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Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of patients with relapsed or refractory hematologic malignancies, but it comes with unique toxicities, notably cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). As experience with CAR T-cell therapy grows, distinct and infrequent neurological complications are becoming increasingly evident. Recently, reports of acute myelopathy following the administration of CAR T-cell therapies have been accumulating. Despite the establishment of consensus guidelines for managing ICANS, there remains limited guidance on appropriate investigations and treatments for this rare complication. Here, we delve into the clinical features, pathophysiology, and strategies for optimally managing acute myelitis after CAR T-cell therapy, drawing insights from reported cases in the literature., (Copyright © 2024 American Society of Hematology.)

With growing indications for chimeric antigen receptor (CAR) T-cell therapy, toxicity profiles are evolving. There is an urgent and unmet need of approaches to optimally manage emerging adverse events that extend beyond the standard paradigm of cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS). Although management guidelines exist for ICANS, there is little guidance on how to approach patients with neurologic comorbidities, and how to manage rare neurotoxicity presentations, such as CAR T-cell therapy-related cerebral edema, severe motor complications or late-onset neurotoxicity. In this study, we present 3 scenarios of patients treated with CAR T cells who develop unique types of neurotoxicity, and we describe an approach for the evaluation and management based on experience because objective data are limited. The goal of this study is to develop an awareness of emerging and unusual complications, discuss treatment approaches, and help institutions and health care providers establish frameworks to navigate how to best address unusual neurotoxicities to ultimately improve patient outcomes., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model., Methods: In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy., Results: A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×10 6 CAR T cells. At the 450×10 6 CAR T-cell dose, 1 patient had grade 4 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome (ICANS), and 2 patients had a grade 3 cerebellar disorder of unclear cause. No cerebellar disorder, ICANS of any grade, or cytokine release syndrome of grade 3 or higher occurred in the 12 patients who received doses of 25×10 6 to 150×10 6 cells. A response was reported in 71% of the patients in the entire cohort and in 58% of those who received doses of 25×10 6 to 150×10 6 cells. The patients who had a response included those who had received previous BCMA therapies; responses were observed in 7 of 10 such patients in the entire cohort and in 3 of 6 such patients who received 25×10 6 to 150×10 6 cells., Conclusions: The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.)., (Copyright © 2022 Massachusetts Medical Society.)

Antibody-drug conjugates have transformed the treatment of HER2+ breast and other cancers. Unfortunately, the CNS remains a sanctuary site for many such patients in part due to poor macromolecule penetration across the blood-brain tumor barrier. Trastuzumab deruxtecan (T-DXd), a high-payload antibody-drug conjugate, was recently found to improve progression-free survival in HER2+ breast cancer patients versus prior-generation trastuzumab emtansine, prompting us to evaluate CNS activity in a woman with brain-only metastatic disease. T-DXd achieved complete response despite heavy pretreatment. Three persistent, previously-irradiated lesions were biopsy-proven to represent treatment effect. Subsequent recurrence occurred upon treatment holiday; partial response was observed with rechallenge. This case suggests T-DXd is active in HER2+ breast cancer brain metastases and supports further prospective evaluation.

Alloreactive and autoimmune responses after allogeneic hematopoietic cell transplantation can occur in nonclassical chronic graft-versus-host disease (chronic GVHD) tissues and organ systems or manifest in atypical ways in classical organs commonly affected by chronic GVHD. The National Institutes of Health (NIH) consensus projects were developed to improve understanding and classification of the clinical features and diagnostic criteria for chronic GVHD. Although still speculative whether atypical manifestations are entirely due to chronic GVHD, these manifestations remain poorly captured by the current NIH consensus project criteria. Examples include chronic GVHD impacting the hematopoietic system as immune mediated cytopenias, endothelial dysfunction, or as atypical features in the musculoskeletal system, central and peripheral nervous system, kidneys, and serous membranes. These purported chronic GVHD features may contribute significantly to patient morbidity and mortality. Most of the atypical chronic GVHD features have received little study, particularly within multi-institutional and prospective studies, limiting our understanding of their frequency, pathogenesis, and relation to chronic GVHD. This NIH consensus project task force report provides an update on what is known and not known about the atypical manifestations of chronic GVHD while outlining a research framework for future studies to be undertaken within the next 3 to 7 years. We also provide provisional diagnostic criteria for each atypical manifestation, along with practical investigation strategies for clinicians managing patients with atypical chronic GVHD features., Competing Interests: Declaration of Competing Interest G.D.E.C. received consultancy fees from Miltenyi Biotech. M.S. received consultancy fees from Chugai/Roche, Hexal/Sandoz, Gilead, AbbVie, Janssen-Cilag, Boehringer/Ingelheim, onkowissen.de, EUSA-Pharma, Novartis, AstraZeneca, Amgen, Medac, and Lilly, travel support from Chugai/Roche, Boehringer/Ingelheim, Celgene, Medac, UCB, Mylan, and honoraria from BMS, Novartis, AbbVie, AstraZeneca, Chugai/Roche, Janssen-Cilag, Gilead, Boehringer/Ingelheim. O.P. received honoraria or travel support from Astellas, Gilead, Jazz, MSD, Neovii Biotech, Novartis, Pfizer and Therakos, received research support from Gilead, Incyte, Jazz, Neovii Biotech and Takeda, and is a member of advisory boards to Jazz, Gilead, MSD, Omeros, Priothera, Shionogi and SOBI. BDS has received consultancy fees from Janssen, Legend Biotech, Kite/Gilead, Celgene, BMS, and Incyte, and is a member of advisory board to In8bio. W.T.K. received grant support and consulting fees from Biogen and NControl Therapeutics, Inc. M. B.-H. received speaker fees from Alexion and Sanofi and received a grant for an advanced training course from Norvatis. R.Z. received speaker fees from Novartis, Incyte and Mallinckrodt. K.A. received travel support from Alexion, Bayer, Biogenldec, MerckSerono, Novartis, Teva (until 2014) and received honoraria from Biogenldec. Y.I. served on advisory boards for Novartis, Janssen, and Meiji Seika Pharma. S.J.L. received consultant fees from Mallinckrodt, Equillium, Kadmon; research funding from Amgen, AstraZeneca, Incyte, Kadmon, Novartis, Pfizer, Syndax, Takeda; drug supply from Janssen; she is on an Incyte Steering Committee. S.P. received research support from the Center for Cancer Research at the National Cancer Institute through the National Institutes of Health Intramural Research Program, which includes Clinical Research Development Agreements with Celgene, Actelion, Eli Lilly, Pharmacyclics and Kadmon Corporation. D.W. received research grant support from Novartis and honoraria from Novartis, Mallinckrodt, Behring, Takeda, Neovii, Gilead and Pfizer., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Chimeric antigen receptor (CAR) T-cell therapies are highly effective for multiple myeloma (MM) but their impressive efficacy is associated with treatment-related neurotoxicities in some patients. In CARTITUDE-1, 5% of patients with MM reported movement and neurocognitive treatment-emergent adverse events (MNTs) with ciltacabtagene autoleucel (cilta-cel), a B-cell maturation antigen-targeted CAR T-cell therapy. We assessed the associated factors for MNTs in CARTITUDE-1. Based on common features, patients who experienced MNTs were characterized by the presence of a combination of at least two variables: high tumor burden, grade ≥2 cytokine release syndrome (CRS) or any grade immune effector cell-associated neurotoxicity syndrome (ICANS) after cilta-cel infusion, and high CAR T-cell expansion/persistence. Strategies were implemented across the cilta-cel development program to monitor and manage patients with MNTs, including enhanced bridging therapy to reduce baseline tumor burden, early aggressive treatment of CRS and ICANS, handwriting assessments for early symptom detection, and extended monitoring/reporting time for neurotoxicity beyond 100 days post-infusion. After successful implementation of these strategies, the incidence of MNTs was reduced from 5% to <1% across the cilta-cel program, supporting its favorable benefit-risk profile for treatment of MM., (© 2022. The Author(s).)

Purpose: To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with immune checkpoint inhibitor (ICPi) therapy., Methods: A multidisciplinary panel of medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to update the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 through 2021., Results: A total of 175 studies met the eligibility criteria of the systematic review and were pertinent to the development of the recommendations. Because of the paucity of high-quality evidence, recommendations are based on expert consensus., Recommendations: Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to the organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, except for some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert ≤ grade 1. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids. Corticosteroids should be tapered over the course of at least 4-6 weeks. Some refractory cases may require other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, except for endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines., Competing Interests: Reprint Requests: Bryan J. SchneiderResearch Funding: Merck Jarushka NaidooHonoraria: Bristol Myers Squibb, AstraZeneca/MedImmune, Merck, Daiichi Sankyo/Lilly, TakedaConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca/MedImmune, Roche/Genentech, Daiichi Sankyo/Lilly, Takeda, Pfizer, Kaleido BiosciencesResearch Funding: Merck, AstraZeneca, Roche/GenentechTravel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca/MedImmune Bianca D. SantomassoConsulting or Advisory Role: Celgene, Janssen, Legend Biotech, Incyte, In8BioResearch Funding: ADC Therapeutics Sherry AdkinsConsulting or Advisory Role: CelgeneTravel, Accommodations, Expenses: Celgene Milan AnadkatStock and Other Ownership Interests: Anthem, Humana, Perrigo, Walgreens Boots Alliance, Abbott Laboratories, Merck, AbbVie, Amgen, Bristol Myers Squibb, Celgene, CVS Health, Gilead Sciences, Incyte, Johnson & Johnson, Lilly, Medtronic, Mylan, Pfizer, Procter & Gamble, United Health Group, Regeneron, Roche, Moderna Therapeutics (I), Dexcom, Quest DiagnosticsHonoraria: Adgero Biopharmaceuticals, Boehringer Ingelheim, Novocure, AbbVie, UCB, InnovadermConsulting or Advisory Role: Adgero Biopharmaceuticals, Boehringer Ingelheim, Novocure, Kintara TherapeuticsResearch Funding: AnaptysBio, Boehringer Ingelheim, Biogen, InflamRx, Lutris, Novartis, OnQuality Pharmaceuticals, Veloce Pharmaceuticals, XBiotech, UCB, AbbVie, Lilly Michael B. AtkinsStock and Other Ownership Interests: Werewolf Pharma, PyxisConsulting or Advisory Role: Genentech, Novartis, Bristol Myers Squibb, Merck, Exelixis, Eisai, Agenus, Arrowhead Pharmaceuticals, Werewolf Pharma, Surface Oncology, Iovance Biotherapeutics, Pyxis, Pneuma Respiratory, Leads Biolabs, Fathom Biotechnology, AVEO, Cota Healthcare, Neoleukin Therapeutics, Adagene, Idera, Ellipses Pharma, AstraZeneca, PACT Pharma, Seattle Genetics, Pfizer, ScholarRock, Asher Bio, Calithera Biosciences, Takeda, SanofiResearch Funding: Bristol Myers Squibb Kelly J. BrassilEmployment: Pack HealthHonoraria: Oncology Nursing Society, WebMD, M Consulting, i3 HealthResearch Funding: AbbVie, Daiichi Sankyo, Astellas Pharma, Genentech, Sanofi, GlaxoSmithKlineTravel, Accommodations, Expenses: Pack Health Jeffrey M. CaterinoStock and Other Ownership Interests: Motive Medical IntelligenceConsulting or Advisory Role: Wellstat TherapeuticsResearch Funding: Stago, Entegrion, JDP Therapeutics, AstraZeneca Ian ChauHonoraria: Lilly, Eisai, ServierConsulting or Advisory Role: Lilly, Bristol Myers Squibb, MSD Oncology, Merck Serono, Roche/Genentech, AstraZeneca, Pierre Fabre, Boehringer Ingelheim, Incyte, OncXerna Therapeutics, Astellas Pharma, GlaxoSmithKline, Eisai, SotioResearch Funding: Janssen-Cilag, LillyTravel, Accommodations, Expenses: MSD, Merck Serono, Lilly, Bristol Myers Squibb, Eisai Marianne J. DaviesSpeakers' Bureau: AstraZeneca, Genentech/Roche, Merck, Bristol Myers Squibb Marc S. ErnstoffStock and Other Ownership Interests: GE Healthcare, Bristol Myers SquibbResearch Funding: Alkermes, EMD SeronoTravel, Accommodations, Expenses: ImmuNext, AlkermesOther Relationship: Bristol Myers Squibb Leslie FecherConsulting or Advisory Role: Via Oncology, Hoosier Cancer Research Network, ElsevierResearch Funding: Merck, Incyte, Bristol Myers Squibb, Pfizer/EMD Serono, Array BioPharma, Kartos TherapeuticsOther Relationship: Array BioPharmaUncompensated Relationships: NCCN, American Association of Clinical Endocrinology, ASCO Monalisa GhoshResearch Funding: Novartis, Celgene Jennifer S. MammenStock and Other Ownership Interests: Johnson & Johnson, Bristol-Myers SquibbConsulting or Advisory Role: Five Prime Therapeutics Aung NaingConsulting or Advisory Role: Novartis, CytomX Therapeutics, OncoSec, STCube Pharmaceuticals Inc, Kymab, Takeda (I), CSL Behring (I), Horizon Pharma (I), Genome & CompanyResearch Funding: NCI, EMD Serono, MedImmune, Atterocor, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance BioSciences Inc, Healios, Lilly, Kymap, PsiOxus Therapeutics, Immune Deficiency Foundation (I), Arcus Biosciences, NeoImmuneTech, ImmuneOncia, Surface Oncology, Baxalta (I), Jeffrey Modell Foundation (I), Chao Physician-Scientist Awards (I)Travel, Accommodations, Expenses: ARMO BioSciences Loretta J. NastoupilHonoraria: Celgene, Gilead Sciences, Novartis, Bayer, Janssen Oncology, Pfizer, Gamida Cell, TG Therapeutics, Bristol Myers Squibb, ADC Therapeutics, Morphosys, Epizyme, GenmabResearch Funding: TG Therapeutics, Janssen Biotech, Celgene, Genentech/Roche, LAM Therapeutics, Epizyme, Novartis, IgM Biosciences, Caribou Biosciences, Gilead Sciences, Allogene Therapeutics, Takeda Tanyanika PhillipsTravel, Accommodations, Expenses: City of Hope Alexander SpiraLeadership: NEXT Oncology VirginiaStock and Other Ownership Interests: LillyHonoraria: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, BayerConsulting or Advisory Role: Array BioPharma, Incyte, Amgen, Novartis, AstraZeneca/MedImmune, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Merck, Bristol Myers Squibb, Takeda, Janssen Research & DevelopmentResearch Funding: Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone Oncology, Plexxikon, Amgen, Loxo, Daiichi Sankyo, ADC Therapeutics, Janssen Oncology, Mirati Therapeutics, Rubius Therapeutics Maria Suarez-AlmazorConsulting or Advisory Role: Agile Therapeutics, AMAG Pharmaceuticals, AbbVie/Genentech, Avenue Therapeutics, Gilead Sciences, ChemoCentryx, Celgene/Bristol Myers Squibb Umang SwamiConsulting or Advisory Role: Seattle Genetics John A. ThompsonConsulting or Advisory Role: Calithera Biosciences, Clinical Care Options/NCCN, BJ Bioscience, Alpine Immune Sciences, Neoleukin Therapeutics, Academy for Continued Healthcare Learning, Meeting Sites Pro, Regeneron, AVEO, Bristol Myers SquibbResearch Funding: Roche, Pfizer, Agensys, Five Prime Therapeutics, Trillium Therapeutics, Merck, Novartis, Xencor, Incyte Praveen VikasStock and Other Ownership Interests: Moderna Therapeutics, NovavaxResearch Funding: Sanofi Yinghong WangConsulting or Advisory Role: Tillotts Pharma, Azurrx Pharma Jeffrey S. WeberStock and Other Ownership Interests: CytomX Therapeutics, Biond, Protean Biodiagnostics, NeximmuneHonoraria: Bristol Myers Squibb, Merck, Genentech, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Amgen, Roche, Celldex, CytomX Therapeutics, Novartis, Sellas Life Sciences, WindMIL, Takeda, Moderna Therapeutics, Jounce Therapeutics, Kirin Pharmaceuticals, Regeneron, Idera, OncosecConsulting or Advisory Role: Celldex, Bristol Myers Squibb, Merck, Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, CytomX Therapeutics, Novartis, Sellas Life Sciences, WindMIL, Jounce Therapeutics, Moderna Therapeutics, Kirin Pharmaceuticals, Protean Biodiagnostics, Idera, OncosecResearch Funding: Bristol Myers Squibb, Merck, GlaxoSmithKline, Genentech, Astellas Pharma, Incyte, Roche, Novartis, NextCure, Moderna TherapeuticsPatents, Royalties, Other Intellectual Property: Named on a patent submitted by Moffitt Cancer Center for an IPILIMUMAB biomarker, named on a patent for 41BB induced TIL by Moffitt Cancer CenterTravel, Accommodations, Expenses: Bristol Myers Squibb, GlaxoSmithKline, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech, Novartis Pauline FunchainConsulting or Advisory Role: EisaiResearch Funding: Pfizer, Bristol Myers Squibb, Taiho OncologyNo other potential conflicts of interest were reported.

Purpose: To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events (irAEs) in patients treated with chimeric antigen receptor (CAR) T-cell therapy., Methods: A multidisciplinary panel of medical oncology, neurology, hematology, emergency medicine, nursing, trialists, and advocacy experts was convened to develop the guideline. Guideline development involved a systematic literature review and an informal consensus process. The systematic review focused on evidence published from 2017 to 2021., Results: The systematic review identified 35 eligible publications. Because of the paucity of high-quality evidence, recommendations are based on expert consensus., Recommendations: The multidisciplinary team issued recommendations to aid in the recognition, workup, evaluation, and management of the most common CAR T-cell-related toxicities, including cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, B-cell aplasia, cytopenias, and infections. Management of short-term toxicities associated with CAR T cells begins with supportive care for most patients, but may require pharmacologic interventions for those without adequate response. Management of patients with prolonged or severe CAR T-cell-associated cytokine release syndrome includes treatment with tocilizumab with or without a corticosteroid. On the basis of the potential for rapid decline, patients with moderate to severe immune effector cell-associated neurotoxicity syndrome should be managed with corticosteroids and supportive care.Additional information is available at www.asco.org/supportive-care-guidelines., Competing Interests: Reprint Requests: Bianca D. SantomassoConsulting or Advisory Role: Celgene, Janssen, Legend Biotech, Incyte, In8BioResearch Funding: ADC Therapeutics (Inst) Loretta J. NastoupilHonoraria: Celgene, Gilead Sciences, Novartis, Bayer, Janssen Oncology, Pfizer, Gamida Cell, TG Therapeutics, Bristol Myers Squibb, ADC Therapeutics, Morphosys, Epizyme, GenmabResearch Funding: TG Therapeutics, Janssen Biotech, Celgene, Genentech/Roche, LAM Therapeutics, Epizyme, Novartis, IgM Biosciences, Caribou Biosciences, Gilead Sciences, Allogene Therapeutics, Takeda Sherry AdkinsConsulting or Advisory Role: CelgeneTravel, Accommodations, Expenses: Celgene Bryan J. SchneiderResearch Funding: Merck Milan AnadkatStock and Other Ownership Interests: Anthem, Humana, Perrigo, Walgreens Boots Alliance, Abbott Laboratories, Merck, AbbVie, Amgen, Bristol Myers Squibb, Celgene, CVS Health, Gilead Sciences, Incyte, Johnson & Johnson, Lilly, Medtronic, Mylan, Pfizer, Procter & Gamble, United Health Group, Regeneron, Roche, Moderna Therapeutics, Dexcom, Quest DiagnosticsHonoraria: Adgero Biopharmaceuticals, Boehringer Ingelheim, Novocure, AbbVie, UCB, InnovadermConsulting or Advisory Role: Adgero Biopharmaceuticals, Boehringer Ingelheim, Novocure, Kintara TherapeuticsResearch Funding: AnaptysBio, Boehringer Ingelheim, Biogen, InflaRx, Lutris, Novartis, OnQuality Pharmaceuticals, Veloce Pharmaceuticals, XBiotech, UCB, AbbVie, Lilly Michael B. AtkinsStock and Other Ownership Interests: Werewolf Pharma, PyxisConsulting or Advisory Role: Genentech, Novartis, Bristol Myers Squibb, Merck, Exelixis, Eisai, Agenus, Arrowhead Pharmaceuticals, Werewolf Pharma, Surface Oncology, Iovance Biotherapeutics, Pyxis, Pneuma Respiratory, Leads Biolabs, Fathom Biotechnology, Aveo, Cota Healthcare, Neoleukin Therapeutics, Adagene, Idera, Ellipses Pharma, AstraZeneca, PACT Pharma, Seattle Genetics, Pfizer, Scholar Rock, Asher Bio, Calithera Biosciences, Takeda, SanofiResearch Funding: Bristol Myers Squibb Kelly J. BrassilEmployment: Pack HealthHonoraria: Oncology Nursing Society, WebMD, M Consulting, i3 HealthResearch Funding: AbbVie, Daiichi Sankyo, Astellas Pharma, Genentech, Sanofi, GlaxoSmithKlineTravel, Accommodations, Expenses: Pack Health Jeffrey M. CaterinoStock and Other Ownership Interests: Motive Medical IntelligenceConsulting or Advisory Role: Wellstat TherapeuticsResearch Funding: Stago, Entegrion, JDP Therapeutics, AstraZeneca Ian ChauHonoraria: Lilly, Eisai, ServierConsulting or Advisory Role: Lilly, Bristol Myers Squibb, MSD Oncology, Merck Serono, Roche/Genentech, AstraZeneca, Pierre Fabre, Boehringer Ingelheim, Incyte, OncXerna Therapeutics, Astellas Pharma, GlaxoSmithKline, Eisai, SotioResearch Funding: Janssen-Cilag, LillyTravel, Accommodations, Expenses: MSD, Merck Serono, Lilly, Bristol Myers Squibb, Eisai Marianne J. DaviesSpeakers' Bureau: AstraZeneca, Genentech/Roche, Merck, Bristol Myers Squibb Marc S. ErnstoffStock and Other Ownership Interests: GE Healthcare, Bristol Myers SquibbResearch Funding: Alkermes, EMD SeronoTravel, Accommodations, Expenses: ImmuNext, AlkermesOther Relationship: Bristol Myers Squibb Leslie FecherConsulting or Advisory Role: Via Oncology, Hoosier Cancer Research Network, ElsevierResearch Funding: Merck, Incyte, Bristol Myers Squibb, Pfizer/EMD Serono, Array BioPharma, Kartos TherapeuticsOther Relationship: Array BioPharmaUncompensated Relationships: NCCN, American Association of Clinical Endocrinology, ASCO Pauline FunchainConsulting or Advisory Role: EisaiResearch Funding: Pfizer, Bristol Myers Squibb, Taiho Oncology Jennifer S. MammenStock and Other Ownership Interests: Johnson & Johnson, Bristol Myers SquibbConsulting or Advisory Role: Five Prime Therapeutics Jarushka NaidooHonoraria: Bristol Myers Squibb, AstraZeneca/MedImmune, Merck, Daiichi Sankyo/Lilly, TakedaConsulting or Advisory Role: Bristol Myers Squibb, AstraZeneca/MedImmune, Roche/Genentech, Daiichi Sankyo/Lilly, Takeda, Pfizer, Kaleido BiosciencesResearch Funding: Merck, AstraZeneca, Roche/GenentechTravel, Accommodations, Expenses: Bristol Myers Squibb, AstraZeneca/MedImmune Aung NaingConsulting or Advisory Role: Novartis, CytomX Therapeutics, OncoSec, STCube Pharmaceuticals Inc, Kymab, Takeda (I), CSL Behring (I), Horizon Pharma (I), Genome & CompanyResearch Funding: NCI, EMD Serono, MedImmune, Atterocor, Amplimmune, ARMO BioSciences, Karyopharm Therapeutics, Incyte, Novartis, Regeneron, Merck, Bristol Myers Squibb, Pfizer, CytomX Therapeutics, Neon Therapeutics, Calithera Biosciences, TopAlliance BioSciences Inc, Healios, Lilly, Kymab, PsiOxus Therapeutics, Immune Deficiency Foundation (I), Arcus Biosciences, NeoImmuneTech, ImmuneOncia, Surface Oncology, Baxalta (I), Jeffrey Modell Foundation (I), Chao Physician-Scientist AwardsTravel, Accommodations, Expenses: ARMO BioSciences Tanyanika PhillipsTravel, Accommodations, Expenses: City of Hope Alexander SpiraLeadership: NEXT Oncology VirginiaStock and Other Ownership Interests: Eli LillyHonoraria: CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen, Janssen Oncology, Novartis, Bristol Myers Squibb, BayerConsulting or Advisory Role: Array BioPharma (Inst), Incyte, Amgen, Novartis, AstraZeneca/MedImmune (Inst), Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Merck (Inst), Bristol Myers Squibb (Inst), Takeda, Janssen Research & DevelopmentResearch Funding: Roche (Inst), AstraZeneca (Inst), Boehringer Ingelheim (Inst), Astellas Pharma (Inst), MedImmune (Inst), Novartis (Inst), Newlink Genetics (Inst), Incyte (Inst), AbbVie (Inst), Ignyta (Inst), LAM Therapeutics (Inst), Trovagene (Inst), Takeda (Inst), Macrogenics (Inst), CytomX Therapeutics (Inst), LAM Therapeutics (Inst), Astex Pharmaceuticals (Inst), Bristol Myers Squibb (Inst), Loxo (Inst), Arch Therapeutics (Inst), Gritstone (Inst), Plexxikon (Inst), Amgen (Inst), Loxo (Inst), Daiichi Sankyo (Inst), ADCT (Inst), Janssen Oncology (Inst), Mirati Therapeutics (Inst), Rubius (Inst) Maria Suarez-AlmazorConsulting or Advisory Role: Agile Therapeutics, AMAG Pharmaceuticals¸ Abbvie/Genentech, Avenue Therapeutics, Gilead Sciences, ChemoCentryx, Celgene/Bristol Myers Squibb Umang SwamiConsulting or Advisory Role: Seattle Genetics John A. ThompsonConsulting or Advisory Role: Calithera Biosciences, Clinical Care Options/NCCN, BJ Bioscience, Alpine Immune Sciences, Neoleukin Therapeutics, Academy for Continued Healthcare Learning, Meeting Sites Pro, Regeneron, AVEO, Bristol Myers SquibbResearch Funding: Roche, Pfizer, Agensys, Five Prime Therapeutics, Trillium Therapeutics, Merck, Novartis, Xencor, Five Prime Therapeutics, Incyte Praveen VikasStock and Other Ownership Interests: NovavaxResearch Funding: Sanofi Yinghong WangConsulting or Advisory Role: Tillotts Pharma, Azurrx Pharma Jeffrey S. WeberStock and Other Ownership Interests: CytomX Therapeutics, Biond, Protean Biodiagnostics, NeximmuneHonoraria: Bristol Myers Squibb, Merck, Genentech, AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Amgen, Roche, Celldex, CytomX Therapeutics, Novartis, Sellas Life Sciences, WindMIL, Takeda, Moderna Therapeutics, Jounce Therapeutics, Kirin Pharmaceuticals, Regeneron, Idera, OncosecConsulting or Advisory Role: Celldex, Bristol Myers Squibb, Merck¸ Genentech, Roche, Amgen, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo, CytomX Therapeutics, Novartis, Sellas Life Sciences, WindMIL, Jounce Therapeutics, Moderna Therapeutics, Kirin Pharmaceuticals, Protean Biodiagnostics, Idera, OncosecResearch Funding: Bristol Myers Squibb, Merck, GlaxoSmithKline, Genentech, Astellas Pharma, Incyte, Roche, Novartis, NextCure (Inst), Moderna Therapeutics (Inst)Patents, Royalties, Other Intellectual Property: Named on a patent submitted by Moffitt Cancer Center for an IPILIMUMAB biomarker, named on a patent from Biodesix for a PD-1 antibody biomarker, and named on a patent for 41BB-induced TIL by Moffitt Cancer CenterTravel, Accommodations, Expenses: Bristol Myers Squibb, GlaxoSmithKline, Roche, Celldex, Amgen, Merck, AstraZeneca, Genentech, Novartis Monalisa GhoshResearch Funding: Celgene (Inst)No other potential conflicts of interest were reported.

Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. All rights reserved.)

Introduction: The optimal management for immune-related adverse events (irAEs) in patients who do not respond or become intolerant to steroids is unclear. Guidelines suggest additional immunosuppressants on the basis of case reports and expert opinion., Methods: We evaluated patients with lung cancers at Memorial Sloan Kettering Cancer Center treated with immune checkpoint blockade from 2011 to 2020. Pharmacy records were queried to identify patients who received systemic steroids and an additional immunosuppressant (e.g., tumor necrosis factor-α inhibitor, mycophenolate mofetil). Patient records were manually reviewed to evaluate baseline characteristics, management, and outcomes., Results: Among 2750 patients with lung cancers treated with immune checkpoint blockade, 51 (2%) received both steroids and an additional immunosuppressant for a severe irAE (tumor necrosis factor-α inhibitor (73%), mycophenolate mofetil (20%)). The most common events were colitis (53%), pneumonitis (20%), hepatitis (12%), and neuromuscular (10%). At 90 days after the start of an additional immunosuppressant, 57% were improved from their irAE, 18% were unchanged, and 25% were deceased. Improvement was more common in hepatitis (five of six) and colitis (18 of 27) but less common in neuromuscular (one of five) and pneumonitis (3 of 10). Of the patients who died, 8 of 13 were attributable directly to the irAE and 4 of 13 were related to toxicity from immunosuppression (three infection-related deaths, one drug-induced liver injury leading to acute liver failure)., Conclusions: Steroid-refractory or resistant irAEs events are rare. Although existing treatments help patients with hepatitis and colitis, many patients with other irAEs remain refractory or experience toxicities from immunosuppression. A more precise understanding of the pathophysiology of specific irAEs is needed to guide biologically-informed treatments for severe irAEs., (Copyright © 2021 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Expanding the US Food and Drug Administration-approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%-12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings., Competing Interests: Competing interests: ACG has served on an advisory board and/or consulted with Alexion, Ra Pharma/UCB and Momenta pharmaceuticals/Janssen. She has received royalties from Oakstone Publishing and research support from the Myasthenia Gravis Foundation of America, the MG Rare Disease Network and Project Data Sphere® for an irAE-N registry. She has received clinical trial support to the institution from Ra Pharma and Momenta. LBB receives salary support from Biogen, royalties from Oakstone Publishing, and research support from Project Data Sphere for an irAE-N registry. BKC reports research support from Project Data Sphere for an irAE-N registry. JH receives research support from Project Data Sphere for an irAE-N registry and from GE Healthcare. THS is an employee at the not-for-profit corporation Project DS, with a trade name of Project Data Sphere. AAA served on medical advisory boards for Alexion, Sarepta, CSL Behring, Strongbridge Pharma, Argenx, Ra Pharmaceuticals, and as a neurology consultant for Johnson & Johnson COVID-19 vaccine trials. ABW served on a medical advisory board or as a consultant with Iovance, Novartis, Shanghai Jo’Ann Medical Technology. PKB has consulted for Angiochem, Genentech-Roche, Lilly, Tesaro, Voyager Therapeutics, ElevateBio, Pfizer (Array), Pfizer, SK Life Sciences and Dantari, received grant/research support (to Massachusetts General Hospital) from Merck, BMS and Lilly and honoraria from Merck, Pfizer, Genentech-Roche and Lilly. TAC has received royalties from Wolters Kluwer. SLC serves as the Editor of the Neurology®Podcast and Neurology Minute™. She has received research and/or clinical fellowship support from the Western Institute for Veterans Research, the Siegel Rare Neuroimmune Association, the Immune Deficiency Foundation, Alexion, the Barbara Gural Steinmetz Foundation, and the Sumaira Foundation for NMO. She has served on an advisory board and/or consulted with Alexion, Genentech, VielaBio, Guidepoint, Clarion Healthcare Consulting, ExpertConnect (majority fees paid to University of Utah). JC has received consulting fees from Sanofi-Genzyme and BMS. JD is a consultant for Blue Earth Diagnostics, Magnolia, Gamaka Bio, and Unum Therapeutics. JD has received research support from Beacon Biosignals, Boehringer Ingelheim, Brystol-Myers Squibb, Eli Lilly, Medimmune, Acerta Pharma, Orbus Therapeutics, and Novartis Pharmaceuticals. JD has received royalties from Wolters Kluwer for serving as an author for UpToDate. MD has research funding from Novartis and Eli Lilly, has served as a consultant for Roche-Genentech, Tillotts Pharma, ORIC Pharmaceuticals, Partner Therapeutics, and Moderna, and is a member of the Scientific Advisory Board for Neoleukin Therapeutics. CTD has served on advisory boards for Argenx and Dysimmune Diseases Foundation. He has received royalties from Oakstone Publishing. He has received grant support from NINDS/NeuroNext. DD has served on an advisory board and/or consulted for UCB, Astellas and Immunovant pharmaceuticals. All compensation for the consulting activities is paid to Mayo Clinic. He has patents pending for KLHL11 and LUZP4 as markers of neurological autoimmunity and germ cell tumors. JG has received research to UCSF support from Genentech/Roche for a clinical trial, performed consulting for Biogen, and received personal compensation for medical-legal consulting. JTG has served as a consultant in past 12 months for Immunovant, Alexion, Momenta, Ra Pharma, Grifols, Jacobus, Cabaletta, Regeneron, Argenx, Signant, UCB, Toleranzia and Piedmont Pharmaceuticals. He receives industry grant support from UCB pharma for a fellowship training grant. Full disclosure statement available at: https://dcri.org/about-us/conflict-of-interest/. DBJ has served on advisory boards for Array Biopharma, BMS, Catalyst Biopharma, Iovance, Jansen, Merck, Novartis, and Oncosec, and has received research funding from BMS and Incyte. VCJ is a site investigator in myasthenia gravis research trials sponsored by PCORI and by Alexion Pharmaceuticals. RK receives research funding from Alexion Pharmaceuticals. NK reports no relevant disclosures. NRL is a consultant and has received honoraria from Bayer, Seattle Genetics, Sanofi, Fortress Biotech, Silverback Therapeutics and SYNOX Therapeutics. JL reports no disclosures. AM reports no disclosures. MM-L reports no relevant disclosures. MJM has served on an advisory board and/or consulted with AstraZeneca Pharmaceuticals, Nektar Therapeutics, Catalyst Pharmaceuticals and Immunai. JN has received research funding from Merck and AstraZeneca; served as a consultant/advisory board member with Merck, AstraZeneca, BMS, Pfizer, Takeda, Roche/Genentech, Daiichi/Sankyo and has received honoraria from Merck, AstraZeneca, BMS, Pfizer, Takeda, Roche/Genentech. TGN reports acting as a consultant for Parexel, Bristol Myers-Squibb, H3 Biomedicine, AbbVie, and Intrinsic Imaging unrelated to the current research. TGN reports grant funding from AstraZeneca unrelated to current research. DR has been an advisor or consultant with AbbVie; Advantagene; Agenus; Agios; Amgen; Bayer; Boston Biomedical; Boehringer Ingelheim; Bristol-Myers Squibb; Celldex; Deciphera; DelMar; EMD Serono; Genenta; Genentech/Roche; Imvax; Inovio; Kintara; Kiyatec; Medicenna Biopharma; Merck; Merck KGaA; Monteris; Neuvogen; Novartis; Novocure; Oncorus; Oxigene; Regeneron; Stemline; Sumitono Dainippon Pharma; Taiho Oncology. Research support to his institution has been provided by Acerta Phamaceuticals; Agenus; Celldex; EMD Serono; Incyte; Inovio; Omniox; Tragara. KMR has served on an advisory board and/or consulted with Merck, BMS, and Eisai. BDS has served on an advisory board and/or consulted with Janssen, Kite/Gilead, and Celgene/BMS. RS has served on an advisory board and/or consulted with AstraZeneca, Bristol-Myers Squib, Eisai, Iovance, Merck, Novartis, Oncosec, Pfizer, and Replimune. He has received research funding from Merck. NW has served on an advisory board with Seattle Genetics, received royalties from Wolters Kluwer and research support from Merck. KW reports no disclosures. LZ has been a consultant for Merck. WCL is an employee of the not-for-profit corporation Project DS, with a trade name of Project Data Sphere. KLR has received personal compensation from Teladoc research support from Project Data Sphere for a irAE-N registry., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Immune checkpoint inhibitors (ICIs) are the standard of care for the treatment of several cancers. While these immunotherapies have improved patient outcomes in many clinical settings, they bring accompanying risks of toxicity, specifically immune-related adverse events (irAEs). There is a need for clear, effective guidelines for the management of irAEs during ICI treatment, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of single and combination ICI irAEs and ultimately developed evidence- and consensus-based recommendations to assist medical professionals in clinical decision-making and to improve outcomes for patients., Competing Interests: Competing interests: PAA—Contracted research: Bristol-Myers Squibb, Roche, Array; Consulting fees: Bristol-Myers Squibb, Roche, Array, Novartis, Merck Serono, Pierre Fabre, Incyte, Medimmune, Sindax, AstraZeneca, Sun Pharma, Sanofy, Idera, Ultimovacs, Sandox, Immunocore, 4sc, Alkermes, Italfarmaco, Nektar, Boehringer-Ingelheim, Eisai, Regeneron; Travel support: MSD. JRB—Contracted research: AstraZeneca, Bristol-Myers Squibb, Genentech/Roche, Merck, RAPT Therapeutics, Inc, Revolution Medicines; Consulting fees: Amgen, Bristol-Myers Squibb, Genentech/Roche, Eli Lilly, GlaxoSmithKline, Merck, Sanofi, Regeneron; Data and safety monitoring board/committees: GlaxoSmithKline, Sanofi. JB—Partner consulting fees: AstraZeneca, Merck, Roche, Pfizer, Lilly, Daiichi, Seattle Genetics, Novartis. LCC—Consulting fees: AbbVie; Contracted research: Bristol-Myers Squibb, Merck, EMD Serono, Alkermes, Iovance, Merrimack, National Cancer Institute. DEG—Consulting fees: Samsung Bioepis, Catalyst Pharmaceuticals, Bristol-Myers Squibb Steering Committee, G1 Therapeutics; Contracted research: AstraZeneca, BerGenBio, Karyopharm, Bristol-Myers Squibb Steering Committee; Ownership interest: Gilead. DBJ—Consulting fees: Bristol-Myers Squibb, Catalyst Biopharma, Iovance, Jansen, Merck, Novartis, Oncosec; Contracted research: Bristol-Myers Squibb, Incyte. MEL—Contracted research: Veloce, US Biotest, Lutris, Paxman, Novocure Inc; Grant funding: National Cancer Institute Cancer Center support grant P30 CA008748, National Institute of Arthritis and Musculoskeletal and Skin Diseases grant U01AR0775; Royalty: Legacy Healthcare Services, Apricity Health, Azitra, Inc, Deciphera, Galderma Research and Development, Johnson and Johnson, NCODA, Novocure Inc, Kyowa Kirin Inc, Loxo, Merck Sharp and Dohme Corporation, Janssen Research & Development, Menlo Therapeutics, Novartis Pharmaceuticals Corporation, QED Therapeutics, F. Hoffmann-La Roche AG, Amgen Inc, AstraZeneca Pharmceuticals, Genentech Inc, Seattle Genetics, Lutris, Paxman Coolers, OnQuality Pharmaceuticals Ltd, Takeda Millenium. JN—Consulting fees: AstraZeneca, Bristol-Myers Squibb, Merck, Roche/Genentech; Contracted research: AstraZeneca, Merck; Non-CME services: Merck, Bristol-Myers Squibb, AstraZeneca. M-AP—Consulting fees: AbbVie, Bellicum, Celgene, Bristol-Myers Squibb, Incyte, Kite/Gilead, Merck, Novartis, Nektar Therapeutics, Omeros, and Takeda; Contracted research: Incyte, Kite/Gilead and Miltenyi Biotec; Ownership interest: NexImmune Member, DSMBs for Cidara Therapeutics, Servier and Medigene. IP—Consulting fees: Merck, Amgen; Ownership interest: Celldex; Partner ownership: Celldex. BDS—Consulting fees: Kite/Gilead, Juno/Celgene; Contracted research: ADC Therapeutics; NPI: 1215164884. SPS—Consulting fees: Takeda, GSK, Kura, Celgene, Daiichi-Sankyo. DS—Scientific advisory board: Allergan, Alimera, Biogen. JAS—Consulting fees: Array, Nektar, Bristol-Myers Squibb, Iovance, Curis; Contracted research: Bristol-Myers Squibb, Corvus, Caltera. HA-S, FBC, MSE, LH, EH, GAM, MN, RS, MT—Nothing to disclose. SITC staff: SMW—Shares owned: Pacific Biosciences of California Inc, Editas Medicine. EG, AK, BL, LL—Nothing to disclose., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Abstract: Chimeric antigen receptor (CAR) T-cell therapy is a highly effective new treatment for relapsed and refractory hematological cancers but is associated with the novel treatment-limiting toxicities of cytokine release syndrome and neurotoxicity. Neurotoxicity, now more commonly referred to as immune effector cell-associated neurotoxicity syndrome (ICANS), is a clinical and neuropsychiatric syndrome that can occur in the days to weeks following CAR T-cell and other T-cell-engaging therapies. While the clinical characteristics of ICANS have been well described, its pathophysiology is poorly understood, and best treatment and preventive strategies remain elusive. Clinical trial experience and animal models suggest a central role for endothelial cell dysfunction, myeloid cells, blood-brain barrier disruption, and elevated central nervous system cytokine levels in the development of ICANS. Here we discuss ICANS incidence, clinical features, risk factors, biomarkers, pathophysiology, and grading and management., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Immune effector cell (IEC) therapies offer durable and sustained remissions in significant numbers of patients with hematological cancers. While these unique immunotherapies have improved outcomes for pediatric and adult patients in a number of disease states, as 'living drugs,' their toxicity profiles, including cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), differ markedly from conventional cancer therapeutics. At the time of article preparation, the US Food and Drug Administration (FDA) has approved tisagenlecleucel, axicabtagene ciloleucel, and brexucabtagene autoleucel, all of which are IEC therapies based on genetically modified T cells engineered to express chimeric antigen receptors (CARs), and additional products are expected to reach marketing authorization soon and to enter clinical development in due course. As IEC therapies, especially CAR T cell therapies, enter more widespread clinical use, there is a need for clear, cohesive recommendations on toxicity management, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of common toxicities in the context of IEC treatment, including baseline laboratory parameters for monitoring, timing to onset, and pharmacological interventions, ultimately forming evidence- and consensus-based recommendations to assist medical professionals in decision-making and to improve outcomes for patients., Competing Interests: Competing interests: CC─Consultant and/or advisory board: Novartis. MLD─Consultant and/or advisory board: Celyad, Novartis; Research/license support: Atara, Celgene; Stock option: Adaptive Biotechnologies, Precision Bioscience. CD─ Consultant and/or advisory board: Evidera, Juno. JD─Consultant and/or advisory board: Unum Therapeutics, Blue Earth Diagnostics; Royalties: Wolters Kluwer. JCF─NIDDK 23 grant. MJF─Consultant and/or advisory board: Arcelex, Celgene, Nkarta, Novartis, Xenetic Bio. JLH-C─At-large board member: ASTCT; Vice Chair: Government affairs, Task force member on Immunotherapies and Palliative Care, ASH; Co-Primary Investigator: Imaging trial haplo/cord, graft failure NHLBI RO1 grant. SAG─Consultant and/or advisory board: Adaptimmune, Allogene, Cellectis, Eureka, GlaxoSmithKline, Humanigen, J&J/Janssen, Juno, Novartis, Roche, TCR2, Vertex/CRISPR Therapeutics; Grant/research support: Kite Gilead, Novartis, Servier, Vertex. KVK─Consultant or SAB: Kite/Gilead, Autolus, Juno/BMS, Celgene, Novartis, Takeda, Kiadis, Incyte, Atara, Legend, Kadmon, Helocyte; Clinical trials support (institutional): Kite/Gilead, Novartis, Atara, Allogene; Nonprofit organizations: National Marrow Donor Program (Board of Directors), ASTCT (Chair, cell therapy committee). DWL─Owner: Immchase, LLC; Consultant and/or advisory board: ACI Clinical (on behalf of Celgene), Harpoon Therapeutics, Juno Therapeutics. FLL─Scientific advisor: Kite/Gilead, Novartis, BMS/Celgene, Allogene, Wugen, Calibr, Gamma Delta Therapeutics; Consultant: Cellular Biomedicine Group Inc; Research support: Kite/Gilead. SLM─Consultant and/or advisory board: Kite, Novartis. MVM─Consultant and/or advisory board: Adaptimmune, Adaptive Biotechnologies, Argentus, BD Sciences, Bluebird Bio, Cell Signaling, Collectis (SAB), CRISPR Therapeutics, EMD Serono, Inysus, Kite, Juno, MPM, Novartis, Takeda, TCR2 (SAB), Third Rock Ventures, WindMIL (SAB); Grant/research support: CRISPR Therapeutics, Kite Gilead. PLM─Consultant and/or advisory board: BlueBird Biotech, BMS, Celgene, Fate Therapeutics, Janssen, Juno, Karyopharm, Magenta Therapeutics, MedScape, Sanofi, Takeda. SSN─Consultant and/or advisory board: Celgene, Cell Medica, Incyte, Kite/Gilead, Merck, Novartis, Pfizer, Precision Biosciences, Unum Therapeutics; Grant/research support: Acerta, BMS, Collectis, Karus, Kite Gilead, Merck, Poseida, Unum Therapeutics. TGN─Consultant on imaging: Parexel, Intrinsic Imaging; SAB on Checkpoint and Myocarditis: BMS; Consultant: H3 Biomedicine, Aprea Therapeutics. BDS─Consultant and/or advisory board: Kite Gilead, Juno/Celgene, Insysus, Novartis, Janssen; Grant/research support: ADC Therapeutics. EJS─Consultant and/or advisory board: Adaptimmune, Cellgene, Magenta, Novartis, Partner Therapeutics. DTT─Advisory board: La Roche, Amgen, Janssen, Novartis. CJT─Consultant and/or advisory board: Aptevo, Arsenal Bio, AstraZeneca, Caribou Biosciences, Century Therapeutics, Eureka Therapeutics, Humanigen, Juno/BMS, Kite/Gilead, Myeloid Therapeutics, Nektar Therapeutics, Novartis, Precision Biosciences, T-CURX; Stock options: Precision Biosciences, Eureka Therapeutics, Caribou Biosciences, Arsenal Bio, Myeloid Therapeutics; Grant/research support: Juno/BMS, Nektar Therapeutics, AstraZeneca. SA, MRB, JNB, TJF, EM, and TW─Nothing to disclose. SITC staff: AK, BL, LL and SMW─Nothing to disclose., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Factors contributing to hematopoietic recovery following chimeric antigen receptor (CAR) T-cell therapy have not been well studied. In an analysis of 83 patients with hematologic malignancies treated with CAR T-cell therapy, we describe patterns of hematopoietic recovery and evaluate potentially associated factors. We included patients who received axicabtagene ciloleucel (n = 30) or tisagenlecleucel (n = 10) for B-cell lymphoma, CD19-28z CAR T therapy for B-cell acute lymphoblastic leukemia (NCT01044069; n = 37), or B-cell maturation antigen targeting CAR T cells for multiple myeloma (NCT03070327; n = 6). Patients treated with CAR T cells who had not progressed, died, or received additional chemotherapy had "recovered" (per definition in Materials and methods section) hemoglobin, platelet, neutrophil, and white blood cell counts at rates of 61%, 51%, 33%, and 28% at month 1 postinfusion and 93%, 90%, 80%, and 59% at month 3 postinfusion, respectively. Univariate analysis showed that increasing grade of immune effector cell-associated neurological syndrome (ICANS), baseline cytopenias, CAR construct, and higher peak C-reactive protein or ferritin levels were statistically significantly associated with a lower likelihood of complete count recovery at 1 month; a similar trend was seen for cytokine release syndrome (CRS). After adjustment for baseline cytopenia and CAR construct, grade ≥3 CRS or ICANS remained significantly associated with the absence of complete count recovery at 1 month. Higher levels of vascular endothelial growth factor and macrophage-derived chemokines, although not statistically significant, were seen patients without complete count recovery at 1 month. This remains to be studied further in larger prospective studies., (© 2020 by The American Society of Hematology.)

CD19-targeted chimeric antigen receptor (CAR) T cell therapy is an effective treatment for diffuse large B cell lymphoma (DLBCL). In addition to cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS), B cell aplasia and hypogammaglobulinemia are common toxicities predisposing these patients to infections. We analyzed 60 patients with DLBCL treated with FDA-approved CD19 CAR T cells and report the incidence, risk factors, and management of infections during the first year after treatment. A total of 101 infectious events were observed, including 25 mild, 51 moderate, 23 severe, 1 life-threatening, and 1 fatal infection. Bacteria were the most common causative pathogens. The cumulative incidence of overall, bacterial, severe bacterial, viral, and fungal infection at 1 year were 63.3%, 57.2%, 29.6%, 44.7%, and 4%, respectively. In multivariate analyses, the use of systemic corticosteroids for the management of CRS or ICANS was associated with an increased risk of infections and prolonged admission. Impaired performance status and history of infections within 30 days before CAR T cell therapy was a risk factor for severe bacterial infection. In conclusion, infections were common within the first 60 days after CAR T cell therapy, however, they were not associated with an increased risk of death.

Cytokine release syndrome (CRS) immune effector cell-associated neurotoxicity syndrome are the most notable toxicities of CD19 chimeric antigen receptor (CAR) T-cell therapy. In addition, CAR T-cell-mediated toxicities can involve any organ system, with varied impacts on outcomes, depending on patient factors and involved organs. We performed detailed analysis of organ-specific toxicities and their association with outcomes in 60 patients with diffuse large B-cell lymphoma (DLBCL) treated with CD19 CAR T cells by assessing all toxicities in organ-based groups during the first year posttreatment. We observed 539 grade ≥2 and 289 grade ≥3 toxicities. Common grade ≥3 toxicities included hematological, metabolic, infectious, and neurological complications, with corresponding 1-year cumulative incidence of 57.7%, 54.8%, 35.4%, and 18.3%, respectively. Patients with impaired performance status had a higher risk of grade ≥3 metabolic complications, whereas elevated lactate dehydrogenase was associated with higher risks of grade ≥3 neurological and pulmonary toxicities. CRS was associated with higher incidence of grade ≥3 metabolic, pulmonary, and neurologic complications. The 1-year nonrelapse mortality and overall survival were 1.7% and 69%, respectively. Only grade ≥3 pulmonary toxicities were associated with an increased mortality risk. In summary, toxicity burdens after CD19 CAR T-cell therapy were high and varied by organ systems. Most toxicities were manageable and were rarely associated with mortality. Our study emphasizes the importance of toxicity assessment, which could serve as a benchmark for further research to reduce symptom burdens and improve tolerability in patients treated with CAR T cells., (© 2020 by The American Society of Hematology.)

Purpose of Review: This article reviews the clinical features, prognosis, and treatment of neurotoxicity from anticancer drugs, including conventional cytotoxic chemotherapy, biologics, and targeted therapies, with a focus on the newer immunotherapies (immune checkpoint inhibitors and chimeric antigen receptor T cells)., Recent Findings: Whereas neurologic complications from traditional chemotherapy are widely recognized, newer cancer therapies, in particular immunotherapies, have unique and distinct patterns of neurologic adverse effects. Anticancer drugs may cause central or peripheral nervous system complications. Neurologic complications of therapy are being seen with increasing frequency as patients with cancer are living longer and receiving multiple courses of anticancer regimens, with novel agents, combinations, and longer duration. Neurologists must know how to recognize treatment-related neurologic toxicity since discontinuation of the offending agent or dose adjustment may prevent further or permanent neurologic injury. It is also imperative to differentiate neurologic complications of therapy from cancer progression into the nervous system and from comorbid neurologic disorders that do not require treatment dose reduction or discontinuation., Summary: Neurotoxicity from cancer therapy is common, with effects seen on both the central and peripheral nervous systems. Immune checkpoint inhibitor therapy and chimeric antigen receptor T-cell therapy are new cancer treatments with distinct patterns of neurologic complications. Early recognition and appropriate management are essential to help prevent further neurologic injury and optimize oncologic management.

Various grading systems are currently used for chimeric antigen receptor (CAR) T-cell-related toxicity, cytokine release syndrome (CRS), and immune effector cell-associated neurotoxicity syndrome (ICANS). We compared the recently proposed American Society for Transplantation and Cellular Therapy (ASTCT) grading system to other grading scores in 2 populations of adults: patients (n = 53) with B-cell acute lymphoblastic leukemia (B-ALL) treated with 1928z CAR T-cells (clinicaltrials.gov #NCT01044069), and patients (n = 49) with diffuse large B-cell lymphoma (DLBCL) treated with axicabtagene-ciloleucel (axi-cel) or tisagenlecleucel after US Food and Drug Administration approval. According to ASTCT grading, 82% of patients had CRS, 87% in the B-ALL and 77% in the DLBCL groups (axi-cel: 86%, tisagenlecleucel: 54%), whereas 50% of patients experienced ICANS, 55% in the B-ALL and 45% in the DLBCL groups (axi-cel: 55%, tisagenlecleucel: 15%). All grading systems agreed on CRS and ICANS diagnosis in 99% and 91% of cases, respectively. However, when analyzed grade by grade, only 25% and 54% of patients had the same grade in each system for CRS and ICANS, respectively, as different systems score symptoms differently (upgrading or downgrading their severity), leading to inconsistent final grades. Investigation of possible management implications in DLBCL patients showed that different recommendations on tocilizumab and steroids across current guidelines potentially result in either overtreating or delaying treatment. Moreover, because these guidelines are based on single products and different grading systems, they cannot be universally applied. To avoid discrepancies in assessing and managing toxicities of different products, we propose that unified grading be used across clinical trials and in practice and that paired management guidelines with product-specific indications be developed., (© 2020 by The American Society of Hematology.)

Background: Melanoma brain metastases historically portend a dismal prognosis, but recent advances in immune checkpoint inhibitors (ICIs) have been associated with durable responses in some patients. There are no validated imaging biomarkers associated with outcomes in patients with melanoma brain metastases receiving ICIs. We hypothesized that radiomic analysis of magnetic resonance images (MRIs) could identify higher-order features associated with survival., Methods: Between 2010 and 2019, we retrospectively reviewed patients with melanoma brain metastases who received ICI. After volumes of interest were drawn, several texture and edge descriptors, including first-order, Haralick, Gabor, Sobel, and Laplacian of Gaussian (LoG) features were extracted. Progression was determined using Response Assessment in Neuro-Oncology Brain Metastases. Univariate Cox regression was performed for each radiomic feature with adjustment for multiple comparisons followed by Lasso regression and multivariate analysis., Results: Eighty-eight patients with 196 total brain metastases were identified. Median age was 63.5 years (range, 19-91 y). Ninety percent of patients had Eastern Cooperative Oncology Group performance status of 0 or 1 and 35% had elevated lactate dehydrogenase. Sixty-three patients (72%) received ipilimumab, 11 patients (13%) received programmed cell death protein 1 blockade, and 14 patients (16%) received nivolumab plus ipilimumab. Multiple features were associated with increased overall survival (OS), and LoG edge features best explained the variation in outcome (hazard ratio: 0.68, P = 0.001). In multivariate analysis, a similar trend with LoG was seen, but no longer significant with OS. Findings were confirmed in an independent cohort., Conclusion: Higher-order MRI radiomic features in patients with melanoma brain metastases receiving ICI were associated with a trend toward improved OS., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We present a case of a patient with multiply relapsed, refractory myeloma whose clinical course showed evidence of a synergistic abscopal-like response to chimeric antigen receptor (CAR) T-cell therapy and localized radiotherapy (XRT). Shortly after receiving B-cell maturation antigen (BCMA)-targeted CAR T-cell therapy, the patient required urgent high-dose steroids and XRT for spinal cord compression. Despite the steroids, the patient had a durable systemic response that could not be attributed to XRT alone. Post-XRT findings included a second wave of fever and increased CRP and IL6, beginning 21 days after CAR T cells, which is late for cytokine-release syndrome from CAR T-cell therapy alone on this trial. Given this response, which resembled cytokine-release syndrome, immediately following XRT, we investigated changes in the patient's T-cell receptor (TCR) repertoire over 10 serial time points. Comparing T-cell diversity via Morisita's overlap indices ( C D ), we discovered that, although the diversity was initially stable after CAR T-cell therapy compared with baseline ( C D = 0.89-0.97, baseline vs. 4 time points after CAR T cells), T-cell diversity changed after the conclusion of XRT, with >30% newly expanded TCRs ( C D = 0.56-0.69, baseline vs. 4 time points after XRT). These findings suggest potential synergy between radiation and CAR T-cell therapies resulting in an abscopal-like response., (©2019 American Association for Cancer Research.)

Chimeric antigen receptor (CAR) T cell therapy is rapidly emerging as one of the most promising therapies for hematologic malignancies. Two CAR T products were recently approved in the United States and Europe for the treatment ofpatients up to age 25years with relapsed or refractory B cell acute lymphoblastic leukemia and/or adults with large B cell lymphoma. Many more CAR T products, as well as other immunotherapies, including various immune cell- and bi-specific antibody-based approaches that function by activation of immune effector cells, are in clinical development for both hematologic and solid tumor malignancies. These therapies are associated with unique toxicities of cytokine release syndrome (CRS) and neurologic toxicity. The assessment and grading of these toxicities vary considerably across clinical trials and across institutions, making it difficult to compare the safety of different products and hindering the ability to develop optimal strategies for management of these toxicities. Moreover, some aspects of these grading systems can be challenging to implement across centers. Therefore, in an effort to harmonize the definitions and grading systems for CRS and neurotoxicity, experts from all aspects of the field met on June 20 and 21, 2018, at a meeting supported by the American Society for Transplantation and Cellular Therapy (ASTCT; formerly American Society for Blood and Marrow Transplantation, ASBMT) in Arlington, VA. Here we report the consensus recommendations of that group and propose new definitions and grading for CRS and neurotoxicity that are objective, easy to apply, and ultimately more accurately categorize the severity of these toxicities. The goal is to provide a uniform consensus grading system for CRS and neurotoxicity associated with immune effector cell therapies, for use across clinical trials and in the postapproval clinical setting., (Copyright © 2018 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

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 ., (©2018 American Association for Cancer Research.)

Purpose To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Methods A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. Results The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert consensus. Recommendations Recommendations for specific organ system-based toxicity diagnosis and management are presented. While management varies according to organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert to grade 1 or less. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .

In the course of modeling the naturally occurring tumor immunity seen in patients with paraneoplastic cerebellar degeneration (PCD), we discovered an unexpectedly high threshold for breaking CD8+ cytotoxic T cell (CTL) tolerance to the PCD autoantigen, CDR2. While CDR2 expression was previously found to be strictly restricted to immune-privileged cells (cerebellum, testes, and tumors), unexpectedly we have found that T cells also express CDR2. This expression underlies inhibition of CTL activation; CTLs that respond to epithelial cells expressing CDR2 fail to respond to T cells expressing CDR2. This was a general phenomenon, as T cells presenting influenza (flu) antigen also fail to activate otherwise potent flu-specific CTLs either in vitro or in vivo. Moreover, transfer of flu peptide-pulsed T cells into flu-infected mice inhibits endogenous flu-specific CTLs. Our finding that T cells serve as a site of immune privilege, inhibiting effector CTL function, uncovers an autorepressive loop with general biologic and clinical relevance.

Paraneoplastic neurologic diseases (PND) involving immune responses directed toward intracellular antigens are poorly understood. Here, we examine immunity to the PND antigen Nova2, which is expressed exclusively in central nervous system (CNS) neurons. We hypothesized that ectopic expression of neuronal antigen in the periphery could incite PND. In our C57BL/6 mouse model, CNS antigen expression limits antigen-specific CD4+ and CD8+ T-cell expansion. Chimera experiments demonstrate that this tolerance is mediated by antigen expression in nonhematopoietic cells. CNS antigen expression does not limit tumor rejection by adoptively transferred transgenic T cells but does limit the generation of a memory population that can be expanded upon secondary challenge in vivo. Despite mediating cancer rejection, adoptively transferred transgenic T cells do not lead to paraneoplastic neuronal targeting. Preliminary experiments suggest an additional requirement for humoral activation to induce CNS autoimmunity. This work provides evidence that the requirements for cancer immunity and neuronal autoimmunity are uncoupled. Since humoral immunity was not required for tumor rejection, B-cell targeting therapy, such as rituximab, may be a rational treatment option for PND that does not hamper tumor immunity., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The onconeural antigens appear to serve as tumor rejection antigens in the paraneoplastic neurologic disorders. Here, we used an unbiased peptide binding screen, followed by studies in HLA-A2.1 transgenic mice to identify naturally processed HLA-A2.1 restricted epitopes of the paraneoplastic cerebellar degeneration breast/ovarian cancer antigen cdr2. These mice were used to clone high-avidity cdr2-specific CD8(+) T cells that recognize human tumor cells presenting endogenously loaded MHC class I-cdr2 peptide. T cells with this specificity were detected in the peripheral blood of two HLA-A2.1(+) paraneoplastic cerebellar degeneration patients. We cloned T cell receptor (TCR) alpha and beta genes from cdr2-specific T cells; electroporation of RNA encoding this TCR turned nonreactive donor T cells into efficient killers of human cdr2-expressing tumor cells. Cloned cdr2-specific TCR genes provide a clinically relevant means for immunologic targeting of human gynecologic cancers.