David Truong ,

Ph.D.

Researchers at New York University are developing a novel cell therapy that could offer a longer-lasting, potentially more effective treatment for Alzheimer’s disease by clearing toxic proteins from the brain.

Instead of requiring repeated antibody infusions, which can be costly and cause inflammation, this new approach aims to use engineered immune cells to target and remove amyloid plaques — one of the hallmarks of Alzheimer’s disease.

The project has been awarded a $4.2 million grant from the National Institutes of Health’s National Institute on Aging to fund research over the next five years.

The multiple-Principal Investigator (MPI) research team is led by contact MPI Martin Sadowski, Professor of Neurology, Psychiatry, and Biochemistry and Molecular Pharmacology at NYU Grossman School of Medicine. He is joined by MPIs Paul M. Mathews, Research Associate Professor in the Department of Psychiatry at NYU Grossman School of Medicine, and David M. Truong, Assistant Professor of Biomedical Engineering and Pathology at NYU Tandon School of Engineering.

Truong’s lab is playing a key role in the genetic engineering of immune cells for the therapy, building on his expertise in stem cell engineering and synthetic biology. His team is working on designing “off-the-shelf” immune cells—cells that do not need to be taken from the patient but can instead be manufactured and prepared in advance.

Truong described the motivation behind the project as deeply personal. “I have Alzheimer's in my family, and I wanted to use my expertise to help introduce an innovative therapy that could really change the way we treat the disease,” he said.

The team is developing a type of engineered macrophage, a kind of immune cell that can identify and remove harmful proteins in the brain. These cells will be created from human induced pluripotent stem cells, a renewable source of cells that can be genetically modified in the lab.

The engineered cells will be designed to target and bind to amyloid plaques for removal, optimize brain access by reducing competition from the brain’s own immune cells, and include built-in safety mechanisms to deactivate the therapy if necessary.

Unlike many other experimental Alzheimer’s treatments, this approach does not require injecting the cells directly into the brain. Instead, they will be delivered through the bloodstream, where they can cross the blood-brain barrier and begin clearing harmful proteins, avoiding invasive procedures while ensuring effective treatment.

To further enhance safety, the therapy includes a built-in “kill switch” that allows doctors to deactivate the cells if needed. If unintended side effects occur, a specific drug can be administered to eliminate them, ensuring the treatment remains both controlled and adaptable.

Once Truong’s lab finalizes the engineering of these human cells, they will be handed off to Sadowski’s team for testing in Alzheimer’s disease models. The Nathan S. Kline Institute for Psychiatric Research will assist in evaluating how well the cells remove amyloid plaques, while NYU Grossman School of Medicine will analyze how the cells behave in the brain.

The therapy is an adaptation of chimeric antigen receptor (CAR) technology, which has been revolutionary in cancer treatment. While CAR-T cell therapies have been used to fight blood cancers, this research aims to adapt similar technology to neurodegenerative diseases like Alzheimer’s.

Truong noted that cell therapy is a rapidly evolving field and that while CAR-T therapy has primarily been used against cancer, this project is pushing the boundaries to see if such an approach could work for Alzheimer’s, a disease that affects millions and has few effective treatment options.

The five-year grant follows an R61/R33 funding model, meaning that the first two years are dedicated to proving the feasibility of the therapy. If the team meets its key scientific milestones, funding will continue for three additional years to move the research toward clinical readiness.

A new therapeutic era has been ushered in with Adoptive Cell Immunotherapy, which uses patient-harvested T cells genetically engineered against tumor-specific targets. However, the number of addressable cancers is limited by a lack of tumor-specific targets and T cell receptors.

A team led by David M. Truong, Ph.D., assistant professor of biomedical engineering, has been awarded a $1.8 million grant from the National Institute of Allergy and Infectious Diseases (NIAID) under the NIH Director’s New Innovator program, to address this issue by expanding the number of human leukocyte antigen (HLA) restricted T cell receptors (TCRs) and tumor-specific antigens (TSAs), thus transforming the entire immunotherapy pipeline.

To accomplish this, Truong proposes the generation of programmable Dendritic cells (DCs), which are professional antigen presenting cells that function to mature and activate naive T cells. These programmable DCs would facilitate the discovery of new TCRs, the validation of TSAs, and could even be used as “living” vaccines to marshal a patient’s own immune system against infectious disease and cancer.

Truong specifically hopes to produce off-the-shelf DCs pre-engineered to match any HLA haplotype, even rarer haplotypes, that are pre-encoded with any combination of TSAs. Truong’s group will search for and validate “universal” TSAs and TCRs that can be used broadly in TCR therapy for any patient.

More specifically, the group will focus on peptides expressed from regions of the genome which are normally epigenetically silenced, but which are reactivated in tumor cells, e.g., endogenous retroviruses. To further this, the group will continue to develop technology enabling the “writing” of millions of DNA base-pairs in human-induced pluripotent stem cells (iPSCs). Such technology allows for direct customization of the large HLA locus iPSCs in a single step, the introduction of libraries of potential TSAs, as well as integration of synthetic reporter constructs for safer and scalable directed differentiation of iPSCs to DCs.

This research on allogeneic programmed DCs may catalyze a wide variety of immunotherapy applications and expand access to advanced treatments for a greater number of patients.