherapies show limited efficacy in poorly immunogenic tumors due to suppressed T cell responses.
- Antigen carriers like viral vectors and mRNA/lipid nanoparticles (LNPs) enable simultaneous expression of multiple transgenes for local immunotherapy.
- Evaluating transgene combinations requires effective preclinical models for rapid in vivo assessment.
Purpose of the Study:
- To develop and validate a preclinical model for empirical testing of immunogenic transgene combinations.
- To identify optimal transgene combinations for enhancing locoregional immunotherapy of solid tumors.
- To investigate the impact of single transgenes versus combinations on the tumor immune microenvironment.
Main Methods:
- Utilized a doxycycline-inducible expression system combined with flow cytometry and multiplex immunohistochemistry imaging.
- Employed animal models of liver and colon cancer to evaluate transgene efficacy.
- Assessed alterations in the tumor microenvironment and therapeutic outcomes.
Main Results:
- Single transgenes had limited and tumor-dependent effects on the immune milieu.
- Transgene combinations induced complex, partially unpredictable changes in the tumor microenvironment but significantly enhanced therapeutic efficacy.
- A combination of IL-12, CXCL9, and FLT3L resulted in complete tumor remission in mice.
Conclusions:
- The developed preclinical model effectively identifies therapeutic transgene combinations for locoregional immunotherapy.
- Combinatorial approaches involving IL-12, CXCL9, and FLT3L show significant potential for treating solid tumors.
- This strategy offers a pathway to more efficacious immunotherapy for challenging cancers.
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