Tumor inflammation-associated neurotoxicity

Jasia Mahdi^{1

2}, Jorg Dietrich³, Karin Straathof⁴, Claire Roddie⁴, Brian J Scott¹, Tom Belle Davidson⁵, Laura M Prolo⁶, Tracy T Batchelor^{7

8}, Cynthia J Campen¹, Kara L Davis^{2

9}, Juliane Gust^{10

11}, Michael Lim⁶, Robbie G Majzner^{2

9}, Julie R Park^{12

13}, Sonia Partap^{1

6

9}, Sneha Ramakrishna^{2

9}, Rebecca Richards^{2

9}, Liora Schultz^{2

9}, Nicholas A Vitanza^{12

13}, Leo D Wang¹⁴, Crystal L Mackall^{15

16

17}, Michelle Monje^{18

19

20

21

22

23}

Affiliations

¹ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
² Stanford Center for Cancer Cell Therapy, Stanford University School of Medicine, Stanford, CA, USA.
³ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
⁴ Research Department of Hematology and Oncology, Cancer Institute, University College London, London, UK.
⁵ Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Department of Neurosurgery, Stanford University, Stanford, CA, USA.
⁷ Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁸ Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA, USA.
⁹ Department of Pediatrics, Stanford University, Stanford, CA, USA.
¹⁰ Department of Neurology, University of Washington, Seattle, WA, USA.
¹¹ Seattle Children's Research Institute, Center for Integrative Brain Research, Seattle, WA, USA.
¹² Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
¹³ Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, USA.
¹⁴ City of Hope, Departments of Pediatrics and Immuno-oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
¹⁵ Stanford Center for Cancer Cell Therapy, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
¹⁶ Department of Pediatrics, Stanford University, Stanford, CA, USA. cmackall@stanford.edu.
¹⁷ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
¹⁸ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
¹⁹ Stanford Center for Cancer Cell Therapy, Stanford University School of Medicine, Stanford, CA, USA. mmonje@stanford.edu.
²⁰ Department of Neurosurgery, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
²¹ Department of Pediatrics, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
²² Department of Pathology, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
²³ Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.

PMID: 37024595
PMCID: PMC10166099
DOI: 10.1038/s41591-023-02276-w

Review

Tumor inflammation-associated neurotoxicity

Jasia Mahdi et al. Nat Med. 2023 Apr.

. 2023 Apr;29(4):803-810.

doi: 10.1038/s41591-023-02276-w. Epub 2023 Apr 6.

Authors

Affiliations

¹ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA.
² Stanford Center for Cancer Cell Therapy, Stanford University School of Medicine, Stanford, CA, USA.
³ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
⁴ Research Department of Hematology and Oncology, Cancer Institute, University College London, London, UK.
⁵ Cancer and Blood Disease Institute, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁶ Department of Neurosurgery, Stanford University, Stanford, CA, USA.
⁷ Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.
⁸ Dana-Farber/Harvard Cancer Center, Harvard Medical School, Boston, MA, USA.
⁹ Department of Pediatrics, Stanford University, Stanford, CA, USA.
¹⁰ Department of Neurology, University of Washington, Seattle, WA, USA.
¹¹ Seattle Children's Research Institute, Center for Integrative Brain Research, Seattle, WA, USA.
¹² Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, WA, USA.
¹³ Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, WA, USA.
¹⁴ City of Hope, Departments of Pediatrics and Immuno-oncology, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA, USA.
¹⁵ Stanford Center for Cancer Cell Therapy, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
¹⁶ Department of Pediatrics, Stanford University, Stanford, CA, USA. cmackall@stanford.edu.
¹⁷ Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA. cmackall@stanford.edu.
¹⁸ Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
¹⁹ Stanford Center for Cancer Cell Therapy, Stanford University School of Medicine, Stanford, CA, USA. mmonje@stanford.edu.
²⁰ Department of Neurosurgery, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
²¹ Department of Pediatrics, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
²² Department of Pathology, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.
²³ Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA. mmonje@stanford.edu.

PMID: 37024595
PMCID: PMC10166099
DOI: 10.1038/s41591-023-02276-w

Abstract

Cancer immunotherapies have unique toxicities. Establishment of grading scales and standardized grade-based treatment algorithms for toxicity syndromes can improve the safety of these treatments, as observed for cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) in patients with B cell malignancies treated with chimeric antigen receptor (CAR) T cell therapy. We have observed a toxicity syndrome, distinct from CRS and ICANS, in patients treated with cell therapies for tumors in the central nervous system (CNS), which we term tumor inflammation-associated neurotoxicity (TIAN). Encompassing the concept of 'pseudoprogression,' but broader than inflammation-induced edema alone, TIAN is relevant not only to cellular therapies, but also to other immunotherapies for CNS tumors. To facilitate the safe administration of cell therapies for patients with CNS tumors, we define TIAN, propose a toxicity grading scale for TIAN syndrome and discuss the potential management of this entity, with the goal of standardizing both reporting and management.

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Conflict of interest statement

Competing interests

C.L.M. holds multiple patents in the arena of CAR T cell therapeutics, is a cofounder and holds equity in Lyell Immunopharma, CARGO Therapeutics and Link Cell Therapies, which are developing CAR-based therapies, and consults for Lyell, CARGO, Link, NeoImmune Tech, Apricity, Nektar, Immatics, Mammoth and Ensoma. R.G.M. holds patents for CAR T cell therapeutics and is a cofounder of and holds equity in CARGO Therapeutics and Link Cell Therapies. R.G.M. has served as a consultant for Lyell Immunopharma, CARGO Therapeutics, Link Cell Therapies, NKarta, Arovella Pharmaceuticals, ImmunAI, Aptorum Group, Zai Labs, Innervate Radiopharmaceuticals, GaDeta and GammaDelta Therapeutics. J.G. is a consultant for Johnson & Johnson. J.D. has been a consultant for Amgen and Unum Therapeutics. M.M. holds patents for CAR T cell therapeutics and holds equity in MapLight Therapeutics. M.L. receives research support from Arbor, BMS, Accuray, Biohaven and Urogen; serves as a consultant to VBI, InCephalo Therapeutics, Merck, Pyramid Bio, Insightec, Biohaven, Sanianoia, Hemispherian, Novocure, Noxxon, InCando, Century Therapeutics, CraniUs, MediFlix and XSense; and is a shareholder in Egret Therapeutics.

Figures

**Fig. 1 |. Herniation syndromes.**
Edema caused by localized therapy-related inflammation depends on the location of the tumor (dark pink) and can cause herniation of brain tissue in the direction indicated by the arrows. Subfalcine herniation: arises when the peri-tumor mass effect compresses and displaces the cingulate gyrus under the falx cerebri and can clinically manifest with altered mental status, aphasia and contralateral leg weakness. Central thalamic herniation: represents downward displacement through the notch of the tentorium cerebelli and resulting compression of the diencephalon, which can lead to decreased arousal and coma. Uncal herniation: occurs when there is downward, transtentorial displacement of the uncus with consequent compression of the midbrain, resulting in a fixed and dilated pupil, a cranial nerve III palsy resulting in a ‘down and out’ eye, and new onset of hemiparesis. Upward brainstem herniation: occurs when a posterior fossa tumor pushes the cerebellar vermis and midbrain upwards, causing herniation through the tentorial notch with impairment of vertical eye movements and decreased level of consciousness. Central brainstem herniation: occurs when there is downward displacement of the brainstem, which can lead to Cushing’s triad (hypertension, bradycardia, abnormal respirations), a decreased level of consciousness (somnolence, with decreased response to noxious stimuli) and pathologic posturing. Tonsillar herniation: occurs because of compression of the cerebellar tonsils against the medulla and through the foramen magnum, compressing the medulla and resulting in Cushing’s triad, a decreased level of consciousness and pathologic extensor posturing. Dural structures are shown in light blue, CSF in darker blue. The illustration was created by SciStories LLC.

**Fig. 2 |. Radiographic changes seen in TIAN.**
Three days after receiving tisagenlecleucel to treat a primary CNS lymphoma, a patient developed increased T2/fluid-attenuated inversion recovery (FLAIR) signal surrounding the tumor bed, indicative of cerebral edema, that increased by day 11. These radiographic findings correlated with transient clinical worsening on day 11, which was associated with increased headaches, somnolence, left hemiparesis and left-sided, painful dysesthesias. Both the clinical and the radiographic findings then resolved over time. RT, radiation therapy.

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Tumor inflammation-associated neurotoxicity

Affiliations

Tumor inflammation-associated neurotoxicity

Authors

Affiliations

Abstract

Conflict of interest statement

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References

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LinkOut - more resources

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Medical