Abstract
Immunotherapies have transformed the therapeutic landscape for various cancer indications; currently several preclinical and clinical studies are exploring immune-based therapies for the treatment of central nervous system (CNS) tumors. The recognition of toxicity syndromes and establishment of toxicity grading scales for cytokine release syndrome (CRS) and immune effector-cell associated neurotoxicity syndrome (ICANS) have improved the administration and management of chimeric antigen receptor (CAR)-based therapies for B cell malignancies. We have observed a localized neurotoxicity syndrome, distinct from CRS and ICANS, in patients treated with immunotherapies for CNS tumors, which we term tumor inflammation-associated neurotoxicity (TIAN). TIAN arises secondary to localized inflammation at the tumor site causing local neuronal dysfunction and/or local inflammation-induced edema leading to tissue shifts and increased intracranial pressure (ICP). Although TIAN can be associated with inflammation-induced tumoral edema and may share similarities with “pseudoprogression,” TIAN can also occur in the absence of edema due to neural-immune interactions causing primary local neural dysfunction. We distinguish two types of TIAN:1) type 1 TIAN occurs when tumor inflammation-induced edema leads to mechanical space constraints and results in increased ICP, hydrocephalus, and if unmanaged, may cause a herniation syndrome 2) type 2 TIAN reflects inflammation-induced local neural electrophysiological dysfunction resulting in transient worsening/development of new neurological symptoms. In order to facilitate the safe administration of immunotherapies for CNS tumors and standardize reporting and clinical management, we have proposed a TIAN grading scale that encompasses both types of TIAN. Even though type 1 TIAN typically consists of higher-grade toxicities than type 2 TIAN, high-grade toxicities can also be seen in type 2 TIAN when tumor inflammation affects critical cardiopulmonary functions. As the promise of immunotherapies for the treatment of CNS tumors materializes, recognizing TIAN as a distinct, local neurotoxicity syndrome will be essential for patient safety and clinical management.