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Publications of the Week

Therapeutic Targeting of Mesothelin with Chimeric Antigen Receptor T Cells in Acute Myeloid Leukemia

By September 3, 2021No Comments

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This week we profile a recent publication in Clinical Cancer Research from the Dr. Quy Le (pictured, sixth from left, back) laboratory of Dr. Soheil Meshinchi (third from right, front) at Fred Hutch.

Can you provide a brief overview of your lab’s current research focus?

Acute myeloid leukemia (AML) is a devastating disease with unacceptable low cure rates. In the Meshinchi lab, we utilize comprehensive genomic data to understand the underlying cause of disease in AML and to guide therapeutic discovery and development. Through multi-omics (transcriptomics, genomics, and epigenomics) profiling of nearly 3000 childhood and young adult AML cases along with a large cohort of normal counterparts, we have identified a library of AML-restricted genes (high expression in AML, silent in normal hematopoiesis), providing ideal candidate targets for immunotherapeutic development in AML that avoid hemopoietic toxicities.  We are currently developing antibody-drug conjugates, chimeric-antigen receptor (CAR) T and NK cells against these AML-restricted targets with the goal of bringing safe and effective immunotherapies to patients with AML.

What is the significance of the findings in this publication?

A significant barrier to effective immunotherapy in AML is the shared immunophenotype between AML and normal hematopoietic cells. Current strategies targeting lineage markers such as CD33 and CD123, if effective, would lead to prolonged myelosuppression or myeloablation, requiring bone marrow transplant to restore hematopoiesis. Our study has addressed this obstacle by defining and validating mesothelin (MSLN) as an AML-restricted target,  initially discovered through interrogation of the AML transcriptome from our massive pediatric AML (TARGET and TpAML) dataset as well as the adult AML (BEAT and NCI TCGA) dataset. We show that MSLN protein is expressed on the cell surface of AML blasts and leukemic stem cells (LSCs) but entirely silent on normal hematopoietic stem and progenitor cells (HSPCs). We developed CAR T cells targeting MSLN and show that the MSLN-directed CAR T cells effectively eliminate both AML blasts and LSCs while sparing normal HPSCs. The ability of MSLN CAR T cells to eradicate LSCs suggest that this might be an effective approach to prevent relapse in AML, as LSCs are thought to resist chemotherapy and can re-initiate the disease.  Our work provides the preclinical data to support further evaluation of MSLN-directed CAR T in clinical trials for refractory/relapse AML.

What are the next steps for this research?

We are in the process of transitioning our MSLN CAR T into clinical testing with clinical vector already under development. We anticipate opening this trial for relapsed/refactory AML in the 3rd-4th quarter of 2022.

If you’d like us to mention your funding sources, please list them.

We would like to thank NCI, Target Pediatric AML (TpAML), Lymphoma & Leukemia Society and St. Baldrick’s Foundation for supporting this research.

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