“By identifying a common immunologic profile for these seemingly disparate side effects, we’re able to better understand and address CAR T immune-related adverse events,” said the study’s co-senior author, Joseph A. Fraietta, PhD, an assistant professor of Microbiology. “This work has immediate clinical implications, and we hope it will give oncologists insights to recognize high-risk patients and reduce mortality.”
A new type of immune-related adverse event Side effects related to immunotherapy have become more manageable over time, as clinicians and researchers have gained more experience recognizing and addressing them. This includes acute side effects associated with CAR T cell therapy, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which typically appear days after the infusion.
However, since B cell maturation-directed (BCMA) CAR T cell therapies for relapsed or refractory multiple myeloma have become commercially available in recent years, physicians have reported different adverse events, including instances of delayed cranial nerve palsies, Parkinson’s disease-like symptoms, and enterocolitis, which can be deadly in those with compromised immune systems. These reactions can happen weeks or even months after treatment. The research team collectively defined these complications as CAR T-associated immune-related adverse events (CirAE).
The team analyzed data from a cohort of 198 patients who received either idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleuce (cilta-cel), the two FDA-approved BCMA-CAR T cell therapies for multiple myeloma, between June 2021 and December 2024 at Penn Medicine. Researchers found that the incidence of any CirAE was 13.6 percent and significantly higher with cilta-cel (20 percent) compared to ide-cel (2.7 percent). Non-relapse mortality—meaning death from a cause other than cancer relapse—at one year after the CAR T infusion was significantly higher (17 percent vs 2.7 percent) in patients who experienced CirAE. All six deaths related to CirAE were in patients who received cilta-cel (accounting for 4.8 percent of cilta-cel treated patients). Infection accounted for 60 percent of non-relapse mortality deaths in the patients with CirAE, compared to 14.3 percent in patients without CirAE, which the researchers attribute to a seven-fold higher cumulative steroid exposure in the CirAE group.
“These findings indicate that even though BCMA-directed CAR T cell therapy is working to control the cancer, we need to keep a close eye on the other effects it may be having in the body so that we can quickly intervene, just as we’ve learned to do with CRS and ICANS,” said Marco Ruella, MD, a co-senior author and an associate professor of Hematology-Oncology.
Defining features and predictors of CirAE The team analyzed enterocolitis biopsies and cerebrospinal fluid (CSF) taken at the time of neurologic CirAE, and found that infiltrating CAR T cells were predominantly CD4+ and were enriched for cytotoxic gene signatures and elevated expression of effector molecules that are associated with tumor killing. Patients who developed CirAE had higher proportion of circulating CD4+ versus CD8+ T-cells post-infusion compared to those without CirAE. Additionally, CD4+ CAR T cells exhibited significantly higher BCMA-binding strength compared to CD8+ CAR T cells. Taken together, these findings indicate that CD4+ CAR T cells play a key role in mediating CirAE.
The study was inspired by a noteworthy case: a patient who had the highest CAR T expansion ever seen at Penn and multiple CirAEs, motivating the clinical team’s scientific collaborators to do a deep dive, eventually expanding their research to the broader scientific question.
The team found additional common clinical features among patients with CirAE, including ICANS, and significantly higher peak absolute lymphocyte count within 14 days post-infusion, which correlated with greater CAR T expansion. CAR T cell therapy requires a minimum expansion of CAR T cells to sufficiently attack the cancer, but experts are learning there may be an upper limit as well to avoid additional side effects.
Immediate impacts and ongoing research to address CirAE Based on these findings, the team made updates to how patients who receive CAR T cell therapy for multiple myeloma are treated at Penn Medicine. Patients treated with cilta-cel who have an unexpectedly high absolute lymphocyte count, high CD4:CD8 ratio, and ICANS of any grade within the first few weeks post-infusion, are considered high-risk and given a brief course of steroids (dexamethasone) to curb excessive CD4+ CAR T expansion.
“Once CirAE are ongoing, it takes large amounts of steroids to treat the issue, which we’ve seen leads to higher rates of infection and death,” said Adam Cohen, MD, a co-senior author, director of Myeloma Immunotherapy, and an associate professor of Hematology-Oncology. “If we can identify high-risk patients early on, and intervene with a lower dose of steroids, we hope to avoid CirAE altogether and reduce mortality.”
Ideally, a strategy that doesn’t involve steroids would be even less toxic and better for patients, so the research team took a closer look at what was causing the high CD4+ CAR T expansion in patients with CirAE. They found a specific circuit (IL‑15–CCL5–CCR5) was driving the proliferation and demonstrated in preclinical tests that blocking CCR5 safely restrained BCMA-CAR T cell expansion to optimal levels, while preserving their ability to attack the cancer cells. These findings suggest that a CCR5-directed targeted strategy would be worth exploring to protect against CirAE.
Learn more at ASH Julia Han Noll, a graduate student in Fraietta’s lab, will present Abstract 14221 in an Oral Abstract Session on Monday, Dec. 8 at 10:30 a.m. ET in West Hall E1. Luca Paruzzo, MD, a postdoctoral fellow in Ruella’s lab will present Abstract 12231 in a Poster Session on Monday, Dec. 8 at 6 p.m. ET in West Halls B3-B4.
Matthew Ho, MB BCh BAO, PhD, a Hematology-Oncology fellow is a co-first author along with Noll and Paruzzo. The research was funded by the NIH (P01 CA214278).
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