Engineered T cell approaches for Alzheimer's disease

Washington University, Saint Louis MO

Investigators

Abstract

Project Abstract Chimeric Antigen Receptor (CAR) T cells have revolutionized the treatment of hematologic malignancies, and recent clinical trials have also shown the potential of using CAR T cells against other pathologies, such as autoimmune diseases. Despite the common notion of brain-immune privilege, the presence of adaptive immune cells within the CNS has long been known to modulate cognition, suggesting that the immune system might be a viable target for improving cognition. We and others have implicated interactions between the CNS and the immune system in the development and progression of Alzheimer's disease (AD). T cells, specifically, have a complex role in AD pathology, with both protective and destructive functions. The exact mechanisms by which T cells convey pro-cognitive benefits remain poorly understood in many cases, although cytokine release remains the prevalent theory. For example, we recently showed a mechanistic link between IL- 4 secretion by meningeal T cells, improved memory, and rescued synapse function, and a pro-cognitive role of IL-4 has also been demonstrated in AD mouse models. While AD treatments using monoclonal antibodies have shown efficacy in reducing the level of amyloid beta (Aβ) plaques, their effects on cognition are limited and more powerful treatments are needed. Here, we propose an alternative approach in which amyloid beta (Aβ) plaques and other AD-related brain antigens are utilized as AD-specific signals to home neuroprotective T cells that will modulate the brain microenvironment to alter AD trajectories and improve cognition. In the Exploratory R61 phase, we will design and develop CARdinal (CAR Disease INterventions for ALzheimer's) T cells that are programmed to expand and persist at the site of AD pathology by utilizing cytokine signaling in our CAR constructs, rather than “classic” cytolytic CAR T cells. These T cells will release neuroprotective payloads that we propose will support neuronal function and improve cognition. Given that IL-4 can modulate memory and that BDNF can have protective effects in rodent and primate models of AD, we will engineer our CAR T cells to secrete IL-4 and/or BDNF as proof-of-concept therapeutic cargos. If defined milestones for the R61 phase are met, we will then pursue the Developmental R33 phase, in which we will test the hypothesis that repurposing our novel CARdinal T cells towards a proliferation and cargo secretion function, rather than a cytotoxic trajectory, will yield CAR T cells that are safe and effective for in vivo delivery of AD-therapeutic cargos to the brain with minimal cytotoxic effects. We will use single-cell multiomic technologies to determine the CARdinal T cells’ mechanism(s) of action by measuring cellular interactions, spatial organization, and temporal transcriptional changes in the CNS. We hypothesize that BDNF- and IL-4-secreting CAR T cells will significantly modify the CNS microenvironment, specifically by reprogramming microglial gene signatures and cellular programs, thus preventing cognitive decline. We expect that these studies will yield engineered neuroprotective CAR T cells that are safe and effective for in vivo use in AD.