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SECTM1-based CAR T cells enriched with CD7-low/negative subsets exhibit efficacy in CD7-positive malignancies
Wenwen Wei1,2, Haiyan Ma1, Dong Yang1
1Laboratory of Animal Tumor Models, Frontiers Science Center for Disease-Related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, China.
Abstract:
CD7 has been found to be a promising chimeric antigen receptor (CAR) T cell target in several clinical trials. However, its expression on normal T cells poses additional challenges in CD7-directed CAR therapy, such as complete fratricide, contamination with malignant cells, and immune suppression due to T-cell aplasia. By taking advantage of evolved affinity between ligand and receptor, we constructed a CD7-directed CAR with the extracellular domain of SECTM1, a natural ligand of CD7, as the recognition domain. SECTM1 CAR T cells killed the majority of T cells with high CD7 expression in vitro. However, SECTM1 CAR T cells with low or negative CD7 expression survived, expanded, and showed strong cytotoxicity to CD7+ malignant cell lines and primary leukemic blasts from patients with T-cell acute lymphoblastic leukemia and acute myelogenous leukemia in vitro. It also exhibited efficacy in inhibiting xenograft tumor growth in vivo. More exploration is needed for clinical efficacy potential to patients with CD7+ malignancies.
Insights
Researchers developed a novel chimeric antigen receptor (CAR) T cell therapy targeting CD7+ malignancies. This approach utilizes SECTM1 to overcome challenges with normal T cell toxicity, showing promise for treating T-cell acute lymphoblastic leukemia.
Area of Science:
- Immunology
- Oncology
- Biotechnology
Background:
- CD7 is a promising target for chimeric antigen receptor (CAR) T cell therapy in hematologic malignancies.
- CD7 expression on normal T cells presents challenges like fratricide and immune suppression in CD7-directed CAR therapy.
Purpose of the Study:
- To engineer a novel CD7-directed CAR T cell therapy utilizing the natural ligand SECTM1 to overcome limitations of current approaches.
- To evaluate the efficacy and safety of SECTM1 CAR T cells against CD7+ malignancies in vitro and in vivo.
Main Methods:
- Constructed a CAR T cell construct using the extracellular domain of SECTM1 as the CD7-binding domain.
- Assessed the cytotoxicity of SECTM1 CAR T cells against CD7-expressing T cells and CD7+ leukemia cell lines in vitro.
- Evaluated the survival, expansion, and anti-leukemic activity of SECTM1 CAR T cells in vivo using a xenograft model.
Main Results:
- SECTM1 CAR T cells effectively eliminated CD7-high T cells in vitro.
- SECTM1 CAR T cells demonstrated selective survival and expansion in the presence of low or negative CD7 expression.
- These CAR T cells exhibited potent cytotoxicity against CD7+ leukemia cell lines and primary patient samples in vitro.
- Significant inhibition of xenograft tumor growth was observed in vivo.
Conclusions:
- SECTM1 CAR T cell therapy offers a potential strategy to overcome fratricide and target CD7+ malignancies.
- This approach shows promise for treating T-cell acute lymphoblastic leukemia and other CD7+ hematologic cancers.
- Further investigation is warranted to explore the clinical potential of SECTM1 CAR T cells.
