I'm Julia. I'm a recently graduated PhD student in the lab of Joseph Fraietta at the Center for Cellular Immunotherapies at the University of Pennsylvania. I will be presenting research that I worked on with Doctor Matthew Ho and Doctor Luca Paruzzo, where we looked at unique toxicities observed in patients who received BCMA CAR-T cell therapy for multiple myeloma.
The unique toxicities we identified fall into four categories: rheumatology-related toxicities, pneumonitis (lung-related), enterocolitis (gut-related, which we studied most), and neurological-related toxicities. The neurological toxicities manifested as facial palsy or parkinsonism.
At the clinical level, we looked at factors associated with higher risk for developing these toxicities. We found that high expansion of CAR-T cells in the patient and receiving a specific CAR-T cell product called cilta-cel (the second CAR-T product approved for multiple myeloma) were significantly associated with higher risk. Most CAR-T cell products are bulk CD3-positive CAR-T cells, with the patient’s own CD4 and CD8 cells infused in the same ratio. We observed that patients with a CD4 skewing were at higher risk for these unique toxicities.
In our project, we were the first to define these toxicities as CAR-T cell immune-related adverse events, or CIRAE. Experimental studies further revealed that hyperproliferation of CD4 CAR-T cells is linked to cytotoxicity in patients. Biopsies of the gut showed that CD4 CAR-T cell infiltration overlapped with antigen expression in the gut, suggesting this infiltration drives enterocolitis toxicities.
We also performed single-cell RNA sequencing of CAR-T cells isolated from the cerebrospinal fluid to study neurological toxicities. These CAR-T cells were predominantly CD4 and exhibited cytotoxic transcriptional programs.
Currently, our project is moving toward a preventative approach. Clinically, our team uses these findings to stratify patients at higher risk for developing these toxicities. They look at the absolute lymphocyte count (ALC), and for patients with high ALC, they further stratify by CD4 T-cell skewing. This could allow preventative strategies, such as early steroid use, to reduce the risk of toxicities.
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HealthTree • December 22, 2025