Faculty Opinions recommendation of Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells.

2021 ◽  
Author(s):  
David Teachey
Keyword(s):  
T Cells ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T

scholarly journals In vivo generation of human CD 19‐ CAR T cells results in B‐cell depletion and signs of cytokine release syndrome

2018 ◽  
Vol 10 (11) ◽  
Author(s):  
Anett Pfeiffer ◽  
Frederic B Thalheimer ◽  
Sylvia Hartmann ◽  
Annika M Frank ◽  
Ruben R Bender ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T

scholarly journals Development of molecular and pharmacological switches for chimeric antigen receptor T cells

2019 ◽  
Vol 8 (1) ◽  
Author(s):  
Bill X. Wu ◽  
No-Joon Song ◽  
Brian P. Riesenberg ◽  
Zihai Li
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Intervention Strategy ◽  
Antigen Receptor ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract The use of chimeric antigen receptor (CAR) T cell technology as a therapeutic strategy for the treatment blood-born human cancers has delivered outstanding clinical efficacy. However, this treatment modality can also be associated with serious adverse events in the form of cytokine release syndrome. While several avenues are being pursued to limit the off-target effects, it is critically important that any intervention strategy has minimal consequences on long term efficacy. A recent study published in Science Translational Medicine by Dr. Hudecek’s group proved that dasatinib, a tyrosine kinase inhibitor, can serve as an on/off switch for CD19-CAR-T cells in preclinical models by limiting toxicities while maintaining therapeutic efficacy. In this editorial, we discuss the recent strategies for generating safer CAR-T cells, and also important questions surrounding the use of dasatinib for emergency intervention of CAR-T cell mediated cytokine release syndrome.

Latest in Clinical Application of CAR Cell Therapy for B-cell Malignancy and Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. SCI-24-SCI-24
Author(s):  
Crystal L. Mackall
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
B Cell ◽  
Graft Failure ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T

Unparalleled remission rates in patients with chemorefractory B-ALL treated with CD19-CAR T cells illustrate the potential for immunotherapy to eradicate chemoresistant cancer. CD19-CAR therapy is poised to fundamentally alter the clinical approach to relapsed B-ALL and ultimately may be incorporated into frontline therapy. Despite these successes, as clinical experience with this novel modality has increased, so has understanding of factors that limit success of CD19-CAR T cells for leukemia. These insights have implications for the future of cell based immunotherapy for leukemia and provide a glimpse of more global challenges likely to face the emerging field of cancer immunotherapy. Five challenges limiting the overall effectiveness of CD19-CAR therapy will be discussed: 1) T cell exhaustion is a differentiation pathway that occurs in T cells subjected to excessive T cell receptor signaling. A progressive functional decline occurs, manifest first by diminished proliferative potential and cytokine production, following by diminished cytolytic function and ultimately cell death. High leukemic burdens predispose CD19-CAR T cells to exhaustion as does the presence of a CD28 costimulatory signal, while a 4-1BB costimulatory signal diminishes the susceptibility to exhaustion. This biology is likely responsible for limited CD19-CAR persistence observed in clinical trials using a CD19-zeta-28 CAR compared to that observed using a CD19-zeta-BB CAR. 2) Leukemia resistance occurs in approximately 20% of patients treated with CD19-CAR and is associated with selection of B-ALL cells lacking CD19 targeted by the chimeric receptor. Emerging data demonstrates two distinct biologies associated with CD19-epitope loss. Isoform switch is characterized by an increase in CD19 isoforms specifically lacking exon 2, which binds the scFvs incorporated into CD19-CARs currently in clinical trials. Lineage switch is characterized by a global change in leukemia cell phenotype, and is associated with dedifferentiation toward a more stem-like, or myeloid leukemia in the setting of CD19-CAR for B-ALL. These insights raise the prospect that effectiveness of immunotherapy for leukemia may be significantly enhanced by targeting of more than one leukemia antigen. 3) CAR immunogenicity describes immune responses induced in the host that can lead to rejection of the CD19-CAR transduced T cells. Anti-CAR immune responses have been observed by several groups, and mapping is underway to identify the most immunogenic regions of the CAR, as a first step toward preventing this complication. 4) The most common toxicities associated with CD19-CAR therapy are cytokine release syndrome, neurotoxicity and B cell aplasia. Cytokine release syndrome is primarily observed in the setting of high disease burdens and efforts are underway to standardize grading and treatment algorithms to diminish morbidity. Increased information is needed to better understand the neurotoxicity observed in the context of this therapy. Although clinical data is limited, B cell aplasia appears to be adequately treated with IVIG replacement therapy. 5) Technical graft failure (e.g. inadequate expansion/transduction) is a challenge that has received limited attention, primarily since many trials have not reported the percentage of patients in whom adequate products could not be generated. We have observed that technical graft failure is often associated with a high frequency of contaminating myeloid populations in the lymphocyte product and selection approaches designed to eradicate myeloid populations have resulted in improved T cell expansion and transduction. These results suggest that optimization of lymphocyte selection may diminish the incidence of technical graft failure. Disclosures Mackall: Juno: Patents & Royalties: CD22-CAR. Off Label Use: cyclophosphamide.

Pre-Emptive Donor Lymphocyte Infusion with CD19-Directed, CAR-Modified T Cells Infused after Allogeneic Hematopoietic Cell Transplantation for Patients with Advanced CD19+ Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 862-862 ◽  
Author(s):  
Partow Kebriaei ◽  
Stefan O. Ciurea ◽  
Mary Helen Huls ◽  
Harjeet Singh ◽  
Simon Olivares ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Hematopoietic Cell Transplantation ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Lymphoid Malignancies ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Equity Ownership

Background: Allogeneic hematopoietic cell transplantation (HCT) can be curative in a subset of patients with advanced lymphoid malignancies but relapse remains a major reason for treatment failure. Donor-derived, non-specific lymphocyte infusions (DLI) can confer an immune anti-malignancy effect but can be complicated by graft-versus-host-disease (GVHD). Chimeric antigen receptor (CAR)-modified T cells directed toward CD19 have demonstrated dramatic efficacy in patients with refractory ALL and NHL. However, responses are often associated with life-threatening cytokine release syndrome. Aim: We hypothesized that infusing CAR-modified, CD19-specific T-cells after HCT as a directed DLI would be associated with a low rate of GVHD, better disease control, and a less severe cytokine release syndrome since administered in a minimal disease state. Methods: We employed a non-viral gene transfer using the Sleeping Beauty (SB) transposon/transposase system to stably express a CD19-specific CAR (designated CD19RCD28 that activates via CD3z & CD28) in donor-derived T cells for patients with advanced CD19+ lymphoid malignancies. T-cells were electroporated using a Nucleofector device to synchronously introduce two DNA plasmids coding for SB transposon (CD19RCD28) and hyperactive SB transposase (SB11). T-cells stably expressing the CAR were retrieved over 28 days of co-culture by recursive additions of g-irradiated activating and propagating cells (AaPC) in presence of soluble recombinant interleukin (IL)-2 and IL-21. The AaPC were derived from K562 cells and genetically modified to co-express CD19 as well as the co-stimulatory molecules CD86, CD137L, and a membrane-bound version of IL-15. Results: To date, we have successfully treated 21 patients with median age 36 years (range 21-62) with advanced CD19+ ALL (n=18) or NHL (n=3); 10 patients had active disease at time of HCT. Donor-derived CAR+ T cells (HLA-matched sibling n=10; 1 Ag mismatched sibling n=1; haplo family n=8; cord blood n=2) were infused at a median 64 days (range 42-91 days) following HCT to prevent disease progression. Transplant preparative regimens were myeloablative, busulfan-based (n=10) or reduced intensity, fludarabine-based (n=11). All patients were maintained on GVHD prophylaxis at time of CAR T-cell infusion with tacrolimus, plus mycophenolate mofeteil for cord, plus post-HCT cyclophosphamide for haplo donors. The starting CAR+ T-cell dose was 106 (n=7), escalated to 107 (n=6), 5x107 (n=5), and currently at 108 (n=3) modified T cells/m2 (based on recipient body surface area). Patients have not demonstrated any acute or late toxicity to CAR+ T cell infusions. Three patients developed acute grades 2-4 GVHD (liver n=1, upper GI n=1, skin=1) which was within the expected range after allogeneic HCT alone. Of note, the rate of CMV reactivation after CAR T cell infusion was 24% vs. 41 % previously reported for our patients without CAR T cell infusion (Wilhelm et al. J Oncol Parm Practice, 2014, 20:257). Nineteen patients have had at least 30 days follow-up post CAR T-cell infusion and are evaluable for disease progression. Forty-eight percent of patients (n=10) remain alive and in complete remission (CR) at median 5.2 months (range 0-21.3 months) following CAR T cell infusion. Importantly, among 8 patients who received haplo-HCT and CAR, 7 remain in remission at median 4.2 months. Conclusion: We demonstrate that infusing donor-derived CD19-specific CAR+ T cells, using the SB and AaPC platform, in the adjuvant HCT setting as pre-emptive DLI may provide an effective and safe approach for maintaining remission in patients at high risk for relapse. Graft-vs-host disease did not appear increased by administration of the donor derived CAR-T cells. Furthermore, the add-back of allogeneic T cells appears to have contributed to immune reconstitution and control of opportunistic viral infection. Disclosures Huls: Intrexon and Ziopharm: Employment, Equity Ownership. Singh:Intrexon and Ziopharm: Equity Ownership, Patents & Royalties. Olivares:Intrexon and Ziopharm: Equity Ownership, Patents & Royalties. Su:Ziopharm and Intrexon: Employment. Figliola:Intrexon and Ziopharm: Equity Ownership, Patents & Royalties. Kumar:Ziopharm and Intrexon: Equity Ownership. Jena:Ziopharm Oncology: Equity Ownership, Patents & Royalties: Potential roylaties (Patent submitted); Intrexon: Equity Ownership, Patents & Royalties: Potential royalties (Patent submitted). Ang:Intrexon and Ziopharm: Equity Ownership. Lee:Intrexon: Equity Ownership; Cyto-Sen: Equity Ownership; Ziopharm: Equity Ownership.

T Cells Expressing a Novel Fully-Human Anti-CD19 Chimeric Antigen Receptor Induce Remissions of Advanced Lymphoma in a First-in-Humans Clinical Trial

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 999-999 ◽  
Author(s):  
Jennifer N. Brudno ◽  
Victoria Shi ◽  
David Stroncek ◽  
Stefania Pittaluga ◽  
Jennifer A. Kanakry ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Low Dose ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T ◽  
Low Dose Chemotherapy ◽  
Cd19 Expression

Abstract Background: Chimeric antigen receptors (CARs) are fusion proteins that combine antigen-recognition domains and T-cell signaling domains. T cells genetically modified to express CARs directed against the B-cell antigen CD19 can cause remissions of B-cell malignancies. Most CARs in clinical use contain components derived from murine antibodies. Immune responses have been reported to eliminate CAR T cells in clinical trials, especially after second infusions of CAR T cells (C. Turtle et al., Journal of Clinical Investigation, 2016). These immune responses could be directed at the murine components of CARs. Such immune responses might limit the persistence of the CAR T cells, and anti-CAR immune responses might be an especially important problem if multiple infusions of CAR T cells are administered. Development of fully-human CARs could reduce recipient immune responses against CAR T cells. Methods: We designed the first fully-human anti-CD19 CAR (HuCAR-19). The CAR is encoded by a lentiviral vector. This CAR has a fully-human single-chain variable fragment, hinge and transmembrane regions from CD8-alpha, a CD28 costimulatory domain, and a CD3-zeta T-cell activation domain. We conducted a phase I dose-escalation trial with a primary objective of investigating the safety of HuCAR-19 T cells and a secondary objective of assessing anti-lymphoma efficacy. Low-dose chemotherapy was administered before HuCAR-19 T-cell infusions to enhance CAR T-cell activity. The low-dose chemotherapy consisted of cyclophosphamide 300 mg/m2 daily for 3 days and fludarabine 30 mg/m2 daily for 3 days on the same days as cyclophosphamide. HuCAR-19 T cells were infused 2 days after the end of the chemotherapy regimen. Patients with residual lymphoma after a first treatment were potentially eligible for repeat treatments if dose-limiting toxicities did not occur with the first treatment. Repeat infusions were given at the same dose level as the first infusion or 1 dose level higher than the first infusion. Findings: A total of 11 HuCAR-19 T-cell infusions have been administered to 9 patients; 2 patients received 2 infusions each. So far, there is an 86% overall response rate (Table). Grade 3 adverse events (AEs) included expected cytokine-release syndrome toxicities such as fever, tachycardia, and hypotension. Corticosteroids were used to treat toxicity in Patient 3. The interleukin-(IL)-6 receptor antagonist tocilizumab was used to treat toxicity in Patient 4, and both tocilizumab and corticosteroids were used to treat toxicity in Patient 8. Only 1 of 8 evaluable patients, Patient 3, has experienced significant neurological toxicity to date. This patient experienced encephalopathy that was associated with a cerebrospinal fluid (CSF) white blood cell count of 165/mm3. Almost all of the CSF white cells were CAR T cells, and the CSF IL-6 level was elevated. All toxicities have resolved fully in all patients. In Patient 1, tumor biopsies revealed a complete loss of CD19 expression by lymphoma cells after 2 HuCAR-19 T-cell infusions, which to our knowledge is the first documented complete loss of CD19 expression by lymphoma after anti-CD19 CAR T-cell therapy. This loss of CD19 expression was associated with lymphoma progression. After first CAR-19 T-cell infusions, HuCAR-19 cells were detectable in the blood of every patient. The median peak number of blood CAR+ cells was 26/microliter (range 3 to 1005 cells/microliter). Blood HuCAR-19 cells were detected after second infusions in the blood of both patients who received second infusions. Patient 1 obtained a partial response after a second infusion after only obtaining stable disease after a first infusion. We detected elevations of inflammatory cytokines including IL-6, interferon gamma, and IL-8 in the serum of patients experiencing clinical toxicities consistent with cytokine-release syndrome. Interpretation: T cells expressing HuCAR-19 have substantial activity against advanced lymphoma, and infusions of HuCAR-19 T cells caused reversible toxicities attributable to cytokine-release syndrome. Disclosures Kochenderfer: Kite Pharma: Patents & Royalties, Research Funding; bluebird bio: Patents & Royalties, Research Funding.

Chimeric Antigen Receptor T-Cell Therapies for Aggressive B-Cell Lymphomas: Current and Future State of the Art

2019 ◽  
pp. 446-453 ◽  
Author(s):  
Jeremy S. Abramson ◽  
Matthew Lunning ◽  
M. Lia Palomba
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Refractory Disease ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Aggressive B-cell lymphomas that are primary refractory to, or relapse after, frontline chemoimmunotherapy have a low cure rate with conventional therapies. Although high-dose chemotherapy remains the standard of care at first relapse for sufficiently young and fit patients, fewer than one-quarter of patients with relapsed/refractory disease are cured with this approach. Anti-CD19 chimeric antigen receptor (CAR) T cells have emerged as an effective therapy in patients with multiple relapsed/refractory disease, capable of inducing durable remissions in patients with chemotherapy-refractory disease. Three anti-CD19 CAR T cells for aggressive B-cell lymphoma (axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene ciloleucel) are either U.S. Food and Drug Administration approved or in late-stage development. All three CAR T cells produce durable remissions in 33%–40% of treated patients. Differences among these products include the specific CAR constructs, costimulatory domains, manufacturing process, dose, and eligibility criteria for their pivotal trials. Notable toxicities include cytokine release syndrome and neurologic toxicities, which are usually treatable and reversible, as well as cytopenias and hypogammaglobulinemia. Incidences of cytokine release syndrome and neurotoxicity differ across CAR T-cell products, related in part to the type of costimulatory domain. Potential mechanisms of resistance include CAR T-cell exhaustion and immune evasion, CD19 antigen loss, and a lack of persistence. Rational combination strategies with CAR T cells are under evaluation, including immune checkpoint inhibitors, immunomodulators, and tyrosine kinase inhibitors. Novel cell products are also being developed and include CAR T cells that target multiple tumor antigens, cytokine-secreting CAR T cells, and gene-edited CAR T cells, among others.

scholarly journals Efficient tumor regression by adoptively transferred CEA-specific CAR-T cells associated with symptoms of mild cytokine release syndrome

2016 ◽  
Vol 5 (9) ◽  
pp. e1211218 ◽  
Author(s):  
Linan Wang ◽  
Ning Ma ◽  
Sachiko Okamoto ◽  
Yasunori Amaishi ◽  
Eiichi Sato ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Regression ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T

scholarly journals Timing of Tocilizumab and Corticosteroids Administration Under the Guidance of IL-6 in CAR-T Therapy for R/R Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4832-4832
Author(s):  
Yinqiang Zhang ◽  
Heng Mei ◽  
Chenggong Li ◽  
Yingnan Li ◽  
Mengyi Du ◽  
...  
Keyword(s):  
T Cells ◽  
Adverse Events ◽  
Lymphoblastic Leukemia ◽  
Fold Change ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T ◽  
High Level ◽  
Level Group

Abstract Background ： Chimeric antigen receptor (CAR) T cells targeting CD19 have achieved great clinical responses in patients with relapsed or refractory acute B lymphoblastic leukemia (R/R B-ALL). However, severe adverse events such as cytokine release syndrome (CRS) and neurotoxicity restrict it to further application. Tocilizumab against human interleukin-6 (IL-6) receptor is a common treatment for CAR-T cell therapy associated cytokine release syndrome. Corticosteroids are used when remission is not reached after the application of tocilizumab as well as neurotoxicity occurs, according to the guidance. However, their suitable timing still remains unclear when taking their efficacy and side effects into consideration. Methods: From January 2016 to July 2020, in our phase 1/2 clinical trials (NCT02965092、NCT04008251), 55 patients with R/R B-ALL were enrolled and injected with anti-CD19 CAR-T cells. Clinical laboratory tests on day 0、4、7、10、14、21、28 after infusion as well as endpoints、adverse events and treatment were recorded. CRS and neurotoxicity were graded according to American Society for Transplantation and Cellular Therapy (ASTCT)，and infection severity was classified as mild, moderate, severe, life-threatening, or fatal. (Young et al. Biol Blood Marrow Transplant 2016; 22:359-70.) Patients were assigned to four cohorts based on the fold change of IL-6 and the use of Tocilizumab. We defined fold change as the ratio of peak before Tocilizumab given to baseline in Tocilizumab group and the ratio of peak within 28 days to baseline in non- Tocilizumab group. According to the statistics, two groups were separated into high level (fold change over 5) and low level (fold change below 5), respectively. Wilcoxon tests、Log-rank tests and Fisher's exact tests were used to analyze statistics in GraphPad Prism 9. Results: During the observation period of 28-day-postinfusion, the use of Tocilizumab or corticosteroids did not significantly reduce the response rate or increase infectious risk (P>0.99, P=0.052). Doing a median follow-up of 7 months, the use of corticosteroids was significantly associated with shorter overall survival (OS) and progression-free survival (PFS), while it did not appear when Tocilizumab was applied alone. In addition, significantly fold change of IL-6, IL-10 were observed among subjects suffering cytokine release syndrome before the use of Tocilizumab or corticosteroids and higher levels of TNF-α were observed in 3 subjects with mild neurotoxicity (P=0.0002, P<0.0001, P=0.0004). In high level group, patients treated with Tocilizumab had mild CRS limiting to grade 1-2, with shorter duration of CRS (median=5) than non-Tocilizumab (median=6) , though it is without significant difference (P=0.874). In low level group, the use of Tocilizumab is associated with shorter PFS（P=0.0275）as well as severe cytokine release syndrome. Two patients developed grade 4 CRS after infusing Tocilizumab，with apparently increased level of IL-10 (fold change=200) or IFN-γ (fold change=114.24). Neurotoxicity occurred in four patients in Tocilizumab group, and their IL-6 levels increased significantly after treatment, reaching an average peak of 1000pg/ml (157-22001.9). No neurotoxicity were observed in non-Tocilizumab group. Conclusion: Our study demonstrate that severe and persistent CRS could be avoided by applying Tocilizumab when IL-6 has increased over 5-fold from baseline. Tocilizumab is not recommended to use with little change of IL-6 because it fails to suppress the inflammatory response, and may trigger the activation of other cytokines and accelerate the progress of disease recurrence in patients. Although corticosteroids were associated with relapse, we still suggested that corticosteroids should be administrated to antagonize neurotoxicity with symptoms and significantly increased IL-6 levels after the infusion of Tocilizumab. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Modified-EASIX predicts severe cytokine release syndrome and neurotoxicity after Chimeric Antigen Receptor (CAR) T cells

2021 ◽  
Author(s):  
Martina Pennisi ◽  
Miriam Sanchez-Escamilla ◽  
Jessica R Flynn ◽  
Roni Shouval ◽  
Ana Alarcon Tomas ◽  
...  
Keyword(s):  
T Cells ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
B Cell Lymphoma ◽  
Endothelial Activation ◽  
Stress Index ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T

Patients who develop CAR T-cells-related severe cytokine release syndrome (CRS) and immune-effector-cells-associated neurotoxicity syndrome (ICANS) exhibit hemodynamic instability and endothelial activation. The EASIX (Endothelial-Activation and Stress-Index) score [lactate dehydrogenase (LDH, U/L) x  creatinine (mg/dL) / platelets (10^9 cells/L)] is a marker of endothelial damage that correlates with outcomes in allogeneic hematopoietic cell transplantation. Elevated LDH and low platelets have been associated with severe CRS and ICANS, as has C-reactive protein (CRP), while increased creatinine is seen only in a minority of advanced severe CRS cases. We hypothesized that EASIX and two new modified EASIX formulas [simplified-EASIX, which excludes creatinine, and modified-EASIX (m-EASIX), which replaces creatinine with CRP (mg/dL)], calculated peri CAR T-cells infusion, would be associated with development of severe (grade ≥3) CRS and ICANS. We included 118 adults, 53 with B-acute lymphoblastic leukemia treated with 1928z CAR T-cells (NCT01044069) and 65 with diffuse large B-cell lymphoma treated with axicabtagene-ciloleucel or tisagenlecleucel. The three formulas showed similar predictive power for severe CRS and ICANS. However, low platelets and high CRP values were the only variables individually correlated with these toxicities. Moreover, only m-EASIX was a significant predictor of disease response. m-EASIX could discriminate patients who subsequently developed severe CRS preceding the onset of severe symptoms (AUC: at lymphodepletion 80.4%, day -1 73.0%, day +1 75.4%). At day +3, it also had high discriminatory ability for severe ICANS (AUC 73%). We propose m-EASIX as a clinical tool to potentially guide individualized management of patients at higher risk for severe CAR T-cells-related toxicities.

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