CAR-T cells secreting BiTEs circumvent antigen escape without detectable toxicity
Bryan D Choi1,2, Xiaoling Yu1, Ana P Castano1
1Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
Nature Biotechnology
|July 24, 2019
Summary
Chimeric antigen receptor (CAR)-T-cell therapy using a novel CART.BiTE approach effectively eliminated heterogeneous glioblastoma tumors in mice. This therapy targets both specific and broadly expressed antigens, overcoming limitations of single-antigen CAR-T treatments.
Area of Science:
- Immunotherapy
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptor (CAR)-T-cell therapy faces challenges in solid tumors due to heterogeneous antigen expression and tumor escape.
- Targeting single antigens can lead to the outgrowth of antigen-negative tumor cells, limiting therapeutic efficacy.
- Glioblastoma exhibits heterogeneous expression of tumor-specific antigens like EGFRvIII and broadly expressed antigens like EGFR.
Purpose of the Study:
- To develop a novel CAR-T-cell construct (CART.BiTE) combining EGFRvIII-specific CAR-T cells with a bispecific T-cell engager (BiTE) targeting EGFR.
- To evaluate the efficacy and safety of CART.BiTE cells in treating heterogeneous glioblastoma models.
- To assess the potential of CART.BiTE cells to overcome antigen escape mechanisms and reduce off-tumor toxicity.
Main Methods:
- Development of a bicistronic construct encoding an EGFRvIII-specific CAR and an EGFR-specific BiTE.
- In vitro characterization of CART.BiTE cell function, including BiTE secretion and T-cell redirection.
- In vivo evaluation of CART.BiTE efficacy and toxicity in orthotopic mouse models of glioblastoma with heterogeneous antigen expression.
Main Results:
- CART.BiTE cells secreted EGFR-specific BiTEs, redirecting CAR-T cells and recruiting bystander T cells against both EGFRvIII and wild-type EGFR.
- EGFRvIII-specific CAR-T cells alone failed to eradicate heterogeneous tumors, resulting in EGFRvIII-negative tumor outgrowth.
- CART.BiTE cells demonstrated complete tumor elimination in heterogeneous glioblastoma models, with no systemic detection of BiTE-EGFR and no observed toxicity in human skin grafts.
Conclusions:
- The CART.BiTE strategy effectively overcomes antigen heterogeneity and prevents tumor escape in glioblastoma models.
- This dual-targeting approach enhances CAR-T-cell therapy efficacy by engaging both CAR-T cells and endogenous T cells.
- CART.BiTE cells offer a promising and safer therapeutic strategy for glioblastoma compared to single-antigen CAR-T therapies.
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