Engineering Next Generation Car T Cells to Treat Pediatric AML: Enhancing Safety Through Dynamic Control and Specificity
Abstract
Acute myeloid leukemia (AML) is curable in less than 30% of patients. Immunotherapeutic approaches have changed the landscape of treatments for patients with B-lineage malignancies but have not yet been effective in myeloid malignancies due to concerns over on-target/off-tumor effects on healthy myeloid cells. No AML-specific cell surface antigens have been identified and using conventional chimeric antigen receptor (CAR) T cell therapy to target myeloid antigens would likely lead to life-threatening myelosuppression. In the Lim lab, we have developed two novel receptors that we believe have the potential to overcome the obstacles of on-target/off-tumor toxicity. Our goal is to improve the treatment of AML by developing next generation immunotherapy with enhanced AML specificity and decreased toxicity. This is a collaborative venture between a leader in T cell therapy engineering(Lim) and a leader in childhood leukemia (Loh). We have made significant progress towards accomplishing the goals of this project. We have taken two approaches using recently developed, novel receptors to generate a CAR T cell with titratable cytotoxic activity and a dual receptor, AND-gate CAR Tcell. We have developed synthetic cellular circuitry to 1) titrate cytotoxic activity of a CAR T cell and 2) to target abnormal combinations of cell surface antigens that are specific to leukemic cells and will spare toxicity to healthy myeloid cells. Over the last year we have focused on studying the dual receptor. Preliminary results show that this receptor is able to achieve titratable and reversible control of CAR T cell activity. In vitro this circuit achieves tumor clearance similar to the constitutive CAR expression and shows less T cell differentiation as well as less exhaustion. These characteristics have been positively correlated with better in vivo performance in mice and humans.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jul 01, 2020
- Accession Number
- AD1106343
Entities
People
- Wendell Lim
Organizations
- University of California, San Francisco