CD19 positive lymphoide Malignome: CAR-transduzierte natürliche Killerzellen nutzen

2021 ◽  
pp. 1-2
Author(s):  
Wolfgang Bethge
Keyword(s):  
Phase I ◽  
Effector Cell ◽  
Wird Eine ◽  
Immune Effector Cell ◽  
Caspase 9 ◽  
Immune Effector ◽  
Natürliche Killerzellen ◽  
Car T ◽  
Klinische Routine

<b>Eine Phase I/II anti-CD19 CAR-NK-Studie</b> Die gegen CD19 gerichtete autologe CAR-T-Zell-Therapie hat mit Zulassung der kommerziell verfügbaren Konstrukte Kymriah® und Yescarta® für ALL/DLBCL bzw. PMBCL/DLBCL Eingang in die klinische Routine gefunden. Allerdings sind diese Therapien mit einer komplexen Logistik verbunden und können auch teilweise nicht unerhebliche Nebenwirkungen wie das Cytokin Release Syndrom (CRS) oder Immune-Effector-Cell-associated-Neurotoxicity-Syndrome (ICANS) verursachen, so dass der Einsatz zertifizierten Therapiezentren vorbehalten ist. Auch Langzeitzytopenien sind relativ häufig. Außerdem ist die Logistik und Zeit, die zur individuellen Produktion von autologen CAR-T-Zellen notwendig ist, eine praktische und kostensteigernde Hürde. Dadurch erhält eine relevante Anzahl von Kandidaten für eine CAR-T-Zell-Therapie diese nie. Auch die Sammlung einer ausreichenden Anzahl vitaler autologer Lymphozyten kann bei ausgedehnt vorthera­pierten Patienten ein Problem darstellen. Einem sehr guten initialen Ansprechen steht ein noch etwas unbefriedigendes Langzeitansprechen bedingt durch eine relativ hohe Rezidivinzidenz nach 3–6 Monaten gegenüber. Dies ist insbesondere angesichts der hohen Therapiekosten von derzeit um 300 000 Euro/Patient noch unbefriedigend. Resistenzmechanismen sind insbesondere der Antigen-Verlust und fehlende Langzeit-CAR-T-Persistenz. Inzwischen werden verschiedene Strategien zur Verbesserung einer CAR-T-Zell-Therapie und insbesondere des Langzeittherapieansprechens durch die Kombination verschiedener Zielantigene, humanisierten CAR-T Konstrukten zur Verbesserung der Persistenz, und auch neue Effektorzellpopulationen geprüft. In ihrer Arbeit beschreiben Liu et al. nun einen sehr innovativen Ansatz zur Verbesserung einiger der oben genannten Probleme durch den Einsatz von off-the-shelf nicht HLA-gematchten anti-CD19 CAR-NK Zellen aus Nabelschnurblut von gesunden Spendern. NK Zellen als Teil des angeborenen («innate») Immunsystems können ohne der Notwendigkeit zu einer kompletten Übereinstimmung des HLA-Typs eingesetzt werden. Nach Transduktion mit einem chimären Antigen Rezeptor (CAR) wird so die Bevorratung und Kryokonservierung eines CAR-NK Produkts für den Einsatz ohne patientenindividuelle Herstellung möglich. Die Arbeitsgruppe hat über einen retroviralen Vektor einen CD19-CAR mit IL-15 kombiniert, um die autokrine Stimmulation zur Expansion und Persistenz der CAR-NK Zellen zu verbessern. Außerdem wird eine induzierbare Caspase-9 mit exprimiert, um auch bei toxischen Effekten ein Abschalten des Konstruktes in vivo zu ermöglichen. Nach erfolgreichen Tierversuchen in der Maus, beschreibt die Arbeitsgruppe nun eine erste Phase I/II Studie. https://clinicaltrials.gov/ct2/show/NCT03056339

Nichts für Schönwetterkapitäne: CAR-T-Zellen – Immunonkologie trifft Intensivmedizin

2020 ◽  
Vol 41 (10) ◽  
pp. 673-679
Author(s):  
Jorge Garcia Borrega ◽  
Michael von Bergwelt-Baildon ◽  
Boris Böll
Keyword(s):  
Real World ◽  
Effector Cell ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Immune Effector Cell ◽  
Immune Effector ◽  
Car T

Zusammenfassung CRS und ICANS als Nebenwirkung von CAR-T-Zellen Das Cytokine-Release-Syndrome (CRS) ist die häufigste Nebenwirkung einer CAR-T-Zell-Therapie und kann von leichtem Fieber bis zu einem Multiorganversagen führen. Pathophysiologisch kommt es beim CRS zu einem Zytokinsturm und trotz einer Therapie mit Tocilizumab sind refraktäre und tödliche Verläufe beschrieben. Die Symptome des Immune-Effector-Cell-associated-Neurotoxicity-Syndrome (ICANS) variieren von leichter Desorientiertheit bis zum lebensbedrohlichen Hirnödem. Die Pathophysiologie und Therapie des ICANS sind noch nicht ausreichend erforscht. Die Differenzialdiagnosen von CRS und ICANS sind komplex und umfassen neben Infektionen und Sepsis unter anderem auch eine Toxizität der vorhergehenden Therapie, ein Tumorlysesyndrom und nicht zuletzt einen Progress der Grunderkrankung. Ein klinischer oder laborchemischer Parameter zum sicheren Beweis oder Ausschluss eines CRS oder ICANS gibt es zum heutigen Zeitpunkt nicht. Intensivmedizinische Relevanz und potenzielle Entwicklungen der CAR-T-Zell-Therapie Erste Auswertungen von Real-world-Daten deuten auf eine höhere Rate an schweren Nebenwirkungen im Rahmen der CAR-T-Zell-Therapie als in den Zulassungsstudien hin. Für die Indikation r/r-DLBCL könnten schätzungsweise bis zu maximal 300 Patienten pro Jahr in Deutschland eine intensivmedizinische Betreuung im Rahmen der CAR-T-Zell-Therapie benötigen. Studien mit wesentlich häufigeren soliden Tumoren könnten die Patientenzahl drastisch erhöhen. Therapieziel bei CAR-T-Zell-Patienten und Entscheidungen bei Therapiezieländerung Aufgrund des neuen Therapiekonzepts kann ein Konflikt zwischen bislang palliativem Patientenkollektiv und nun möglicherweise langfristigen Remissionen entstehen. Eine frühzeitige Aufklärung über potenziell lebensbedrohliche Nebenwirkungen im Rahmen der Therapie und eine interdisziplinäre Besprechung der Therapieziele mit den Patienten ist entscheidend.

scholarly journals IMMU-07. IMMUNE EFFECTOR CELL ASSOCIATED NEUROTOXICITY (ICANS) AMONG PEDIATRIC AND AYA PATIENTS: MD ANDERSON CANCER CENTER EXPERIENCE

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii361-iii361
Author(s):  
Brandon Brown ◽  
Paolo Tambaro ◽  
Kris Mahadeo ◽  
Sajad Khazal ◽  
Priti Tewari ◽  
...  
Keyword(s):  
B Cell ◽  
Effector Cell ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Altered Mental Status ◽  
Cancer Center ◽  
Immune Effector Cell ◽  
Immune Effector ◽  
Impaired Ability ◽  
Car T

Abstract INTRODUCTION Immune effector cell associated neurotoxicity (ICANS) and cytokine release syndrome (CRS) are potentially life-threatening complications associated with immune effector cell (IEC) therapies. We characterize ICANS in pediatric and adult young adolescent (AYA) patients receiving IEC therapy at our institution. METHODS We reviewed clinical characteristics and severity (based on ASTCT Consensus Criteria) in pediatric and AYA patients with IEC products from 2018–2019 at MDACC. RESULTS Nine patients, median age 15.5 (range: 3–25) years received chimeric antigen receptor (CART) IEC therapy. Four (44%) developed ICANS within median of 8 (range: 3–27) days of CAR T cell infusion and median 6 (range: 2–7) days after CRS. Primary diagnoses were pre-B cell acute lymphoblastic leukemia (8) and mediastinal large B-cell lymphoma (1). Median CRS and ICANS severity grade was 2 (range 1–4). Symptoms included altered mental status (AMS) (5), seizure (1), aphasia (2), impaired ability to write a standard sentence (4). Neuroimaging did not correlate to ICANS symptoms or severity. EEG was performed in 3 and 1 had background slowing correlating with aphasia. CSF was obtained in two revealing lymphocytosis. All received prophylactic anti-epileptic medication and tocilizumab for concomitant CRS. Three received steroids. CONCLUSION ICANS may present in almost half of pediatric patients within one week of receiving CART products associated with CRS. CAR-T trafficking into the CSF may explain pleocytosis in the CSF. Prospective studies may clarify. Impaired ability to write a standard sentence and the Cornell Assessment of Pediatric Delirium (CAPD) may be early indicators of ICANS in pediatric/AYA patients.

scholarly journals Exploitation of Synthetic mRNA To Drive Immune Effector Cell Recruitment and Functional Reprogramming In Vivo

2018 ◽  
Vol 202 (2) ◽  
pp. 608-617 ◽  
Author(s):  
Yitian Xu ◽  
Lu Huang ◽  
Jonathan L. Kirschman ◽  
Daryll A. Vanover ◽  
Pooja M. Tiwari ◽  
...  
Keyword(s):  
Effector Cell ◽  
Immune Effector Cell ◽  
Immune Effector ◽  
Cell Recruitment ◽  
Synthetic Mrna

scholarly journals Single-center experience using anakinra for steroid-refractory immune effector cell-associated neurotoxicity syndrome (ICANS)

2022 ◽  
Vol 10 (1) ◽  
pp. e003847
Author(s):  
Marc Wehrli ◽  
Kathleen Gallagher ◽  
Yi-Bin Chen ◽  
Mark B Leick ◽  
Steven L McAfee ◽  
...  
Keyword(s):  
T Cell ◽  
Effector Cell ◽  
Standard Treatment ◽  
Treatment Guidelines ◽  
Immune Effector Cell ◽  
T Cell Therapy ◽  
Immune Effector ◽  
Car T Cell ◽  
Car T ◽  
Steroid Refractory

In addition to remarkable antitumor activity, chimeric antigen receptor (CAR) T-cell therapy is associated with acute toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Current treatment guidelines for CRS and ICANS include use of tocilizumab, a monoclonal antibody that blocks the interleukin (IL)-6 receptor, and corticosteroids. In patients with refractory CRS, use of several other agents as third-line therapy (including siltuximab, ruxolitinib, anakinra, dasatinib, and cyclophosphamide) has been reported on an anecdotal basis. At our institution, anakinra has become the standard treatment for the management of steroid-refractory ICANS with or without CRS, based on recent animal data demonstrating the role of IL-1 in the pathogenesis of ICANS/CRS. Here, we retrospectively analyzed clinical and laboratory parameters, including serum cytokines, in 14 patients at our center treated with anakinra for steroid-refractory ICANS with or without CRS after standard treatment with tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) CD19-targeting CAR T. We observed statistically significant and rapid reductions in fever, inflammatory cytokines, and biomarkers associated with ICANS/CRS after anakinra treatment. With three daily subcutaneous doses, anakinra did not have a clear, clinically dramatic effect on neurotoxicity, and its use did not result in rapid tapering of corticosteroids; although neutropenia and thrombocytopenia were common at the time of anakinra dosing, there were no clear delays in hematopoietic recovery or infections that were directly attributable to anakinra. Anakinra may be useful adjunct to steroids and tocilizumab in the management of CRS and/or steroid-refractory ICANs resulting from CAR T-cell therapies, but prospective studies are needed to determine its efficacy in these settings.

Next-Generation Implementation of Chimeric Antigen Receptor T-Cell Therapy Using Digital Health

2021 ◽  
pp. 668-678
Author(s):  
Rahul Banerjee ◽  
Nina Shah ◽  
Adam P. Dicker
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Effector Cell ◽  
Antigen Receptor ◽  
Machine Learning Algorithms ◽  
Immune Effector Cell ◽  
Next Generation ◽  
Immune Effector ◽  
Patient Reported ◽  
Car T

Chimeric antigen receptor T-cell (CAR-T) therapy is a paradigm-shifting immunotherapy modality in oncology; however, unique toxicities such as cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome limit its ability to be implemented more widely in the outpatient setting or at smaller-volume centers. Three operational challenges with CAR-T therapy include the following: (1) the logistics of toxicity monitoring, ie, with frequent vital sign checks and neurologic assessments; (2) the specialized knowledge required for toxicity management, particularly with regard to CRS and immune effector cell–associated neurotoxicity syndrome; and (3) the need for high-quality symptomatic and supportive care during this intensive period. In this review, we explore potential niches for digital innovations that can improve the implementation of CAR-T therapy in each of these domains. These tools include patient-facing technologies and provider-facing platforms: for example, wearable devices and mobile health apps to screen for fevers and encephalopathy, electronic patient-reported outcome assessments–based workflows to assist with symptom management, machine learning algorithms to predict emerging CRS in real time, clinical decision support systems to assist with toxicity management, and digital coaching to help maintain wellness. Televisits, which have grown in prominence since the novel coronavirus pandemic, will continue to play a key role in the monitoring and management of CAR-T–related toxicities as well. Limitations of these strategies include the need to ensure care equity and stakeholder buy-in, both operationally and financially. Nevertheless, once developed and validated, the next-generation implementation of CAR-T therapy using these digital tools may improve both its safety and accessibility.

scholarly journals IMMU-52. IMMUNE EFFECTOR CELL ASSOCIATED NEUROTOXICITY (ICANS) AMONG PEDIATRIC AND AYA PATIENTS: MD ANDERSON CANCER CENTER EXPERIENCE

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii116-ii116
Author(s):  
Brandon Brown ◽  
Kris Mahadeo ◽  
Sajad Khazal ◽  
Demetrios Petropoulos ◽  
Priti Tewari ◽  
...  
Keyword(s):  
B Cell ◽  
Effector Cell ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Altered Mental Status ◽  
Cancer Center ◽  
Immune Effector Cell ◽  
Immune Effector ◽  
Impaired Ability ◽  
Car T

Abstract INTRODUCTION Immune effector cell associated neurotoxicity (ICANS) and cytokine release syndrome (CRS) are potentially life-threatening complications associated with immune effector cell (IEC) therapies. We characterize ICANS in pediatric and adult young adolescent (AYA) patients receiving IEC therapy at our institution. METHODS We reviewed clinical characteristics and severity (based on ASTCT Consensus Criteria) in pediatric and AYA patients who received IEC products from 2018–2019 at MDACC. RESULTS Nine patients, median age 15.5 (range: 3–25) years received chimeric antigen receptor (CART) IEC therapy. Four (44%) developed ICANS within median of 8 (range: 3–27) days of CAR T cell infusion and median 6 (range: 2–7) days after CRS. Primary diagnoses were pre-B cell acute lymphoblastic leukemia (8) and mediastinal large B-cell lymphoma (1). Median CRS and ICANS severity grade was 2 (range 1–4). Symptoms included altered mental status (AMS) (5), seizure (1), aphasia (2), impaired ability to write a standard sentence (4). Neuroimaging did not correlate to ICANS symptoms or severity. EEG was performed in 3 and 1 had background slowing correlating with aphasia. CSF was obtained in two revealing lymphocytosis. All received prophylactic anti-epileptic medication and tocilizumab for concomitant CRS. Three received steroids. CONCLUSION ICANS may present in almost half of pediatric patients within one week of receiving CART products associated with CRS. CAR-T trafficking into the CSF may explain pleocytosis in the CSF. Prospective studies may clarify. Impaired ability to write a standard sentence and the Cornell Assessment of Pediatric Delirium (CAPD) may be early indicators of ICANS in pediatric/AYA patients.

scholarly journals Real World Evaluation of Deviation Outcomes in an Immune Effector Cell Quality Program

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-10
Author(s):  
Geoffrey Shouse ◽  
Sylvia O Dulan ◽  
Jamie Wagner ◽  
Michelle Mott ◽  
Alex Ly ◽  
...  
Keyword(s):  
Real World ◽  
Research Funding ◽  
Effector Cell ◽  
Cellular Immunotherapy ◽  
Survival Outcomes ◽  
Immune Effector Cell ◽  
Immune Effector ◽  
Quality Program ◽  
Car T ◽  
Post Infusion

Introduction City of Hope (COH) was one of the first institutions to be granted Immune Effector Cell (IEC) Therapy accreditation by the Foundation for the Accreditation of Cellular Therapy, which supports our mission to provide safe, high quality patient care through expanded standardization. As part of the accreditation requirements, COH expanded established processes developed to monitor standard of care (SOC) deviations for the Hematopoietic Cell Transplantation Program to our IEC Clinical Program. As part of process improvement, we monitored our IEC Quality program to determine if there were any outcome changes as a result of deviations. Therefore, we performed a retrospective analysis of electronically submitted SOC deviations for patients treated with commercially available chimeric antigen receptor (CAR) T cell products (tisagenlecleucel or axicabtagene ciloleucel [Axi-cel]) between December 2017- March 2020 at COH. Methods During the reporting timeframe, 122 patients were planned to be treated with an IEC product. We retrieved 28 requests for SOC deviations from our electronic database for 24 of 122 patients. We analyzed for volume, trends and patient outcomes of submitted deviation requests, including trends in type of deviation, transfer to the intensive care unit (ICU), length of inpatient hospital stay and safety outcomes at 30 days post infusion. Patients who did not receive their SOC product for any reason during the reporting timeframe, or were lost to follow-up were excluded from the outcomes analysis. Results Sixteen of 24 patients were planned to be treated with SOC Axi-cel and 8 of 24 patients were planned to be treated with tisagenlecleucel; only 19 of 24 patients (10 women and 9 men) underwent infusion with their respective SOC product, 15 with Axi-cel and 4 with tisagenlecleucel. Five of 24 patients, including 1 Axi-cel and 4 tisagenlecleucel patients were excluded due to change in medical condition or infusion after the reporting timeframe. We identified elevated creatinine levels as the most common reason for SOC deviation requests for patients to be treated with tisagenlecleucel (4 of 8 patients), while deviations relating to rest days between lymphodepletion and CAR T cell infusion were the most common submitted deviations for patients planned to be treated with Axi-cel (9 of 16 patients). We also descriptively compared patients who required SOC deviations to a cohort of patients (n=98) who did not require deviations and were treated with either axicabtagene ciloleucel (n=86) or tisagenlecleucel (n=12) during the same timeframe. Eight of 98 (8%) of patients who did not have requests for SOC deviation were transferred to the ICU compared to 4 of 19 (21%) patients who required SOC deviations. Seventeen of 19 and 94 of 98 patients were discharged. The median length of inpatient hospital stay post infusion for SOC deviations cohorts who were discharged was 16 days (11-40) and 15 days (8-100) for non-SOC deviations patients. When we descriptively compared survival outcomes at 30 days post infusion, we found that all (4 of 4) patients who required SOC deviations and received tisagenlecleucel survived compared to 11 of 12 patients without SOC deviations. For patients who received Axi-cel, 14 of 15 patients with SOC deviations survived at day 30 post infusion compared to 85 of 86 patients without SOC deviations. The response to treatment and toxicities will be reported at the meeting. Conclusion These data suggest that careful selection of patients who may benefit from SOC deviations and still receive their infusion may not negatively affect survival outcomes at 30 days. The SOC deviation review process offers physicians a forum to evaluate non-SOC eligible cases and advise on SOC policy changes. While preliminary, our quality review identifies a role for comprehensive analysis of all IEC SOC deviations as part of standard practice, especially as the field of cellular immunotherapy expands to include more SOC cellular products. Overall, further monitoring of SOC deviations in real world patient populations treated with commercially available IEC products will allow us to continue to support patient safety, assess patient care management practices, expand patient access, meet accreditation standards and monitor SOC practice changes while advancing the field of cellular immunotherapy. Disclosures Shouse: Kite Pharma: Honoraria, Speakers Bureau. Mott:Janssen/Johnson & Johnson: Consultancy; Juno/BMS: Consultancy. Budde:Gilead Sciences: Consultancy; AstraZeneca: Research Funding; Merck: Research Funding; Mustang Therapeutics: Research Funding; Kite, a Gilead Company: Consultancy; Roche: Consultancy; Amgen: Research Funding.

scholarly journals Management of Immune-Related Adverse Events in Patients Treated With Chimeric Antigen Receptor T-Cell Therapy: ASCO Guideline

2021 ◽  
Author(s):  
Bianca D. Santomasso ◽  
Loretta J. Nastoupil ◽  
Sherry Adkins ◽  
Christina Lacchetti ◽  
Bryan J. Schneider ◽  
...  
Keyword(s):  
T Cell ◽  
Supportive Care ◽  
Effector Cell ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Immune Effector Cell ◽  
T Cell Therapy ◽  
Immune Effector ◽  
Car T Cell ◽  
Car T

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 .

scholarly journals Practical aspects of building a new immunotherapy program: the future of cell therapy

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 579-584
Author(s):  
Jesús G. Berdeja
Keyword(s):  
T Cells ◽  
Effector Cell ◽  
Hematologic Malignancies ◽  
Immune Effector Cell ◽  
Optimal Care ◽  
Immune Effector ◽  
Car T Cells ◽  
Car T ◽  
Challenges And Opportunities ◽  
Disease Specialist

Abstract Cellular-redirecting therapies, including bispecific T-cell engagers and chimeric antigen receptor (CAR) T cells, are rapidly changing the treatment landscape of hematologic malignancies and solid tumor malignancies. I will discuss the unique safety profile and logistical aspects that pose challenges and opportunities for the safe and successful delivery of these therapies. Close interaction, communication, and established partnerships between the primary oncologist, the disease specialist, and the immune effector cell provider will be needed to provide optimal care longitudinally for any patient. I will discuss practical ways for any program to deliver these therapies and how future advances may widen availability beyond just a few centers.

scholarly journals NCMP-24. PRE-INFUSION NEUROFILAMENT LIGHT CHAIN (NFL) LEVELS PREDICT THE DEVELOPMENT OF IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME (ICANS)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii127-ii128
Author(s):  
Omar Butt ◽  
Alice Zhou ◽  
Suzanne Schindler ◽  
Anne Fagan ◽  
John Dipersio ◽  
...  
Keyword(s):  
Cell Therapy ◽  
Light Chain ◽  
Effector Cell ◽  
Immune Effector Cell ◽  
Neurofilament Light Chain ◽  
Neurofilament Light ◽  
T Cell Therapy ◽  
Immune Effector ◽  
Car T Cell Therapy ◽  
Car T

Abstract Neurological side effects after chimeric antigen receptor-modified (CAR) T cell therapy are common and potentially devastating. Termed immune effector cell-associated neurotoxicity syndrome (ICANS), symptoms range from mild encephalopathy to diffuse cerebral edema. No predictive biomarkers exist to identify individuals at risk for developing ICANS. Serum neurofilament light chain (NfL) is a well-established marker of neural injury known to dynamically change in neuro-inflammatory disorders (e.g. multiple sclerosis). We hypothesized individuals undergoing CAR T cell therapy who ultimately developed ICANS would have early and sustained elevations in serum NfL. We performed a retrospective analysis of serum samples from 11 individuals treated with tisagenlecleucel or axicabtagene ciloleucel (mean age 61.3, 18% female, 27% ICANS, all with peak severity score 3). Most individuals had a longitudinal sampling at baseline, pre-infusion, post-transfusion day (PTD) 1, PTD 3, PTD 7, PTD 14, and PTD 30. Serum NfL were assayed using a Simoa HD-1/HD-X kit (QuanterixTM). We found that individuals who developed ICANS had early and sustained elevations in serum NfL levels at baseline (p = 0.0075), pre-infusion (p = 0.0172), and PTD 3 (p = 0.0026) and PTD 30 (p = 0.0066). All group comparisons survived multiple comparison testing using false-discovery rate (FDR). Receiver operating characteristic (ROC) curve classification by logistic regression of serum NfL revealed an area under the curve (AUC) of 1.0 with a cut-off of 44 pg/mL. No correlation was observed between NfL levels and age, sex, or history of central nervous system involvement of the underlying malignancy. In summary, we found serum NfL levels are a robust, early marker for the development of ICANS. Our findings suggest the risk of developing ICANS reflects pre-transfusion host-factors, permitting the screening well in advance of drug administration.

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