Frontal predominant encephalopathy with early paligraphia as a distinctive signature of CAR T-cell therapy-related neurotoxicity

Pensato, Umberto; Amore, Giulia; D’Angelo, Roberto; Rinaldi, Rita; Nicodemo, Marianna; Rondelli, Francesca; Mondini, Susanna; Santoro, Raffaela; Sammali, Susanna; Farolfi, Andrea; Spinardi, Luca; Faccioli, Luca; Casadei, Beatrice; Dicataldo, Michele; Bonifazi, Francesca; Zinzani, P. L.; Cortelli, Pietro; Stracciari, Andrea; Guarino, Maria

doi:10.1007/s00415-021-10766-5

Cited by 15 publications

(31 citation statements)

References 18 publications

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“…The overall response rate to CAR-T cells in lymphoma patients is approximately 50-60% (3,4) and its efficacy is hampered by systemic hyper-inflammatory adverse events, including cytokines release syndrome (CRS) and Immune effector Cell-Associated Neurotoxicity Syndrome (ICANS). The clinical manifestations of ICANS are heterogeneous, ranging from language disturbances and frontal-predominant encephalopathy to akinetic mutism and, anecdotally, fulminant diffuse cerebral oedema (5)(6)(7)(8)(9). Patients with high baseline inflammatory serum profile as defined by pro-inflammatory cytokines (e.g., IL-6), C-reactive protein (CRP), ferritin and Ddimer have increased risk of developing ICANS (10)(11)(12).…”

Section: Introductionmentioning

confidence: 99%

Peripheral blood cellular profile at pre-lymphodepletion is associated with CD19-targeted CAR-T cell-associated neurotoxicity

et al. 2023

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BackgroundInfusion of second generation autologous CD19-targeted chimeric antigen receptor (CAR) T cells in patients with R/R relapsed/refractory B-cell lymphoma (BCL) is affected by inflammatory complications, such as Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS). Current literature suggests that the immune profile prior to CAR-T infusion modifies the chance to develop ICANS.MethodsThis is a monocenter prospective study on 53 patients receiving approved CAR T-cell products (29 axi-cel, 24 tisa-cel) for R/R-BCL. Clinical, biochemical, and hematological variables were analyzed at the time of pre-lymphodepletion (pre-LD). In a subset of 21 patients whose fresh peripheral blood sample was available, we performed cytofluorimetric analysis of leukocytes and extracellular vesicles (EVs). Moreover, we assessed a panel of soluble plasma biomarkers (IL-6/IL-10/GDF-15/IL-15/CXCL9/NfL) and microRNAs (miR-146a-5p, miR-21-5p, miR-126-3p, miR-150-5p) which are associated with senescence and inflammation.ResultsMultivariate analysis at the pre-LD time-point in the entire cohort (n=53) showed that a lower percentage of CD3+CD8+ lymphocytes (38.6% vs 46.8%, OR=0.937 [95% CI: 0.882-0.996], p=0.035) and higher levels of serum C-reactive protein (CRP, 4.52 mg/dl vs 1.00 mg/dl, OR=7.133 [95% CI: 1.796-28], p=0.005) are associated with ICANS. In the pre-LD samples of 21 patients, a significant increase in the percentage of CD8+CD45RA+CD57+ senescent cells (median % value: 16.50% vs 9.10%, p=0.009) and monocytic-myeloid derived suppressor cells (M-MDSC, median % value: 4.4 vs 1.8, p=0.020) was found in ICANS patients. These latter also showed increased levels of EVs carrying CD14+ and CD45+ myeloid markers, of the myeloid chemokine CXCL-9, as well of the MDSC-secreted cytokine IL-10. Notably, the serum levels of circulating neurofilament light chain, a marker of neuroaxonal injury, were positively correlated with the levels of senescent CD8+ T cells, M-MDSC, IL-10 and CXCL-9. No variation in the levels of the selected miRNAs was observed between ICANS and no-ICANS patients.DiscussionOur data support the notion that pre-CAR-T systemic inflammation is associated with ICANS. Higher proportion of senescence CD8+ T cells and M-MDSC correlate with early signs of neuroaxonal injury at pre-LD time-point, suggesting that ICANS may be the final event of a process that begins before CAR-T infusion, consequence to patient clinical history.

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Section: Introductionmentioning

confidence: 99%

Peripheral blood cellular profile at pre-lymphodepletion is associated with CD19-targeted CAR-T cell-associated neurotoxicity

et al. 2023

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“…However, its high efficacy is hampered, in a subset of patients, by an exaggerated systemic hyper-inflammatory response, namely cytokine release syndrome (CRS), and neurological adverse events, namely immune effector cell-associated neurotoxicity syndrome (ICANS) [ 2 ]. Clinical manifestations of ICANS are heterogeneous, ranging from language disturbances and frontal-predominant encephalopathy to akinetic mutism and, anecdotally, fulminant diffuse cerebral edema [ 1 – 3 ]. The latter is characterized by rapid neurological deterioration which may lead to death within 24 h, therefore representing the most fearsome complication of CAR T-cell therapy [ 1 , 4 , 5 ].…”

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confidence: 99%

Fulminant cerebral edema following CAR T-cell therapy: case report and pathophysiological insights from literature review

et al. 2022

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“…clinical and investigative similarities have been underlined between neurological manifestations of different cytokine storm disorders, mostly COVID-19, and CAR T-cell therapyrelated neurotoxicity (11,(15)(16)(17). Indeed, COVID-19-related encephalopathy/encephalitis is characterized by a frontalpredominant electro-clinical dysfunction associated with elevated CSF cytokines levels, together with several other shared features (11,16,18). Accordingly, these neurological disorders may represent an etiological coherent disease continuum, sharing cytokine storm as a common denominator.…”

Section: • Meningitismentioning

confidence: 99%

“…Unfortunately, up to 12% of patients treated with ICIs develop central or, more frequently, peripheral neurological disorders (3). The underlying mechanisms seem utterly different from those involved in ICANS, where encephalopathy is associated with the cytokine storm (11,19). Indeed, following treatment with ICIs, unrestrained T-cells may result in antigen-directed autoimmunity, either antibody-or T cellmediated.…”

Section: Immune Checkpoint Inhibitors Therapy-related Neurotoxicity A...mentioning

confidence: 99%

“…Clinical and instrumental findings of neurotoxicity have been poorly characterized thus far, yet some recurrent features have emerged. Encephalopathy, variably accompanied by early language disturbances, such as expressive aphasia and dysgraphia, and frontal lobe dysfunction represent recurrent clinical features ( 2 , 9 , 11 , 12 ). The disease has a heterogeneous course, and while some patients experience mild neurological manifestations with spontaneous recovery, a subgroup progresses to develop seizures, akinetic mutism, and coma, potentially leading to death ( 2 , 13 , 14 ).…”

Section: Car T-cell Therapy-related Neurotoxicity and Cytokine Storm-...mentioning

confidence: 99%

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The role of neurologists in the era of cancer immunotherapy: Focus on CAR T-cell therapy and immune checkpoint inhibitors

Pensato

Guarino²,

Muccioli³

2022

Front. Neurol.

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Cancer immunotherapy represents a novel anticancer strategy that acts directly on the immune system, promoting its activation toward cancer cells to enhance its natural ability to fight cancer. Among various treatments currently used or investigated, chimeric antigen receptors (CAR) T-cell therapy and immune checkpoint inhibitors (ICIs) have consistently proven their efficacy. These innovations are progressively improving the standard of care in cancer treatment, yet they are hampered by novel neurological adverse events, attributing to neurologists a key role in the multidisciplinary oncological team. Indeed, neurotoxicity may develop in up to 77% of patients who received CAR T-cell therapy and usually presents with encephalopathy characterized by a predominant frontal lobe dysfunction. This neurotoxicity is related to cytokine release syndrome, a systemic hyperinflammatory condition triggered by CAR T-cells. On the other hand, following treatment with ICIs, unrestrained T-cells may lead to central and peripheral neurological disorders by antigen-directed autoimmunity. Notably, biological and clinical similarities have been underlined between neurotoxicity related to CAR T-cell therapy and neurological manifestations of cytokine storms (e.g. COVID-19-related encephalopathy), as well as between a subgroup of ICI-related neurological adverse events and paraneoplastic neurological syndromes. Therefore, these cancer immunotherapy-related neurological syndromes may provide an unprecedented, perhaps transitory, opportunity to shed light on the underlying pathogenic mechanisms of a wide spectrum of neurological syndromes and to push forward our knowledge in neuroimmunology.

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Frontal predominant encephalopathy with early paligraphia as a distinctive signature of CAR T-cell therapy-related neurotoxicity

Cited by 15 publications

References 18 publications

Peripheral blood cellular profile at pre-lymphodepletion is associated with CD19-targeted CAR-T cell-associated neurotoxicity

Peripheral blood cellular profile at pre-lymphodepletion is associated with CD19-targeted CAR-T cell-associated neurotoxicity

Fulminant cerebral edema following CAR T-cell therapy: case report and pathophysiological insights from literature review

The role of neurologists in the era of cancer immunotherapy: Focus on CAR T-cell therapy and immune checkpoint inhibitors

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