A Novel Anti-LILRB4 CAR-T Cell for the Treatment of Monocytic AML

Abstract

To effectively improve treatment for acute myeloid leukemia (AML), new molecular targets and therapeutic approaches need to be identified. Chimeric antigen receptor (CAR)-modified T cells targeting tumor-associated antigens have shown promise in the treatment of some malignancies. However, CAR-T cell development for AML has been limited by lack of an antigen with high specificity for AML cells that is not present on normal hematopoietic stem cells, and thus will not result in myelotoxicity. Here we demonstrate that leukocyte immunoglobulin-like receptor-B4 (LILRB4) is a tumor-associated antigen highly expressed on monocytic AML cells. We generated a novel anti-LILRB4 CAR-T cell that displays high antigen affinity and specificity. These CAR-T cells display efficient effector function in vitro and in vivo against LILRB4 AML cells. Furthermore, we demonstrate anti-LILRB4 CAR-T cells are not toxic to normal CD34 umbilical cord blood cells in colony-forming unit assays, nor in a humanized hematopoietic-reconstituted mouse model. Our data demonstrate that anti-LILRB4 CAR-T cells specifically target monocytic AML cells with no toxicity to normal hematopoietic progenitors. This work thus offers a new treatment strategy to improve outcomes for monocytic AML, with the potential for elimination of leukemic disease while minimizing the risk for on-target off-tumor toxicity.

Disrupting LILRB4/APOE Interaction by an Efficacious Humanized Antibody Reverses T-cell Suppression and Blocks AML Development

“…In agreement with the finding from Dobrowolska and colleagues (15), we reported that LILRB4, a member of the LILRB family, is a marker for monocytic AML (16,17). We further demonstrated that LILRB4 is more highly expressed on monocytic AML cells than on their normal counterparts and that LILRB4 expression inversely correlates with overall survival of patients with AML (16,17). LILRB4 (also known as CD85K, ILT3, LIR5, and HM18) has two extracellular Ig-like domains (D1 and D2) and three ITIMs.…”

High expression of WTAP leads to poor prognosis of gastric cancer by influencing tumour‐associated T lymphocyte infiltration

“…Studies have also shown that CD86 and CD163 have a significant correlation with the proliferation and progression of GC . LCP2, CSF1R, LILRB2 and TLR8 both interact with T lymphocytes in tumour immune regulation and affect tumour prognosis. These core genes in patients with low WTAP expression enhance the function of tumour immunity, conferring patients with low WTAP expression with a better survival prognosis and better gene expression levels.…”

Methylome-based cell-of-origin modeling (Methyl-COOM) identifies aberrant expression of immune regulatory molecules in CLL

“…In preclinical models of colorectal and breast carcinoma, TIGIT blockade was shown to reverse the exhaustion phenotype of cytotoxic T cells and to inhibit tumor growth [63]. Another immune inhibitory receptor, LILRB4, was reported as tumor-associated antigen that is highly expressed on monocytic AML cells [64,65]. It was also reported as a selective marker of neoplastic B cells and HSCs from CLL patients [66].…”