The University of Alabama at Birmingham
Project Term: July 1, 2022 - June 30, 2025
Evolving insights into the B cell-restricted FCRL1 surface protein reveal that it integrates with critical signaling pathways and is a promising immunotherapeutic target in CLL. Based on preclinical evaluation of novel FCRL1 monoclonal antibodies, we propose developing chimeric antigen receptor (CAR) T cells for targeting in unique mouse models and patient-derived cells. The results will form the basis for strategic drug development and clinical testing in CLL and related B cell malignancies.
Defects that cause accumulation of B cells are responsible for more than 85% of leukemias and lymphomas, including chronic lymphocytic leukemia (CLL). Recent advances in therapeutic strategies avoid the non-specific damage and toxicity of traditional chemotherapies. One advance selectively targets B cell-restricted markers with antibodies that bind cell surface proteins and directly kills cells or tags them for immune system elimination. A second approach uses small molecule drugs that block communication pathways that promote the survival and growth of CLL cells. Although these strategies represent major advances in the care of CLL patients, they do not cure the disease and resistance to them is emerging. This fuels a need for new therapies that extend patient survival. One innovative approach that holds promise for potentially curing CLL is a form of adoptive cell therapy that harnesses the immune system by engineering hybrid antibody molecules known as chimeric antigen receptors (CARs). CARs can be made by modifying T cells harvested from patients and then reinfusing them with the goal of eradicating the cancer cell population. Here we hypothesize that targeting a cell surface protein called Fc receptor-like 1 (FCRL1) by generating CARs from modified monoclonal antibodies will provide a novel therapeutic advance for CLL patients. This premise is based on studies in the field carried out by the principal investigator and other laboratories over the last two decades since its discovery. The basis for developing FCRL1 as a new immunotherapeutic target includes its: (a) restricted expression by B cells, which would minimize toxicities/adverse effects linked to reactivity of the therapy with other cell types; (b) high expression by CLL cells, which would minimize the problem of incomplete responses; (c) integration with critical survival pathways that could be targeted with combinatorial therapies; and (d) expression by other B cell malignancies, which would likely extend its use to a large number of leukemia/lymphoma patients. We propose to carry out preclinical studies with FCRL1-specific monoclonal antibodies we have generated using human and mouse models to: (1) Develop CAR molecules with our skilled co-Investigator and characterize their binding and cellular biologic properties; (2) Test the ability of FCRL1-targeted CAR T cells to respond and kill cells in cultured conditions; and (3) Validate the efficacy of FCRL1-targeted CAR T cell immunotherapy by in vivo treatment employing novel FCRL1 and CLL mouse models. The results will provide the foundation necessary to launch further cellular immunotherapeutic drug development and foster the design of clinical trials in CLL patients and those with related B cell malignancies.