New Insights Link Delayed Side Effects of CAR T Therapy to Immune Response, Offering Path to Reduced Mortality
A common immune pathway underlying serious, delayed side effects following CAR T cell therapy for multiple myeloma has been identified, potentially paving the way for earlier intervention and reduced mortality. The findings, presented today – December 8, 2024 – at the 67th American Society of Hematology (ASH) Annual Meeting and Exposition (Abstracts 14221 and 12231), suggest that these complications, often appearing weeks or months after treatment, are largely driven by a specific type of immune cell and may be avoidable.
Researchers from the Abramson Cancer Center (ACC) of the University of Pennsylvania and Penn’s Perelman School of Medicine have pinpointed a shared immunological profile for these previously disparate adverse events. “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,” explained a study co-senior author. “This work has immediate clinical implications, and we hope it will give oncologists insights to recognize high-risk patients and reduce mortality.”
Understanding CAR T-Associated Immune-Related Adverse Events (CirAE)
While immunotherapy side effects have become more manageable with experience, a new class of complications has emerged with the increasing use of B cell maturation-directed (BCMA) CAR T cell therapies for relapsed or refractory multiple myeloma. These include delayed cranial nerve palsies, Parkinson’s disease-like symptoms, and enterocolitis – inflammation of the intestines – which can be fatal, particularly in patients with weakened immune systems. The research team collectively termed these delayed reactions CAR T-associated immune-related adverse events (CirAE).
Cilta-cel Linked to Higher Risk, Infection a Major Concern
An analysis of 198 patients treated with either idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleuce (cilta-cel) between June 2021 and December 2024 at Penn Medicine revealed that 13.6% experienced any CirAE. Critically, the incidence was significantly higher in patients receiving cilta-cel (20%) compared to ide-cel (2.7%).
The data showed a stark difference in non-relapse mortality – death from causes other than cancer relapse – at one year post-infusion: 17% in patients with CirAE versus 2.7% in those without. All six deaths linked to CirAE occurred in patients treated with cilta-cel, representing 4.8% of that patient group. A significant factor contributing to mortality was infection, accounting for 60% of non-relapse deaths in the CirAE group, compared to just 14.3% in patients without CirAE. Researchers attribute this disparity to a seven-fold higher cumulative steroid exposure in patients experiencing CirAE.
“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,” stated Marco Ruella, MD, a co-senior author and associate professor of Hematology-Oncology.
The Role of CD4+ T Cells in CirAE
Delving into the underlying mechanisms, the team analyzed biopsies and cerebrospinal fluid, discovering that infiltrating CAR T cells in CirAE cases were predominantly CD4+ T cells. These cells exhibited characteristics associated with tumor killing, including cytotoxic gene signatures and elevated expression of effector molecules. Patients who developed CirAE also had a higher proportion of circulating CD4+ T cells compared to CD8+ T cells post-infusion. Furthermore, CD4+ CAR T cells demonstrated a stronger binding affinity to BCMA than their CD8+ counterparts, suggesting a key role for CD4+ cells in mediating these adverse events.
The research was sparked by a particularly striking case – a patient with exceptionally high CAR T cell expansion who also experienced multiple CirAEs – prompting a deeper investigation into the broader phenomenon. Researchers also observed a correlation between CirAE and higher peak absolute lymphocyte counts within 14 days of infusion, indicating a link to greater CAR T cell expansion. While CAR T cell expansion is necessary for effective cancer treatment, these findings suggest there may be an upper limit beyond which the risk of side effects increases.
Early Intervention Strategies and Future Directions
Based on these findings, Penn Medicine has already updated its treatment protocols for patients receiving CAR T cell therapy for multiple myeloma. Patients treated with cilta-cel who exhibit unexpectedly high absolute lymphocyte counts, a high CD4:CD8 ratio, and any grade of immune effector cell-associated neurotoxicity syndrome (ICANS) within the first few weeks post-infusion are now considered high-risk and receive a short course of steroids (dexamethasone) to manage excessive CD4+ CAR T cell 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,” explained Adam Cohen, MD, a co-senior author and director of Myeloma Immunotherapy. “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.”
Looking beyond steroids, the team identified a specific pathway – IL‑15–CCL5–CCR5 – driving CD4+ CAR T cell proliferation. Preclinical tests demonstrated that blocking CCR5 safely restrained BCMA-CAR T cell expansion to optimal levels while preserving their anti-cancer activity. This suggests a targeted CCR5-directed strategy could offer a less toxic approach to preventing CirAE. .
Further details on these findings will be presented at the ASH meeting: Julia Han Noll will present Abstract 14221 on Monday, December 8 at 10:30 a.m. ET in West Hall E1, and Luca Paruzzo, MD, will present Abstract 12231 in a Poster Session on Monday, December 8 at 6 p.m. ET in West Halls B3-B4. The research was funded by the NIH (P01 CA214278).
