T cells with native and chimeric receptors against multiple tumor targets for acute myeloid leukemia
Catherine Bollard
MDChildren's Research Institute
Project Term: October 1, 2021 - September 30, 2024
Adoptive T cell therapies for acute myeloid leukemia face numerous hurdles such as limited target antigens, immunosuppressive tumor environment as well as the loss of efficacy due to downregulation of the targeted antigen. The goal of our project is to address some of these challenges with a single T cell product targeting multiple tumor associated antigens that have limited expression on healthy tissues via a novel combination of native T cell receptor and gene engineered CAR targeting.
Despite the ground-breaking impact of chimeric antigen receptor (CAR)-T cell therapy in curing many blood cancers, its success has not been recapitulated for other leukemias such as acute myeloid leukemia (AML). Often the tumor cells develop resistance to the CAR-T treatment by losing the protein (antigen) that the T cells were targeting. Our laboratory’s current approach to prevent this escape mechanism by the tumor is to manufacture specialized T cells capable of recognizing multiple proteins on the tumor without genetic modification. We have demonstrated that this approach can be effective in preventing the cancer from coming back in patients who have already relapsed from conventional chemotherapy or stem cell transplant. Some of the challenges of our approach include the need to give multiple T cell infusions and lack of complete responses in patients with active disease. The goal of this project is to improve the efficacy of our current multi- antigen T cell therapy by expanding the number of tumor proteins the T cell product recognizes by gene engineering the cancer killing T cells to recognize additional proteins on the tumor and provide the immune boost necessary for rapid expansion inside the body. Hence in this application we propose to develop a specialized T cell product than can not only recognize multiple proteins through the patient’s natural immune system but can also expand rapidly by the co-stimulation provided by the engineered T cells. We will determine if these engineered T cells have enhanced killing ability compared to the non- engineered T cells. It will provide the preliminary evidence to enable testing this novel T cell product in a variety of “hard to treat” lymphomas. Our therapy has the potential to benefit other blood cancers such as high risk leukemia, solid tumors and brain cancer which often express the proteins targeted by our specialized T cells.