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<p>CD19 CAR-T cells have established a new standard for relapsed/refractory B-cell malignancies. However, the treatment fails in 50% of patients, often due to CD19 antigen loss. Alternative immunotherapies targeting other antigens are being tested but show limited efficacy, especially in cases of lineage switching or loss of B-cell phenotype, highlighting the need for novel targets. Herein, we identified leukocyte-immunoglobulin-like-receptor-B1 (LILRB1, CD85j) as a novel target for CAR-T cells through cell surface proteomics on patient-derived samples of high-risk B-cell acute lymphoblastic leukemia (B-ALL). LILRB1, an immune inhibitory receptor, is normally expressed only on monocytes and B-cells. We observed stable LILRB1 expression in B-ALL and B-cell non-Hodgkin lymphoma (B-NHL), even after CD20/CD19-based immunotherapies. LILRB1 CAR-T cells showed antigen-specific antitumor activity in vitro against B-ALL/B-NHL cells, including those resistant to CD19 CAR-T-cells, and in vivo in B-ALL xenografts. Additionally, we identified LILRB1 in monocytic acute myeloid leukemia (AML) and demonstrated LILRB1 CAR-T cell cytotoxicity against AML cell lines in vitro and in vivo. These findings establish LILRB1 as a novel target for cancer immunotherapy and show evidence for the preclinical efficacy of LILRB1 CAR-T cells against haematological malignancies, including cases resistant to previous lines of immunotherapy, thus holding promise for further clinical development.</p>

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LILRB1-directed CAR-T cells for the treatment of hematological malignancies

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年4月5日

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  • Katsiaryna Marhelava,
  • Klaudyna Fidyt,
  • Monika Pepek,
  • Marta Krawczyk,
  • Christopher Forcados,
  • Agata Malinowska,
  • Bianka Swiderska,
  • Narcis Fernandez-Fuentes,
  • Natalia Czerwik,
  • Iwona Baranowska,
  • Agnieszka Krzywdzinska,
  • Lukasz Sedek,
  • Lukasz Slota,
  • Bartosz Perkowski,
  • Alicia Villatoro,
  • Thibault Leray,
  • Ewa Lech-Maranda,
  • Pablo Menendez,
  • Else Marit Inderberg,
  • Sébastien Wälchli,
  • Magdalena Winiarska,
  • Malgorzata Firczuk

摘要

CD19 CAR-T cells have established a new standard for relapsed/refractory B-cell malignancies. However, the treatment fails in 50% of patients, often due to CD19 antigen loss. Alternative immunotherapies targeting other antigens are being tested but show limited efficacy, especially in cases of lineage switching or loss of B-cell phenotype, highlighting the need for novel targets. Herein, we identified leukocyte-immunoglobulin-like-receptor-B1 (LILRB1, CD85j) as a novel target for CAR-T cells through cell surface proteomics on patient-derived samples of high-risk B-cell acute lymphoblastic leukemia (B-ALL). LILRB1, an immune inhibitory receptor, is normally expressed only on monocytes and B-cells. We observed stable LILRB1 expression in B-ALL and B-cell non-Hodgkin lymphoma (B-NHL), even after CD20/CD19-based immunotherapies. LILRB1 CAR-T cells showed antigen-specific antitumor activity in vitro against B-ALL/B-NHL cells, including those resistant to CD19 CAR-T-cells, and in vivo in B-ALL xenografts. Additionally, we identified LILRB1 in monocytic acute myeloid leukemia (AML) and demonstrated LILRB1 CAR-T cell cytotoxicity against AML cell lines in vitro and in vivo. These findings establish LILRB1 as a novel target for cancer immunotherapy and show evidence for the preclinical efficacy of LILRB1 CAR-T cells against haematological malignancies, including cases resistant to previous lines of immunotherapy, thus holding promise for further clinical development.