First in Human Mesothelia-Directed Artemis CART in Childhood AML

AML remains one of the most lethal childhood malignancies. Until now, identification of appropriate targets for immunotherapy development had remained elusive. Using transcriptome data from over 3000 patients, we have identified a library of targets that are highly expressed in AML leukemic blasts, but entirely absent in normal blood cells. Effective targeting such AML-specific proteins can eliminate leukemia without causing cytopenia. One of these AML-specific targets is Mesothelin (MSLN) which is highly expressed in a subset of very high-risk AML cases, including KMT2A-rearranged AML with no expression in normal blood cells. We have validated MSLN as a viable target in AML and have demonstrated that MSLN-directed immunotherapy (CAR-T cells) can effectively eliminate leukemic cells in both cell culture, as well as in animal models, facilitating its transition to the clinic. In addition to AML, MSLN is highly expressed in several high-risk adult malignancies, including pancreatic cancer with significant efforts being made towards development of therapies for solid tumors. Eureka Therapeutics, a biopharmaceutical company has developed a unique technology called ARTEMIS to optimize efficacy and minimize toxicity of CARTs by incorporating a distinct co-stimulatory component to the CART vector. The Eureka MSLN-directed ARTEMIS CART is entering clinical trials in pancreatic cancer. In close collaboration and support of the company at the highest level (please see letter from Dr. Liu, CEO, Eureka), we propose to conduct the first-in-human phase I trial with this asset in childhood AML. This will be an international collaborative effort between US, EU with a pharma representative. Dr. Meshinchi will oversee activation of the trial in US (Dr. Tarlock; clinical PI). Dr. Locatelli will oversee activation and conduct of the trial in EU (Dr. Becilli, clinical PI). Dr. Liu, CEO Eureka will work directly with Dr. Meshinchi and Locatelli for timely manufacturing and delivery of the MSLN ARTEMIS CART. To ensure timely completion of the trial, Eureka will support IND submission, T-cell collection (apheresis), and CART manufacturing and delivery. Support from LLS ACT grant will ensure all clinical trial costs are covered and ensure timely and successful completion of the study.