OUTREACH
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T cells
T cells are extraordinary cells! They are a type of immune cell that patrols the body searching for tell-tale signs of infection or cancer. They use their T cell receptors (TCRs) to identify and recognize harmful foreign material, like viruses, bacteria, and cancer cells. T cells can attack and destroy these invaders directly by releasing substances that kill the infected or cancerous cells. T cells allow your body to “remember” threats that you have previously encountered to help you respond faster and more efficiently to future attacks.
Synthetic receptors
We can harness these functions of T cells and equip them with a synthetic receptor (a Chimeric Antigen Receptor or CAR) that allows them to focus their attention on and kill cancer cells. This chimeric protein combines the specificity of an antibody with intracellular T cell signalling molecules that deliver an activation signal akin to a TCR signal.
Clinical outcomes
CAR T cell therapy has been very powerful clinically for patients with B cell cancers (leukemias and lymphomas) who have failed other types of treatment. While many patients are cured by CAR T cell therapy, others either do not respond or relapse and thus there remains a great deal of room for innovation.
CAR T in the lab
We use mouse models that are highly representative of human lymphoma to better understand the mechanisms that underlie CAR T cell treatment failures and test new strategies to enhance CAR T cell efficacy. While some lymphomas are largely restricted to lymph nodes, others are broadly distributed outside of lymph nodes, and patients with this latter form of the disease have been shown to have inferior responses to CAR T cell therapy. We predict that different sites of disease pose distinct challenges to effective CAR T cell responses. We seek to characterize how CAR T cells behave across anatomic sites, and test CAR T cells that have been engineered to express genes that we hypothesize will increase their efficacy in non-lymphoid tissues.
Combination therapy
Once a T cell expresses a CAR, it can still receive signals through its T cell receptor (TCR), and therefore it has dual specificity. Our previous work elucidated how viruses can expand subsets of CAR T cells by providing TCR signals as well as accessory cues to stimulate T cell activities. To expand on these findings, we are trying to understand how the CAR and the TCR cooperate to direct T cell activity and persistence. We are using lipid nanoparticle-formulated mRNA vaccines to stimulate CAR T cells that also have TCR specificity to model antigens.
Making a CAR T cell
The preparation of CAR T cells requires complex and costly manipulations in the lab using viruses to insert the CAR gene. To streamline this process, we are using use lipid nanoparticles to deliver RNA to generate these cells directly in the body. We anticipate that these novel off-the-shelf approaches will empower us to directly manipulate cells in the body to treat disease while enhancing accessibility and simplifying implementation.
