期刊
BLOOD
卷 140, 期 1, 页码 25-37出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021013648
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- Children with Cancer
- Carol's Smile Charities
- Great Ormond Street Hospital Children's Charity
- Blood Cancer UK
- Cancer Research UK
- UK Medical Research Council
- UCL/University College London Hospital Biomedical Research Centre
- Children with Cancer UK [17-249]
- UK Medical Research Council [MR/S021000/1]
- Children with Cancer UK [17-249] Funding Source: researchfish
CCR9 expression is found in the majority of T-ALL cases, making it a potential target for CAR-T cell therapy. CAR-T cells targeting CCR9 can effectively inhibit leukemia cell proliferation without harming healthy T cells, providing a promising treatment strategy for T-ALL.
T cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy of immature T lymphocytes, associated with higher rates of induction failure compared with those in B cell acute lymphoblastic leukemia. The potent immunotherapeutic approaches applied in B cell acute lymphoblastic leukemia, which have revolutionized the treatment paradigm, have proven more challenging in T-ALL, largely due to a lack of target antigens expressed on malignant but not healthy T cells. Unlike B cell depletion, T-cell aplasia is highly toxic. Here, we show that the chemokine receptor CCR9 is expressed in 70% of cases of T-ALL, including >85% of relapsed/refractory disease, and only on a small fraction (<5%) of normal T cells. Using cell line models and patient-derived xenografts, we found that chimeric antigen receptor (CAR) T-cells targeting CCR9 are resistant to fratricide and have potent antileukemic activity both in vitro and in vivo, even at low target antigen density. We propose that anti-CCR9 CAR-T cells could be a highly effective treatment strategy for T-ALL, avoiding T cell aplasia and the need for genome engineering that complicate other approaches.
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