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Clinical Trial
. 2018 Aug;8(8):958-971.
doi: 10.1158/2159-8290.CD-17-1319. Epub 2018 Jun 7.

Clinical and Biological Correlates of Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia

Bianca D Santomasso  1   2 , Jae H Park  3   4   5   6 , Darin Salloum  7 , Isabelle Riviere  6   8 , Jessica Flynn  9 , Elena Mead  10 , Elizabeth Halton  5   11 , Xiuyan Wang  6   8 , Brigitte Senechal  6   8 , Terence Purdon  5 , Justin R Cross  12 , Hui Liu  12 , Behroze Vachha  13 , Xi Chen  1 , Lisa M DeAngelis  1 , Daniel Li  14 , Yvette Bernal  5 , Mithat Gonen  9 , Hans-Guido Wendel  7 , Michel Sadelain  5   6 , Renier J Brentjens  3   4   5   6
Affiliations
Clinical Trial

Clinical and Biological Correlates of Neurotoxicity Associated with CAR T-cell Therapy in Patients with B-cell Acute Lymphoblastic Leukemia

Bianca D Santomasso et al. Cancer Discov. 2018 Aug.

Abstract

CD19-specific chimeric antigen receptor (CAR) T-cell therapy is highly effective against relapsed or refractory acute lymphoblastic leukemia (ALL), but is hindered by neurotoxicity. In 53 adult patients with ALL, we found a significant association of severe neurotoxicity with high pretreatment disease burden, higher peak CAR T-cell expansion, and early and higher elevations of proinflammatory cytokines in blood. Patients with severe neurotoxicity had evidence of blood-cerebrospinal fluid (CSF) barrier disruption correlating with neurotoxicity grade without association with CSF white blood cell count or CAR T-cell quantity in CSF. Proinflammatory cytokines were enriched in CSF during severe neurotoxicity with disproportionately high levels of IL6, IL8, MCP1, and IP10, suggesting central nervous system-specific production. Seizures, seizure-like activity, myoclonus, and neuroimaging characteristics suggested excitatory neurotoxicity, and we found elevated levels of endogenous excitatory agonists in CSF during neurotoxicity.Significance: We detail the neurologic symptoms and blood, CSF, and neuroimaging correlates of neurotoxicity associated with CD19 CAR T cells and identify neurotoxicity risk factors. Our findings implicate cellular components other than T cells and suggest novel links between systemic inflammation and characteristic neurotoxicity symptoms. Cancer Discov; 8(8); 958-71. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 899.

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Figures

Figure 1.
Figure 1.
Timeline of neurotoxicity (NTX) and association with CRS after conditioning chemotherapy and 19–28z CAR T cell infusion. A. Colors on the swimmer lane plot indicate the highest grade of any neurologic symptom recorded on each day for patients who developed grade ≥ 1 NTX through the first 30 days after CAR T infusion (n=33; 11 grade 1–2 NTX, 22 grade 3–4 NTX). Two patients died within 30 days of CAR-T cell infusion (CRS, n=1; sepsis n=1). Two patients had ongoing grade 3 or 4 NTX (sensorimotor neuropathy) at day 30 which improved to mild by day 39 and 96, respectively. Median time to first fever (≥38°C) for patients with mild NTX (blue dotted line) and severe NTX (red dotted line) and median time to first severe (grade ≥3) NTX (red dashed line) are indicated. B. Number of patients with each grade of CRS and neurotoxicity.
Figure 2.
Figure 2.
Brain MRI findings in patients with severe neurotoxicity after 19–28z CAR T cell therapy. A. Axial FLAIR images demonstrate symmetric hyperintense signal abnormality in bilateral thalami (upper panels, arrowheads) and the pons (lower panels, arrowheads) in 4 patients (labeled 1 to 4) with acute neurotoxicity. Two patients (patient 1 and 3) demonstrate additional hyperintense signal abnormality in the extreme and external capsule (arrows). B. Brain MRI findings in a patient during (left panel) and after (right panel) resolution of acute symptoms of neurotoxicity. C. Axial DWI (left panel) and FLAIR (right panel) images in 2 patients with severe neurotoxicity demonstrating reversible lesions of the splenium of the corpus callosum (arrow) characterized by restricted diffusion (left panel, arrowhead)and FLAIR hyperintensity (right panel, arrowhead).
Figure 3.
Figure 3.
Systemic inflammation in patients with severe neurotoxicity (NTX). A. Severe NTX associated with higher peak CAR T expansion (vector copy number per mL) in blood. B. Maximum temperature, serum C-reactive protein (CRP), and ferritin are shown for patients at the indicated time windows after CAR T cell infusion. C. Volcano plots visualizing the relative significance of serum cytokines associated with severe NTX by pre-lymphodepletion, day 3 post-infusion, and peak post-infusion during the first 28 days. Cytokines with p<0.05 are indicated in red. D. Serum cytokine concentrations within indicated time windows comparing grade 0–2 versus grade 3–4 NTX for significant cytokines in C. All are maximum cytokine concentrations within the indicated time window except for EGF which is minimum cytokine concentration. For B and D: Within each time window, the y-axis shows the mean ± SEM of the values for all patients according to the NTX severity. P values were determined using the Kruskal-Wallis test. *** P < .001, **.001 < P < .01, *.01 < P < .05. Pre-LD, prior to the start of lymphodepletion chemotherapy; d0, prior to CAR T cell infusion; d, days after CAR-T cell infusion. G, grade.
Figure 4.
Figure 4.
Increased blood-cerebrospinal fluid (CSF) barrier permeability during neurotoxicity (NTX). CSF samples were collected from patients with Gr0–2 and Gr3–4 NTX following 19–28z CAR T cell infusion and were analyzed for CSF cell count (A, B), CSF CAR vector copy number per mL (VCN/mL) (C), and CSF protein concentration (D, E). Box whisker plots indicate mean and interquartile range. B. Nucleated cell count in CSF in patients who developed Gr 0–4 NTX by grade. E. Protein concentration in CSF in patients who developed Gr 0–4 NTX by grade. F. CSF/serum albumin ratio (Qalb, albumin quotient) in pre- and post-treatment CSF samples from individual patients with NTX. Dots represent single time points from a single patient. Gr0 post indicates CSF from a patient at day 14 post CAR infusion who did not develop NTX. Jonckheere-Terpsta Test and paired test were used to compare CSF WBC and protein among the different grades of NTX in B and E. Unpaired test was used for comparison between pre and acute time points in F. *, P <0.05; **, P<0.01, ***, P <0.001.
Figure 5.
Figure 5.
Elevated cytokine concentrations and excitatory neurotoxins in CSF during neurotoxicity (NTX). CSF was collected from patients with or without severe NTX. A-B. Concentrations of cytokines in paired serum and CSF samples obtained from patients who developed Gr0–1 (n=4) or Gr3–4 (n=7) NTX. There was no CSF from patients with Gr2 available for cytokine analysis. A. CSF cytokines with significantly higher levels in severe NTX (Gr 3–4) than mild (Gr0–1) NTX. B. Cytokines with significantly higher levels in CSF than blood during severe NTX. C. NMDA receptor agonists quinolinic acid (QA) and glutamate (GLUT) in pre-treatment CSF and CSF collected from individual patients during NTX. Dots represent time points from a single patient. Gr0 post indicates CSF from a patient at day 14 post CAR infusion who did not develop NTX. P values in A-B were calculated using Wilcoxon Test (two-sided). Unpaired test was used for comparison between pre and NTX time points in C.
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