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. 2022 May 12;2(1):49.
doi: 10.1038/s43856-022-00116-5. eCollection 2022.

Patient-reported outcomes and neurotoxicity markers in patients treated with bispecific LV20.19 CAR T cell therapy

Jennifer M Knight  1   2 , Aniko Szabo  3 , Igli Arapi  1 , Ruizhe Wu  3 , Amanda Emmrich  1 , Edward Hackett  4 , Garrett Sauber  5 , Sharon Yim  6 , Bryon Johnson  6 , Parameswaran Hari  6 , Dina Schneider  7 , Boro Dropulic  7 , Rachel N Cusatis  8 , Steve W Cole  9 , Cecilia J Hillard #  5 , Nirav N Shah #  6
Affiliations

Patient-reported outcomes and neurotoxicity markers in patients treated with bispecific LV20.19 CAR T cell therapy

Jennifer M Knight et al. Commun Med (Lond). .

Abstract

Background: With the rising number of chimeric antigen receptor (CAR) T cell treated patients, it is increasingly important to understand the treatment's impact on patient-reported outcomes (PROs) and, ideally, identify biomarkers of central nervous system (CNS) adverse effects.

Methods: The purpose of this exploratory study was to assess short-term PROs and serum kynurenine metabolites for associated neurotoxicity among patients treated in an anti-CD20, anti-CD19 (LV20.19) CAR T cell phase I clinical trial (NCT03019055). Fifteen CAR T treated patients from the parent trial provided serum samples and self-report surveys 15 days before and 14, 28, and 90 days after treatment.

Results: Blood kynurenine concentrations increased over time in patients with evidence of neurotoxicity (p = 0.004) and were increased in self-reported depression (r = 0.52, p = 0.002). Depression improved after CAR T infusion (p = 0.035). Elevated 3-hydroxyanthranilic acid (3HAA) concentrations prior to cell infusion were also predictive of neurotoxicity onset (p = 0.031), suggesting it is a biomarker of neurotoxicity following CAR T cell therapy.

Conclusions: Elevated levels of kynurenine pathway metabolites among CAR T cell recipients are associated with depressed mood and neurotoxicity. Findings from this exploratory study are preliminary and warrant validation in a larger cohort.

Keywords: Cancer immunotherapy; Predictive markers.

Plain language summary

This study examined the impact of chimeric antigen receptor (CAR) T cell therapy—a therapy that gets immune cells to fight cancer by changing them in the lab to find and destroy cancer cells—on blood markers associated with depression, anxiety, pain, fatigue, and poor sleep. Fifteen CAR T cell patients provided blood samples and completed surveys before and three timepoints after treatment. We found that the amount of kynurenine, a normal blood constituent, and related molecules was higher in patients who experienced significant CAR T cell side effects on the brain and in patients reporting more depression. These results identify the excessive elevation of blood constituents related to the mood that may also be associated with depression and brain dysfunction following CAR T. These blood constituents could potentially be used as markers and targeted with interventions to prevent brain dysfunction.

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Conflict of interest statement

Competing interestsThe authors declare the following competing interests. P.H. reports receiving honoraria from Incyte, BMS, Legend, Jannsen, Takeda, Amgen, Karyopharm, GSK, Pfizer. C.J.H. is a member of the Scientific Advisory Boards of Phytecs, Inc, and has equity in Formulate Biosciences. B.J. reports receiving research support and honoraria and travel support from Miltenyi Biotec. D.S. and B.D. are authors on a patent for the 20.19 CAR. N.N.S. reports receiving honoraria and/or travel support from Incyte, Celgene, Lily, and Miltenyi Biotec; serving on scientific advisory boards for Lily, Kite, Celgene, Legend, Epizyme, Seattle Genetics, and TG therapeutics; equity ownership in Exelixis, Geron; receiving institutional research support for clinical trials from Miltenyi Biotec. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Kynurenine metabolic pathway.
3-HK 3-Hydroxykynurenine, 3-HAA 3-Hydroxyanthranilic acid, QA Quinolinic acid, NMDA-R N-methyl-D-aspartate receptor, nAChR Nicotinic acetylcholine receptor.
Fig. 2
Fig. 2. Patient-reported outcome (PRO) mean changes over time.
BL baseline, BPIF Brief Pain Inventory Fatigue, BPII Brief Pain Inventory Intensity, FSID Fatigue Symptom Inventory Duration, FSIF Fatigue Symptom Inventory Interference, FSII Fatigue Symptom Inventory Intensity, IDAS Inventory of Depression and Anxiety Symptoms, PSQI Pittsburgh Sleep Quality Index. Pain, fatigue, depression, and anxiety were analyzed via a mixed effect longitudinal model fitted for all eligible patients (n = 15) and sleep was analyzed via a mixed effect logistic regression model (p = 0.035 for depression; remaining variables did not demonstrate significant differences over time). Error bars indicate standard error of the mean.
Fig. 3
Fig. 3. Kynurenine metabolites over time compared between low neurotoxicity (grades 0–1) and high neurotoxicity (grades 3–4) groups.
BL baseline, NTX Neurotoxicity, TRP Tryptophan, KYN Kynurenine, KA Kynurenic acid, 3-HK 3-Hydroxykynurenine, 3-HAA 3-Hydroxyanthranilic acid, QA Quinolinic acid. Observations from each subject (n = 15) relate to thin lines. Thick lines relate to means with error bars indicating standard error. Linear mixed-effects model showed 3HAA and 3HK were elevated in patients with neurotoxicity grades over the study period (p = 0.031 and p = 0.10, respectively).
Fig. 4
Fig. 4. Spearman ranked correlation between kynurenine and depression fold-changes.
BL baseline, KYN Kynurenine. Kynurenine concentration changes over time between timepoints was significantly correlated to change in depression scores between the same timepoints (n = 15, p = 0.002).
Fig. 5
Fig. 5. Spearman ranked correlations between peak cytokine concentrations and tryptophan metabolites measured across baseline, D14, and D28.
BL baseline, TRP Tryptophan, KYN Kynurenine, KA Kynurenic acid, 3-HK 3-Hydroxykynurenine, 3-HAA 3-Hydroxyanthranilic acid, QA Quinolinic acid. Spearman ranked correlations were done utilizing all available participants (n = 15).
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