Cilta-Cel CAR T Cell Therapy: Rapid Expansion Linked to Delayed Neurotoxicity in Patients

Rapid CAR T-Cell Expansion Linked to Delayed Neurotoxicity in Multiple Myeloma Patients

New research presented at the 2025 International Myeloma Society Annual Meeting suggests a connection between how quickly CAR T-cells expand in the body and the risk of developing delayed neurotoxicity (DNT) in individuals with relapsed or refractory multiple myeloma (RRMM) undergoing treatment with ciltacabtagene autoleucel (cilta-cel). This finding could help doctors personalize treatment strategies and proactively address potential complications.

Cilta-cel, a CAR T-cell therapy targeting BCMA, received FDA approval in 2022 for RRMM patients who had previously undergone at least four lines of therapy.This approval was later expanded in 2024 to include patients with just one prior line of treatment, based on the promising results from the CARTITUDE-1 trial, which demonstrated notable progression-free survival and deep responses.Recent data from August 2025 showed that 33% of patients in the study were still alive and progression-free after five years without needing maintenance therapy.

Though, the use of cilta-cel is frequently enough limited by its potential side effects, notably DNT. Researchers aimed to understand the link between CAR T-cell expansion and DNT, using flow cytometry to analyze the data. They also explored whether the absolute lymphocyte count (ALC) could serve as a marker to predict DNT risk and establish clinically relevant ALC thresholds. The study involved two groups: 256 patients with RRMM treated between 2022 and 2024 (the ALC cohort), and a separate cohort of 54 patients undergoing CAR expansion analysis.

The median age of patients in the ALC cohort was 64, with 54% being male and 38% classified as penta-refractory. After a median follow-up of 14.7 months, the median progression-free survival was 28.7 months. DNT occurred in 29 patients – 20 experiencing cranial nerve palsy and 8 developing Parkinsonism. The CAR expansion cohort showed similar characteristics, efficacy, and toxicity profiles. 16% of patients in this cohort (8 individuals) experienced DNT, including 4 cases of Parkinsonism.

The study found that patients who developed DNT had significantly higher peak CAR T-cell levels (p=0.04) and a strong correlation with peak ALC (r=0.84,p<0.001). Establishing clinically relevant ALC thresholds could help identify patients at higher risk of DNT.

What is the mechanism by which rapid CAR T-cell expansion may contribute to neurotoxicity, and how does this differ from cytokine release syndrome (CRS)?

Understanding Cilta-Cel and CAR T-Cell Therapy

Cilta-Cel (ciltacabtagene autoleucel), marketed as Carvykti, represents a important advancement in the treatment of relapsed or refractory multiple myeloma. As a B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy, it harnesses the patient’s own immune system to target and destroy cancer cells. CAR T-cell therapy involves extracting T cells from the patient, genetically modifying them to express a CAR that recognizes BCMA on myeloma cells, expanding these modified cells ex vivo, and then infusing them back into the patient. This process, while highly effective, isn’t without potential side effects. A growing body of evidence links the degree of CAR T-cell expansion to the risk of delayed neurotoxicity.

the Correlation Between CAR T-Cell Expansion and Neurotoxicity

Delayed neurotoxicity,manifesting weeks to months after CAR T-cell infusion,is an increasingly recognized complication of CAR T-cell therapies,including cilta-Cel. Research indicates a strong correlation between the peak CAR T-cell expansion and the likelihood of developing these neurological events.

* Rapid Expansion: Patients experiencing a notably robust and rapid expansion of CAR T cells post-infusion appear to be at higher risk. This suggests a potential “cytokine release syndrome (CRS)-independent” mechanism contributing to neurotoxicity.

* Peak CAR T-Cell Levels: Higher peak CAR T-cell counts in the peripheral blood are consistently observed in patients who subsequently develop neurological complications.

* Sustained Expansion: Prolonged CAR T-cell persistence,even after myeloma remission,can also contribute to the risk of delayed neurotoxicity.

Types of Neurotoxicity Observed with Cilta-Cel

The neurological manifestations associated with Cilta-Cel and other CAR T-cell therapies are diverse, ranging in severity from mild cognitive impairment to life-threatening conditions. Common presentations include:

* Encephalopathy: A broad term encompassing altered mental status, confusion, and difficulty with concentration. This is frequently reported.

* Aphasia: Difficulty with speech and language comprehension.

* Seizures: Both focal and generalized seizures have been documented.

* Tremors: involuntary shaking, often affecting the hands and limbs.

* Dysphasia: Difficulty swallowing.

* Posterior Reversible Encephalopathy Syndrome (PRES): A condition characterized by headache, altered mental status, seizures, and visual disturbances, often linked to hypertension.

* Cerebral Edema: Swelling of the brain, a perhaps life-threatening complication.

Proposed Mechanisms Linking Expansion to Neurotoxicity

While the exact mechanisms remain under inquiry, several hypotheses attempt to explain the link between CAR T-cell expansion and delayed neurotoxicity:

1. Bystander Activation: Highly expanded CAR T cells may inadvertently activate other immune cells, leading to inflammation and damage in the central nervous system (CNS).
2. Cytokine-Mediated Damage: Even though distinct from acute CRS,a more subtle and prolonged release of cytokines by the expanded CAR T cells could contribute to neuroinflammation. IL-6, TNF-alpha, and IFN-gamma are key cytokines implicated.
3. Direct CAR T-Cell Infiltration: CAR T cells,particularly those expressing high-affinity CARs,may cross the blood-brain barrier and directly target cells within the CNS,causing damage. This is more likely with BCMA expression in non-myeloma cells.
4. Endothelial Dysfunction: CAR T-cell activation and cytokine release can disrupt the integrity of the blood-brain barrier, increasing its permeability and allowing inflammatory molecules to enter the CNS.

Monitoring and Management Strategies

Early detection and proactive management are crucial for mitigating the risk of Cilta-Cel-associated neurotoxicity.

* Frequent Neurological Assessments: Regular neurological examinations, including cognitive testing, are recommended throughout the post-infusion period, extending beyond the typical CRS monitoring window.

* CAR T-Cell Monitoring: Serial monitoring of CAR T-cell expansion kinetics using qPCR or flow cytometry can help identify patients at high risk.

* Imaging Studies: MRI of the brain should be considered in patients exhibiting neurological symptoms to assess for PRES, cerebral edema, or other structural abnormalities.

* Pharmacological Interventions:

* Corticosteroids: Frequently enough the first-line treatment for neurotoxicity, used to suppress inflammation.

* Anticonvulsants: Used to manage seizures.

* Tocilizumab & Anakinra: While primarily used for CRS management, these IL-6 and IL-1 inhibitors may have a role in mitigating neuroinflammation.

* Supportive care: Maintaining adequate hydration, electrolyte balance, and blood pressure control is essential.

Real-World Case Example

In a case reported at the ASCO 2023 annual meeting, a 68-year-old male with relapsed/refractory multiple myeloma experienced grade 3 encephalopathy 6 weeks after Cilta-Cel infusion. Peak CAR T-cell expansion was substantially higher than the median for the cohort. MRI revealed mild cerebral edema. The patient responded to high-dose corticosteroids, with neurological symptoms resolving over several weeks.This case