Engineering chimeric antigen receptor T Cells against human LILRB3 for treatment of acute myeloid leukaemia (AML)

Lead Research Organisation: University of Southampton
Department Name: Cancer Sciences

Abstract

Skills Priority Alignment: Whole Organism, Advanced Therapeutics

Acute Myeloid Leukemia (AML) remains an unmet medical need with ~20,000 new cases and ~10,000 deaths in the US alone each year. Current treatments for AML fail to induce long-term tumour regression, demonstrating the need for new therapies. Recent studies demonstrate a role for leukocyte immunoglobulin-like receptors (LILRs) in regulating leukocyte function, and that inhibitory LILRs (LILRBs) are dysregulated in haematological malignancies, including AML.

BioInvent and Southampton have produced and extensively characterised a unique panel of monoclonal antibodies (mAb) specific for human LILRB3. Moreover, alongside Prof Chen at MIT, by genetically modifying human CD34+ hematopoietic stem cells and engrafting them into NOD-SCID Il2rg-/- recipient mice, a humanized mouse model of AML with an autologous human immune system has been successfully developed. Using the previously generated reagents and established pre-clinical platforms and existing expertise in mAb and CAR T cell therapy, it is proposed to develop autologous LILRB3-specific CAR-T cells and evaluate their capacity against AML in vivo.

This proposal aims to 1) generate and optimise autologous T cells expressing chimeric antigen receptors based on BioInvent n-CoDeR generated/derived anti-LILRB3 antibodies (LILRB3-CAR T cells), and 2) evaluate the efficacy and safety of LILRB3-CAR T cells in humanized
AML and patient-derived xenograft mouse models.

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