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Published on: February 16, 2015
The peptide-based bispecific CAR T cells target EGFR and tumor stroma for effective cancer therapy
Cuijuan Liu1, Qianqian Wang2, Lin Li3
1School of Nano Technology and Nano Bionics, University of Science and Technology of China, Hefei 230026, China; CAS Key Laboratory of Nano-Bio Interface, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China; The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100071, China.
Background And Purpose:
The efficacy of chimeric antigen receptor (CAR)-T cell for solid tumors is limited partially because of the lack of tumor-specific antigens and off-target effects. Low molecular weight peptides allowed CAR T cell to display several antigen receptors to reduce off-target effects. Here, we develop a peptide-based bispecific CAR for EGFR and tumor stroma, which are expressed in a variety of tumor types.
Experimental Approach And Key Results:
The peptide-based CAR T cells show excellent proliferation, cytotoxicity activity and are only activated by tumor cells overexpressing EGFR instead of normal cells with low EGFR expressing. In mouse xenograft models, the peptide bispecific CAR T cells can be delivered into the inner of tumor masses and thus are effective in inhibiting tumor growth. Meanwhile, they show strong expansion capacity and the property of maintaining long-term function in vivo. During treatment, no off-tumor toxicity is observed on healthy organs expressing lower levels of EGFR.
Conclusions & Implications:
Our findings demonstrate that peptide-based bispecific CAR T holds great potential in solid tumor therapy due to an excellent targeting ability towards tumors and tumor microenvironment.
Insights
This study introduces a peptide-based bispecific chimeric antigen receptor (CAR)-T cell therapy for solid tumors. This novel approach enhances tumor targeting and reduces off-target effects, showing promise for effective cancer treatment.
Area of Science:
- Immunotherapy
- Oncology
- Molecular Biology
Background:
- Chimeric antigen receptor (CAR)-T cell therapy faces limitations in solid tumors due to scarce tumor-specific antigens and off-target effects.
- Low molecular weight peptides can enable CAR T cells to display multiple antigen receptors, mitigating off-target toxicities.
Purpose of the Study:
- To develop a peptide-based bispecific CAR construct targeting both epidermal growth factor receptor (EGFR) and tumor stroma.
- To evaluate the efficacy and safety of this novel CAR T cell therapy in solid tumor models.
Main Methods:
- Development of a peptide-based bispecific CAR targeting EGFR and tumor stroma.
- In vitro assessment of CAR T cell proliferation and cytotoxicity.
- In vivo evaluation using mouse xenograft models to assess tumor inhibition, CAR T cell expansion, and long-term function.
- Assessment of off-tumor toxicity in healthy organs.
Main Results:
- Peptide-based CAR T cells exhibited robust proliferation and potent cytotoxicity.
- CAR T cell activation was specific to tumor cells overexpressing EGFR, sparing normal cells with low EGFR expression.
- In vivo studies demonstrated effective tumor growth inhibition, strong CAR T cell expansion, and sustained function.
- No significant off-tumor toxicity was observed in healthy organs with lower EGFR levels.
Conclusions:
- Peptide-based bispecific CAR T cells show significant potential for solid tumor therapy.
- The enhanced targeting of tumors and their microenvironment contributes to improved therapeutic efficacy.
- This approach offers a promising strategy to overcome current limitations in CAR T cell therapy for solid malignancies.
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