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Sensitizing solid tumors to CAR-mediated cytotoxicity by lipid nanoparticle delivery of synthetic antigens
Lena Gamboa1, Ali H Zamat1, Chloé A Thiveaud1
1Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory School of Medicine, Atlanta, GA, USA.
Abstract:
Chimeric antigen receptor (CAR) T cell immunotherapy relies on CAR targeting of tumor-associated antigens; however, heterogenous antigen expression, interpatient variation and off-tumor expression by healthy cells remain barriers. Here we develop synthetic antigens to sensitize solid tumors for recognition and elimination by CAR T cells. Unlike tumor-associated antigens, we design synthetic antigens that are orthogonal to endogenous proteins to eliminate off-tumor targeting and that have a small genetic footprint to facilitate efficient tumor delivery to tumors by lipid nanoparticles. Using a camelid single-domain antibody (VHH) as a synthetic antigen, we show that adoptive transfer of anti-VHH CAR T cells to female mice bearing VHH-expressing tumors reduced tumor burden in multiple syngeneic and xenograft models of cancer, improved survival, induced epitope spread, protected against tumor rechallenge and mitigated antigen escape in heterogenous tumors. Our work supports the in situ delivery of synthetic antigens to treat antigen-low or antigen-negative tumors with CAR T cells.
Insights
Researchers developed synthetic antigens to improve chimeric antigen receptor (CAR) T cell therapy for solid tumors. This approach overcomes challenges like heterogeneous antigen expression and off-tumor targeting, enhancing cancer treatment efficacy.
Area of Science:
- Immunotherapy
- Synthetic Biology
- Oncology
Background:
- Chimeric antigen receptor (CAR) T cell therapy faces limitations due to heterogeneous tumor antigen expression and off-tumor targeting.
- Existing CAR T cell strategies struggle with antigen-low or antigen-negative tumors and variations between patients.
- Off-tumor expression of tumor-associated antigens on healthy cells can lead to severe side effects.
Purpose of the Study:
- To engineer synthetic antigens for sensitizing solid tumors to CAR T cell recognition and elimination.
- To overcome barriers of heterogeneous antigen expression, interpatient variation, and off-tumor targeting in CAR T cell immunotherapy.
- To enable CAR T cell treatment for tumors with low or absent endogenous antigen expression.
Main Methods:
- Designed synthetic antigens orthogonal to endogenous proteins to prevent off-tumor targeting.
- Utilized a small genetic footprint for efficient tumor delivery via lipid nanoparticles.
- Employed a camelid single-domain antibody (VHH) as a model synthetic antigen.
Main Results:
- Adoptive transfer of anti-VHH CAR T cells significantly reduced tumor burden in both syngeneic and xenograft cancer models.
- Demonstrated improved survival, induced epitope spread, and protection against tumor rechallenge in treated mice.
- Successfully mitigated antigen escape in tumors with heterogeneous antigen expression.
Conclusions:
- Synthetic antigens can effectively sensitize solid tumors for CAR T cell-mediated elimination.
- This approach offers a strategy to overcome major limitations of current CAR T cell therapies.
- In situ delivery of synthetic antigens holds promise for treating antigen-low or antigen-negative tumors.
