LAMP5 Is an AML-Restricted Immunotherapeutic Target Enriched in High-Risk Acute Myeloid Leukemia

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LAMP5, Lysosomal Associated Membrane Protein Family Member 5, a neuronal protein that plays a role in synaptic plasticity is normally found primarily in the brain, however limited studies have identified it to be expressed in leukemia, particularly KMT2A-rearranged leukemias. Importantly, there is low expression of LAMP5 in normal hematopoiesis making it an ideal potential immunotherapeutic target for both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). As a newly identified aberrant protein in leukemias, there is little data available on the prevalence or clinical implications of LAMP5 expression. We interrogated the transcriptome and associated clinical and laboratory data from a large cohort of pediatric AML patients to define the prevalence, co-occurring cytomolecular aberrations and clinical outcomes associated with LAMP5 expression. Ribo-depleted RNA seq data from 2,241 patients with AML (Pediatric ages 0-29 years N=1,412, from recent Phase 3 COG clinical trials; Adult ages 18-88 years from BEAT AML N=451, SWOG N=199, TCGA-LAML N=179) with available cytogenetic, molecular, and clinical data were utilized. Gene fusions, internal tandem duplications (ITD) and partial tandem duplications (PTD) were detected by Cicero. Conventional karyotyping and mutational analysis including NGS were used to determine additional cytogenetic and molecular abnormalities. Response was measured by 5-year overall survival (OS), event-free survival (EFS) and relapse risk (RR). Of the 1,412 pediatric patients, LAMP5 was expressed (positive defined as mRNA transcripts per million (TPM) >2) in 396 patients (28%) with mRNA TPM ranging from 0-884 with similar prevalence found in adult AML (28%; BEAT AML N=126/452, SWOG N= 59/199 TCGA N=50/179), but with significantly higher TPM ranging from 0-3,200. Of the 396 pediatric patients with LAMP5 expression, there was a notable enrichment in KMT2A-r AML (N=203, 51%), which accounts for 59% of the total KMT2A-r cohort. Within the KMT2A-r cohort, there is enrichment in the MLLT1 (N=17/18, 94%), MLLT3 (N=61/93, 66%) and MLLT10 (N=58/69, 84%) fusion groups. Additionally, LAMP5 expression was seen in other high risk fusion subtypes including 100% of patients with KAT6A-CREBBP (N=12/12) and 29% of NUP98 fusions (N=45/154). There is absent LAMP5 expression in normal lymphoid and myeloid cells, but there is moderate expression seen in plasmacytoid dendritic cells, which could provide a therapeutic target for Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN). Given the association with high-risk AML fusion subtypes, the impact of LAMP5 on clinical outcome in AML pediatric patients was evaluated. High rates of relapse were seen in patients with LAMP5 expression, with a relapse rate of 45% compared to 36% in LAMP5-negative patients. 5 year event-free survival (EFS) was 36% for LAMP5-positive patients compared 45% for LAMP5-negative patients (p=0.0005). Similar poor outcomes were seen with overall survival 54% for LAMP5-positive patients vs. 62% for LAMP5-negative patients (p=0.001). In an analysis of a large cohort of AML patients, we found that LAMP5 expression is highly enriched in many high-risk fusion subtypes including KMT2A-rearranged AML, KAT6A-CREBBP and NUP98 fusions. Patients with LAMP5 expression have high rates of relapse with significantly worse outcomes compared to patients without LAMP5. Given low levels of LAMP5 in normal hematopoiesis, LAMP5 is an ideal AML-restricted immunotherapy target with broad applicability for many high-risk fusion subtypes of AML. Current efforts to generate a LAMP5 chimeric antigen receptor (CAR) T cell are underway which will be used to evaluate preclinical efficacy in AML via cell- and patient-derived xenograft models with the goal to translate this novel therapy into clinical use to improve the current dismal outcomes for these high-risk patients.