Preclinical Efficacy of CD276 (B7-H3) CAR T in Acute Myeloid Leukemia

Immuno-therapies selectively directed against leukemia-restricted antigens (with limited to no expression in normal tissue) are desirable for optimizing efficacy without on-target off-tumor toxicity, although this goal has been elusive in acute myeloid leukemia (AML). One such tumor-restricted targe...

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Published in:Blood 2024-11, Vol.144 (Supplement 1), p.4793-4793
Main Authors: Lira, Isabel, Kirkey, Danielle C., Nicolaidou, Marilena, Muller, Henrike, Barisa, Marta, Blankenfeld, Melia, Hawkins, Grace, McKay, Cyd, Root, Christina, Pardo, Laura, Loken, Michael R., Hylkema, Tiffany, Quintarelli, Concetta, Locatelli, Franco, Anderson, John, Meshinchi, Soheil
Format: Article
Language:English
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Summary:Immuno-therapies selectively directed against leukemia-restricted antigens (with limited to no expression in normal tissue) are desirable for optimizing efficacy without on-target off-tumor toxicity, although this goal has been elusive in acute myeloid leukemia (AML). One such tumor-restricted target is CD276 (B7-H3), an immune checkpoint inhibitor upregulated in numerous malignancies including AML. Through transcriptomic evaluation of over 2000 AML patients, we have previously characterized CD276 expression to be highly expressed in both pediatric and adult AML and absent in normal hematopoietic cells (Kirkey, Blood, 2023). We have also demonstrated that CD276 is highly enriched in patients with high-risk AML, including KMT2A-rearranged, CBFA2T3::GLIS2, and KAT6A::CREBBP fusion genes (Kirkey, Blood, 2023). Flow-cytometry analysis of 1,500 pediatric AML patients demonstrated homogenous cell surface expression of CD276 in 22% (Kirkey, Blood, 2023). Using a CD276- targeting second generation CAR with TE9 binder and CD28 costimulatory domain developed at the University College, London, we conducted both in vitro and in vivo preclinical studies to evaluate efficacy and target-specificity in AML models. In vitro cytotoxicity assays following co-incubation of CD276-positive NOMO-1 cells and CD276 negative Kasumi-1 cells with either CD276 CAR T or unmodified T cells showed robust target specific cell killing across a variety of effector: target cell ratios in the NOMO-1 cells with no significant cytotoxicity in the CD276-negative Kasumi-1 cells (p
ISSN:0006-4971
1528-0020
DOI:10.1182/blood-2024-206227