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Our research
Developing CAR T Cells for AML
Acute myeloid leukemia (AML) was once at the forefront of immunotherapy as the primary indication for allogeneic hematopoietic stem cell transplant, which provided initial proof of concept that the immune system has activity against cancer. However, AML has thus far proven resistant to the more recent developments in immunotherapy such as checkpoint blockade, T cell engaging antibodies, and CAR T cells. The lack of efficacy of these agents in AML is unexpected given their proven success in other malignancies and illustrates that there is still much to be learned about their mechanism of action. One goal of our research is to elucidate the barriers to successful T cell immunotherapy for AML and identify methods to improve the outcomes of therapy.
Understanding the Interactions of CAR T Cells and Host Myeloid Cells
On a related note, while T cells may be the initial driving force of the immune response against tumors, this response is amplified by activation of endogenous myeloid cells, which can in turn improve T cell activity in a positive feedback loop. Hematopoietic stem and progenitor cells (HSPCs), myeloid precursors, and mature myeloid cells all have active roles in modulating T cell function and can influence the potency of CAR T cell therapy. Another goal of our research is to better understand the interactions of CAR T cells and host myeloid cells so that we can leverage these interactions to improve therapy.
Engineering HSPCs to Improve CAR T Cell Therapy
We are also investigating methods by which HSPCs can be engineered to overcome the limitations of CAR T cell therapy. By using lentiviral gene transfer and/or CRISPR/Cas9-based gene editing of HSPCs, we can manipulate HSPCs that can in turn reprogram the entire hematopoietic system to work in concert with CAR T cells to achieve optimal targeting of disease.
Defining the Optimal Immune Environment for CAR T Cells
Finally, we are investigating how to best create the optimal immune environment for CAR T cell therapy. Lymphodepletion is a form of low-dose chemotherapy that is given prior to CAR T cell treatment in human patients. This usually consists of a combination of two different chemotherapy agents, cyclophosphamide and fludarabine, that is designed to suppress the patient’s native immune system so that it does not interfere with CAR T cell activity. It is generally accepted that lymphodepleting chemotherapy is essential for CAR T cells to be effective. However, why lymphodepletion is necessary for CAR T cells has not been clearly established, and this represents a missed opportunity to improve upon the status quo to increase the impact of CAR T cell therapy. We aim to develop lymphocyte depletion methods that can be more effective in creating an environment for CAR T cells to thrive.
