Neuroinflammation detected by TSPO-PET precedes dopaminergic neuronal loss in mnt following BCMA-directed CAR-T therapy: Longitudinal multimodal neuroimaging and biomarker insights

Abstract

Abstract Background: Ciltacabtagene autoleucel (cilta-cel) targets B-cell maturation antigen (BCMA) in multiple myeloma (MM). Rare, potentially life-threatening late-onset neurotoxicity syndromes associated with BCMA targeting encompass movement and neurocognitive treatment-emergent adverse events (MNTs). Underlying pathomechanisms of this toxicity and their temporal dynamics remain poorly understood. BCMA expression in the caudate nucleus (Van Oekelen et. al., Nat. Med. 2021) hints towards on-target, off-tumor CAR-T cytotoxicity contributing to MNT pathophysiology. However, reliable biomarkers for predicting or monitoring MNT are currently lacking. We previously suggested positron emission tomography (PET) targeting the 18 kDa translocator protein (TSPO) as a surrogate marker of microglial activation and imaging correlate of ICANS in patients following CD19 CAR-T cell therapy (Vinnakota et al., Nat. Cancer, 2024). Aims: To explore potential biomarkers and gain insight into the pathomechanisms of MNT, we analyzed clinical trajectories under multimodal neuromonitoring in patients (pts) with grade 3/4 MNT following cilta-cel. Methods: We report results from two MNT pts, encompassing longitudinal flow cytometry analyses of peripheral blood (PB) and cerebrospinal fluid (CSF), resting-state fMRI (imaging biomarker for functional CNS connectivity), multimodal positron emission tomography (PET) imaging ([18F]Fluoroethyl-L-tyrosine ([18F]FDG-PET), dopamine transporter single-photon emission computed tomography (DaT-SPECT), and PET imaging with a high-affinity ligand binding TSPO, pyrazolo pyrimidine acetamide [18F]DPA-714 as well as immunoassays of inflammatory markers and established serum biomarkers indicative for neuroaxonal injury and astroglial activation (neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP)). Biomarker analyses were carried out at MNT onset and over a period of 2 months. Informed consent was obtained prior to CAR-T treatment in both pts. Results: Both pts (2 males, 68 & 63y/o) received cilta-cel due to refractory MM (3 and 4 prior therapy lines, respectively). Short-term toxicity included max. grade (G)2 cytokine release syndrome (CRS) in both pts. MNT (G3 in both at onset, assessed as Gmax of reported symptoms per CTCAE) was diagnosed on day 48 (pt 1), and day 21 (pt 2) after cilta-cel transfusion. Neurological examination at onset revealed hypokinetic movement disorder with right-sided rigor pronounced to the upper body, as well as psychomotor retardation and dysexecutive syndrome. MNT rapidly progressed to CTCAE G4 in both patients despite therapies including dexamethasone, anakinra, and IVIGs. Intrathecal chemotherapy was subsequently administered without significant effect. It was followed by i.v. cyclophosphamide, which did not result in resolution, but until days 84/92 post-onset has prevented further MNT progression. Flow cytometry demonstrated extensive CAR-T cell expansion at MNT onset (%CAR-T of CD3+ cells in PB: 93.6% & 100%; in CSF: 95.8% & 97.4%), with sustained persistence in both PB and CSF. In both patients, NfL and GFAP showed a marked increase prior to symptom onset compared to CAR-T baseline and remained elevated throughout the MNT course. Routine MRIs at MNT onset were without pathological findings, whereas resting-state fMRI revealed alterations in frontal and striatal neuronal networks at both MNT onset and later timepoints. Multimodal PET at MNT onset showed marked TSPO tracer uptake in the basal ganglia, whereas FDG-PET and DaT-SPECT did not reveal any uptake changes nor evidence of presynaptic dopaminergic neuron loss. Over the clinical course, TSPO-PET showed significant uptake within the basal ganglia at 2 and 4 weeks after onset, followed by a progressive decline over the following two months. By 2 months, FDG-PET showed reduced metabolic activity in the striatum and thalamus, while DaT-SPECT revealed presynaptic dopamine transporter degeneration, indicating evolving neurodegenerative dopaminergic loss. Conclusion: This is the first report to demonstrate in vivo proof of neuroinflammation of the basal ganglia by TSPO-PET imaging and elevated NfL and GFAP levels in the context of cilta-cel induced MNT at symptom onset, preceding neurodegeneration of presynaptic dopamine transporters. Our results significantly contribute to an improved understanding of MNT pathomechanisms and lay the foundation for future potential therapies of these hard-to-manage neurotoxicities.