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Published on: February 27, 2019
Parallel 4-1BB Signaling in Dual DLL3/CD56-Targeting CAR-T Cells Triggers Adaptive Proliferation and Functional
Yan-Na Lei1, Diyuan Qin2, Yan He1
1West China Hospital of Sichuan University chengdu China.
Abstract:
Limited intratumoral persistence and insufficient proliferative capacity severely restrict the efficacy of chimeric antigen receptor (CAR)-T cell therapies in solid tumors. Here, we demonstrated that DLL3-targeting CAR-T cells co-expressing a CD56 chimeric switch receptor (CSR) and incorporating parallel 4-1BB costimulatory signaling (DBBζ.CBB) effectively address these limitations. In preclinical small cell lung cancer (SCLC) models, DBBζ.CBB exhibited sustained tumor infiltration, prolonged persistence, and superior antitumor activity. Mechanistically, parallel 4-1BB signaling dynamically programed CAR-T cell fate by promoting early expansion and memory maintenance, driving a highly proliferative effector state at the intermediate stage, and delaying terminal exhaustion at the later stage, thereby sustaining in vivo persistence and enabling durable antitumor responses. Building upon the intratumoral T-cell pool established by DBBζ.CBB, subsequent DLL3 trispecific T-cell engager (TriTCE) administration synergistically enhanced tumor eradication by further boosting CD8+ T cell infiltration and overall activation while mitigating exhaustion and terminal differentiation. Collectively, these findings establish a clinically translatable combinatorial framework to enhance the efficacy and durability of CAR-T therapy in solid tumors.
Insights
Engineered chimeric antigen receptor (CAR)-T cells co-expressing a CD56 chimeric switch receptor (CSR) and 4-1BB signaling (DBBζ.CBB) enhance persistence and efficacy in solid tumors. Combining DBBζ.CBB with DLL3 trispecific T-cell engagers (TriTCE) synergistically eradicates tumors.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- Chimeric antigen receptor (CAR)-T cell therapy faces challenges in solid tumors due to limited persistence and proliferation.
- DLL3 is a promising target for small cell lung cancer (SCLC) therapy.
Purpose of the Study:
- To develop an enhanced CAR-T cell strategy for solid tumors.
- To improve the efficacy and durability of CAR-T cell therapy in preclinical SCLC models.
Main Methods:
- Engineered DLL3-targeting CAR-T cells (DBBζ.CBB) co-expressing CD56 CSR and incorporating parallel 4-1BB costimulatory signaling.
- Preclinical evaluation in SCLC models.
- Combination therapy with DLL3 trispecific T-cell engagers (TriTCE).
Main Results:
- DBBζ.CBB demonstrated sustained tumor infiltration, prolonged persistence, and superior antitumor activity in SCLC models.
- Parallel 4-1BB signaling dynamically programmed T cell fate, promoting expansion, memory maintenance, and delaying exhaustion.
- Combination therapy synergistically enhanced tumor eradication, boosted T cell infiltration and activation, and mitigated exhaustion.
Conclusions:
- The engineered DBBζ.CBB CAR-T cells effectively overcome limitations of current CAR-T therapies in solid tumors.
- The combinatorial framework of DBBζ.CBB and TriTCE offers a promising strategy for enhancing CAR-T cell efficacy and durability.
- This approach is clinically translatable for solid tumor treatment.
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