CAR-T cell therapy 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. UTHealth Houston and UTSW researchers discovered that leukocyte immunoglobulin-like receptor-B4 (LILRB4) is a tumor-associated antigen highly expressed on monocytic AML cells. They further generated a novel anti-LILRB4 CAR-T cell that displays high antigen affinity and specificity, which offers a new treatment strategy for monocytic AML.
Background
Acute myeloid leukemia (AML) is the most common acute leukemia of adults and a common pediatric cancer. Currently, AML treatment involves intensive cytotoxic chemotherapy often followed by myeloablative conditioning and stem cell transplant. Despite treatment, relapsed and refractory disease remains a significant problem for both adults and children with AML, with survival rates of less than 15% in the relapsed setting. Chimeric antigen receptor (CAR)-T cells targeting tumor-associated antigens have shown promise in the treatment of some malignancies. However, a major limitation to CAR-T cell therapy for the treatment of other tumors is the potential for on-target/off-tumor elimination of normal cells. To effectively utilize CAR-T cells against tumor, an antigen with high specificity for tumor cells or tumor microenvironment (TME) cells must be identified and target.
Significance and Impact
Researchers at UTHealth Houston and The University of Texas Southwestern Medical Center (UTSW) discovered that expression of LILRB4 in AML is more specific, making it able to differentiate monocytic AML (M5) from AML M1-M3 more accurately than CD14, HLA-DR, or CD11c. Additionally, LILRB4 is expressed on cells at all stages of AML cell maturation, including CD34+/c-kit+ cells that are likely enriched for leukemia stem cells. They then generated a novel LILRB4 CAR-T cell and demonstrated targeting specific subtypes of AML based on normal HSC-sparing restricted immunophenotype represents an effective treatment strategy that may minimize off-target toxicity against vital healthy cells including HSCs and progenitors.
Benefits/Technology Advantages
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