Optimizing next-generation cellular therapies to eliminate residual AML

About This Grant

PROJECT SUMMARY/ABSTRACT Acute myeloid leukemia (AML) is a devastating disease with only 30% 5-year overall survival. As a blood cancer, AML appears poised to benefit from the revolution in engineered cellular therapies and bispecific antibodies. However, a lack of disease-specific targets has resulted in significant toxicity and lack of efficacy at clinically tolerable doses. The tumor necrosis superfamily member CD70 has attracted attention as a possible target to overcome these limitations, given its expression on AML and lack of or >20 fold lower expression on all normal tissues. However, current anti-CD70 CAR-Ts have shown only modest efficacy in AML models. Here, my long-term goal is to develop a new therapeutic approach to overcome these hurdles. The core hypotheses of this proposal is that 1) I can use computational engineering to create a best-in-class, naturalligand based CAR-T capable of clearing even CD70-low AML blasts and leukemic stem cells, and in parallel 2) develop a multifunctional anti-CD70 T cell therapy capable of secreting multiple T-cell-engager (TCE) antibodies in the LSC niche. Success here will define new classes of cellular therapy with curative potential in AML. This work may also outline a new therapeutic strategy use across cancers, to eliminate heterogeneous tumor in the microenvironment while sparing normal cells. To achieve these objectives, I have assembled a multidisciplinary mentorship team with complementary expertise, which includes Dr. Arun Wiita (mentor), Dr. Kevin Shannon (co-mentor), and advisory members Dr. Alexander Marson, Dr. Ansuman Satpathy, and Dr. Catherine Smith. My goal is to establish myself as an academic hematologist with a laboratory-based research program dedicated to translating cutting-edge cellular engineering technologies to solve clinically relevant problems in malignant hematology. This proposal outlines a comprehensive 5-year mentored career development plan that will provide me the essential knowledge and scientific training necessary to successfully become an independently-funded investigator. The training plan includes acquiring various new skills in cutting-edge techniques including murine cancer models and single cell biology and analysis interrogating T cell:tumor cell immunology, as well as enhancing skills in bioinformatics and R programming skills. Murine (vertebrate) studies are required as it is well known in the cell therapy field that in vitro assays are not predictive of therapeutic efficacy in human patients. UCSF provides an exceptional research environment, equipped with cutting-edge technologies and a range of leaders across multiple disciplines in addition to those on my advisory panels, in relevant fields including immunology, cellular engineering, and translational leukemia research. UCSF provides state-of-art facilities and world-renowned faculty, including those at Gladstone Institute for Genomic Immunology, UCSF Cell Design Institute (focused on cell engineering), the UCSF Center for Synthetic Immunology, the Living Therapeutics Initiative, and the UCSF Helen Diller Family Comprehensive Cancer Center.