CAR-T-cell-related Encephalopathy Syndrome Research Articles

CAR T-Cell Therapy Combined with PD-1 Inhibitors Significantly Improve the Efficacy and Prognosis of r/r DLBCL with TP53 Alterations

More than 40% of patients diagnosed with diffuse large B-cell lymphoma (DLBCL) eventually develop relapsed or refractory (r/r) disease and typically have poor outcomes. Autologous chimeric antigen receptor T-cell therapy (CART) has emerged as a crucial second line treatment option for r/r DLBCL, but 60-70% of patients still relapse or are refractory. Recent research has shed light on the role of TP53 alterations (mutation or deletion) in r/r DLBCL patients who do not respond well to CART cell therapy. The findings in this study will show that the combination of CART with PD-1 inhibitors (ICIs) had a significant impact on the efficacy and prognosis of r/r DLBCL patients with TP53 alterations. This retrospective analysis included adult DLBCL patients who were treated at Shanghai Tongji Hospital of Tongji University with autologous CD19 (N=20) or CD20 (N=2, patient 6 and 7, Fig.1 A) CART-cell therapy between January 1, 2019, and September 30, 2022. All enrolled patients provided their informed consent to participate in the study. The protocol of the study was reviewed and approved by the Institutional Review Board of the National Cancer Institute, ensuring ethical practices were followed. A total of 22 patients with TP53 alterations undergoing CD19-CART therapy were included, of which 2 patients received CD20 CART cell after recurrence of CD19 CART cell therapy. The total dose of CD19 or CD20-CAR T-cell is between 1- 3x10^6/kg. Sintilimab/Tislelizumab was used as PD-1 inhibitors (3 mg/kg in patients weighing <60 kg or 200 mg in patients weighing ≥60 kg) every three weeks within 6 weeks after CAR-T infusion. 1 case had grade 3-4 Cytokine Release Syndrome (CRS) and no case had CART-cell-related encephalopathy syndrome (CRES). In Table 1, the patients are divided into two groups. One group received CART cells combined with PD-1 inhibitors (ICI+), while the other group received CART cells only (ICI-). The median ICIs treatment time after CART infusion was 17 days (IQR 11-38 days). Baseline factors such as age, gender, disease severity, previous treatment history and etc. had no substantial differences between the groups. Treatment regimen and the subsequent response were shown in Fig.1 A and B. Patient 1-9 received ICIs treatment after CART cell therapy, of which 8 cases (88.9%) showed the best objective response rate (ORR) at day 90 after CART infusion (Fig.1B) and 6 cases (66.7%) achieved complete remission (CR). In comparison, among the 13 individuals who were treated with CART alone, only 3 cases (23.1%) showed the best ORR at day 90 after CART infusion and only 1 case (7.7%) achieved complete remission. We found a significant difference between the two treatment groups by performing a Chi-square test (P=0.009). Our results suggest that the addition of PD-1 inhibitors to the CART regimen significantly improves the treatment outcome in patients with TP53 alterations. In Fig.1 C and D, we show that the median progression-free survival (PFS) was NR (not reached) vs. 1.7 months (95% CI:1.0 month-2.3 months) and the median overall survival (OS) was NR vs.10.9 months (95% CI: 3.8 months-18.1 months) in the ICI+ and the ICI- groups. The p-values for PFS and OS was 0.001 (HR=0.18, 95% CI: 0.07-0.47) and 0.003 (HR=0.15, 95% CI: 0.05-0.42) between the two groups. These results suggest that patients in the combination treatment group experienced less disease progression and were more likely to survive longer. Overall, our study demonstrates the potential benefits of combining immunotherapies, specifically CART with PD-1 inhibitors, in the treatment of relapsed or refractory DLBCL patients with TP53 alterations.

CAR T-cell-associated neurotoxicity in central nervous system hematologic disease: Is it still a concern?

Chimeric antigen receptor (CAR) T-cell systemic immunotherapy has revolutionized how clinicians treat several refractory and relapsed hematologic malignancies. Due to its peculiar mechanism of action, CAR T-cell-based therapy has enlarged the spectrum of neurological toxicities. CAR T-cell-associated neurotoxicity-initially defined as CAR T-cell-related encephalopathy syndrome (CRES) and currently coined within the acronym ICANS (immune effector cell-associated neurotoxicity syndrome)-is perhaps the most concerning toxicity of CAR T-cell therapy. Importantly, hematologic malignancies (especially lymphoid malignancies) may originate in or spread to the central nervous system (CNS) in the form of parenchymal and/or meningeal disease. Due to the emergence of deadly and neurological adverse events, such as fatal brain edema in some patients included in early CAR T-cell trials, safety concerns for those with CNS primary or secondary infiltration arose and contributed to the routine exclusion of individuals with pre-existing or active CNS involvement from pivotal trials. However, based primarily on the lack of evidence, it remains unknown whether CNS involvement increases the risk and/or severity of CAR T-cell-related neurotoxicity. Given the limited treatment options available for patients once they relapse with CNS involvement, it is of high interest to explore the role of novel clinical strategies including CAR T cells to treat leukemias/lymphomas and myeloma with CNS involvement. The purpose of this review was to summarize currently available neurological safety data of CAR T-cell-based immunotherapy from the clinical trials and real-world experiences in adult patients with CNS disease due to lymphoma, leukemia, or myeloma. Increasing evidence supports that CNS involvement in hematologic disease should no longer be considered per se as an absolute contraindication to CAR T-cell-based therapy. While the incidence may be high, severity does not appear to be impacted significantly by pre-existing CNS status. Close monitoring by trained neurologists is recommended.

A Phase I Dose Finding Trial of MB-CART20.1 in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Introduction: Approved Chimeric Antigen Receptor (CAR) T-cell therapies in refractory or relapsed B-cell Non-Hodgkin lymphoma (r/r B-NHL) target CD19; however, their efficacy is limited to about half of the patients treated. We thus developed a CAR targeting CD20 (MB-CART20.1) consisting of CAR transduced CD4 /CD8 enriched T-cells, derived from an autologous leukapheresis. Here, we report on the first part of a phase I first-in-human clinical trial that evaluates the safety of MB-CART20.1 in patients with r/r B-NHL. Methods: Patients with r/r B-NHL with no curative treatment option were eligible for this phase I multi-center, open label, dose escalation trial of MB-CART20.1 (EudraCT 2017-000121-12). The primary objective was to determine safety of MB-CART20.1. Secondary objectives included response to treatment, phenotype and persistence of MB-CART20.1. The primary endpoint was determination of the maximum tolerated dose (MTD), defined as the highest dose level at which < 33% of patients experience Dose Limiting Toxicities (DLTs) until day 28 post infusion (follow-up safety period). Patient leukapheresis products were enriched for CD4/CD8 T-cells, transduced with the vector and expanded using the CliniMACS Prodigy System.. Apheresis and the MB-CART20.1 were fresh products with a turnaround time of 14 days. Patients underwent lymphodepletion with fludarabine (30 mg/m2) and cyclophosphamide (300 mg/m2), each from day -5 to day -3. Dose escalation was planned with 3 + 3 patients at Dose Level (DL) 0 (1x105 CAR T-cells/kg BW), followed by DL1 (1x106 CAR T-cells/kg BW ) and DL2 (3x106 CAR T-cells/kg BW) with 6 + 3 patients, each. Results: In total 10 patients were treated. 9 patients were included in this analysis. 1 patient was treated with an out of specification product, these data are not included. 7 patients were enrolled at DL0 and 2 at DL1. 8 of 9 patients completed the follow-up safety period. At DL0, 3 of 7 patients experienced CRS (grade I) starting 1 to 10 days post infusion. One CRS case was managed with tocilizumab. This patient further developed CAR T-cell related encephalopathy syndrome (CRES; grade II) and bone marrow aplasia (grade III). On day 17 post infusion the patient died because of a septic shock. The Safety Monitoring Board thus recommended to extend DL0 with 3 additional patients. In this extension cohort, no further neurotoxicity or any DLT occurred. 1 of 7 patients achieved complete response (CR), remained in remission until month 12 and then entered long-term follow-up. 5 patients progressed at 4 weeks (n=2), 12 weeks (n=2) and 6 months (n=1) post infusion, respectively. Analysis of expansion for the 3 patients reaching at least partial response (PR) within 12 weeks (responders) showed a notable increase of the maximum cell concentration (Cmax, values between 3,1 to 104,7 cells/µl), as well as an enhanced area under the curve from day 0 to 28 (AUC D0-28, between 28,5 and 1273,0 days/cells/µl). This increase of values was not observed in the 3 non-responders. Time to Cmax is similar between responders and non-responders (mean 16 days). At DL1, 2 of 2 patients experienced CRS shortly post infusion (grade I and II respectively). Tocilizumab was used in one patient. Neither DLT nor ICANS occurred. Short-lived Grade III and IV neutropenia was observed in both patients. Both patients completed the active part of the trial (12 months post infusion) with CR, entered the long-term follow-up and remained in CR until data cut-off. Analysis of expansion showed an increase of Cmax with 198,6 and 79,8 cells/µl, respectively and AUC D0-28 with 2495,0 and 610,1 days/cells/µl. Time to Cmax is 14 days for both patients. The sponsor stopped the trial early due to the COVID pandemic with relevant impact on enrollment and study conduct. In addition there are no current plans for further development of this vector. Conclusions: No DLT was observed in this first trial of a CD20 targeting CAR T-cell product in r/r B-NHL patients; however, early termination of the trial does not allow conclusions on a MTD. In total 3 patients achieved a CR and remained in remission for at least one year. The two patients treated at the higher DL, achieved a CR indicating a dose-response correlation. The results strongly support further evaluation of MB-CART20.1 in r/r B-cell NHL.

Long-Term Activity of Combining CNCT19 with HDT/ASCT in Refractory Large B-Cell Lymphoma: Two-Year Follow-up of a Prospective Phase 1/2 Clinical Trial

Background: We have previously reported the preliminary results of a phase 1/2 clinical trial of administrating CNCT19 (a second-generation anti-CD19 CAR T-cell) following high-dose chemotherapy and autologous stem-cell transplantation (HDT/ASCT) in large B-cell lymphoma (LBCL) patients with diseases refractory to first-line and/or subsequent lines of chemotherapy. Eight of 10 (80%) patients achieved complete response (CR), and the estimated proportion of progression-free survival (PFS) and overall survival (OS) at 12 months was 66.7% and 77.1%, respectively (Wei liu et al. ASH 2019, 2020). Here we reported this study's updated enrollment, efficacy, and follow-up. This trial was registered at www.chictr.org.cn as ChiCTR1900025419. Methods: Patients with LBCL with a history of refractory to first-line rituximab-containing anthracycline-based chemotherapy and/or subsequent salvage chemotherapy were eligible for this study. Conditioning regimen of GBC/M (Gemcitabine 600 mg/m2/h, infused for 3 hours with loading bolus of 75 mg/m2, day -7, -3, busulfan 105 mg/m2, day -7 until -5, cyclophosphamide 45mg/kg or melphalan 60 mg/m2, day -3, -2) was administered once the CNCT19 product was available. Autologous stem cells were infused on day 0, and CNCT19 cells were infused on day +3 (±1 day). Cytokine release syndrome (CRS) and CAR-T-cell-related encephalopathy syndrome (CRES) were graded according to the CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group criteria. Results: From December 2017 through May 2021, 21 subjects were consecutively enrolled in this study. CNCT19 cells were successfully manufactured for 20 subjects and administered to 18 subjects. The median age was 44 (range 23 to 64), and 56% were male. Patients included 11 (67%) with diffuse large B-cell lymphoma (not otherwise specified), 4 (22%) with high-grade B-cell lymphoma with MYC, BCL2 and/or BCL6 rearrangement, 2 (11%) with primary mediastinal large B-cell lymphoma and 1 (6%) with transformed follicular lymphoma. The median number of lines of prior therapy was 3 (range, 2 to 5). Eighty-nine percent of patients had a history of refractory to first-line immunochemotherapy of R-CHOP (rituximab, cyclophosphamide, adriamycin, vincristine, prednisone) or R-DA-EPOCH (rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and adriamycin), and 72% were refractory to subsequent platinum-based salvage therapy. TP53 deletion and/or mutation were detected in 7 of 11 (64%) patients. The median dose of infused stem cells was 2.6×106 (range, 1.8~8.7×106) per kilogram of body weight and the median dose of infused CNCT19 cells was 2×106 (range, 1.6~4.0×106) per kilogram of body weight. The CRS occurred in 16 patients (89%), and all were low grades (grade 1, 83%; grade 2, 6%). CRES occurred in two patients on day 5 and day 6 after CNCT19 infusion, respectively. Both of the ICANS were grade 4 and resolved completely after glucocorticoids treatment. We did not observe any unexpected toxicity or treatment-related death throughout the therapy. The median times to neutrophil and platelet recovery were ten days (range, 8 to 30 days) and 16.5 days (range, 8 to 265 days) after stem cells reinfusion, respectively. As of July 26, 2022, the median follow-up from CNCT19 infusion to the data-cutoff date was 28.2 (95% CI 16.9-39.1) months. The best overall response rate was 94.4%, with a best CR rate of 72.2%. The median PFS, duration of response (DOR), disease-free survival (DFS) and OS were not reached, and the probability of 2-year PFS, DOR, DFS and OS were 59.3% (95% CI 32.5%-78.4%), 63.5% (95% CI 35.9%-81.8%), 74.1% (95% CI 39.1%-90.9%) and 64.2% (95% CI 36.2%-82.4%), respectively. Of the patients who were in durable response at three months or six months post CNCT19 infusion, 66.7% and 83.3% were in ongoing response at the date of data cutoff, respectively. Conclusions: CNCT19 could be safely administered following HDT/ASCT in patients with relapsed or refractory LBCL. The strategy of combining CAR T-cell therapy with HDT/ASCT might improve response rate and prolong survival compared to CAR T-cell therapy alone.

CNCT19 CAR T-Cell Therapy in Relapsed or Refractory B-Cell Lymphoma: Long-Term Results of a Pilot Prospective Clinical Study

Background: Chimeric antigen receptor (CAR) T-cell targeting tumor cells depends on the single chain variable fragment (scFv) against the specific tumor antigen. Most anti-CD19 CAR-T products have the scFv deriving from hybridoma clone FMC63. We developed a new hybridoma clone HI19α which binds to distinct CD19 episodes. CNCT19 was a second-generation CAR T-cell with scFv derived from clone HI19α and 4-1BB/CD3-ζ costimulatory domain. The results of CNCT19 in pediatric and adult patients with relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia had previously been reported [Runxia Gu et al. J Hematol Oncol. 2020 Sep 7;13(1):122]. Herein, we reported the outcome and long-term follow-up of a pilot study administrating CNCT19 in relapsed or refractory B-cell lymphoma. This trial was registered at www.clinicaltrials.gov as NCT03029338. Methods: Patients with R/R CD19-positive B-cell lymphoma were eligible for this study. Subjects with active central nervous system involvement were excluded. Lymphodepleting chemotherapy comprising fludarabine (25~30mg/m2, day -4,-3,-2) and cyclophosphamide (350mg/m2 day -4, -2) was administrated once the CNCT19 product was available. We infused CNCT19 cells in three regimens: three-day split dose (10%-30%-60%, patient (P)1-P10), two-day split dose (40%-60%, P11-P17), and single dose (P18-20). Results: From May 2017 through March 2019, 20 patients were enrolled. Diagnosis of histological subtypes included diffuse large B-cell lymphoma not otherwise specified (DLBCL, NOS) in 14 (70%) patients, DLBCL transformed from chronic lymphocytic leukemia in 1 (5%) patient, follicular lymphoma (FL) grade 3b in 1 (5%) patient, and mantle cell lymphoma (MCL) in 4 (20%) patients. Considering the differences in efficacy and survival between the population with MCL and those with LBCL, we here reported the results of 16 patients who had diseases of DLBCL or FL 3b. The median age was 51 (range 16 to 69), and 62.5% were male. The majority (87.5%) of patients had advanced stage disease, and 11 (68.8%) had non-GCB immunophenotype. Double expressor lymphoma (DEL, cut-off for MYC, >=40%, BCL2, >=50%) was identified in 11 (68.8%) patients, with one of them having MYC and BCL2 rearrangement. TP53 mutation and/or deletion were detected in 5 of 6 (83.3%) patients. The patients had received a median of 3 (range 2 to 7) lines of prior therapy. Thirteen (81.3%) patients had diseases refractory to last-line therapy. The median dose of infused CNCT19 cells was 2.48×106 (range 1.87 to 5.06×106) per kilogram of body weight. Cytokine release syndrome (CRS) occurred in 11 (68.8%) patients, all of whom were grade 1. Only one patient experienced CAR-T-cell-related encephalopathy syndrome (CRES), manifesting as distal muscle weakness of the bilateral upper limb, and he recovered completely after corticosteroids treatment. Twelve (75.0%) patients achieved a response after CNCT19 infusion, with a complete response (CR) rate of 37.5%. The ORR and CR rate at 3 months was 62.5% and 31.3%, respectively. Two patients with ongoing partial remission underwent allogeneic hematopoietic stem-cell transplantation, and both of them died of progressive disease at 6 months and 11 months post CNCT19 infusion, respectively. As of July 5, 2022, the median follow-up from CNCT19 infusion to the data-cutoff date was 44.5 months. The median progression-free survival and overall survival were 6.5 (95% CI 1.0 to NA) months and 12.7 (95% CI 2.9 to NA) months, respectively. Six (37.5%) patients remained alive by data cut-off. Conclusions: CNCT19 cells exhibited comparable efficacy and favorable safety in patients with R/R DLBCL and FL3b. A phase 2 clinical trial (NCT04586478) of administrating CNCT19 in R/R large B-cell lymphoma and high-grade B-cell lymphoma is underway.

CAR-T Cell Therapy in Hematological Malignancies: Current Opportunities and Challenges.

Chimeric antigen receptor T (CAR-T) cell therapy represents a major breakthrough in cancer treatment, and it has achieved unprecedented success in hematological malignancies, especially in relapsed/refractory (R/R) B cell malignancies. At present, CD19 and BCMA are the most common targets in CAR-T cell therapy, and numerous novel therapeutic targets are being explored. However, the adverse events related to CAR-T cell therapy might be serious or even life-threatening, such as cytokine release syndrome (CRS), CAR-T-cell-related encephalopathy syndrome (CRES), infections, cytopenia, and CRS-related coagulopathy. In addition, due to antigen escape, the limited CAR-T cell persistence, and immunosuppressive tumor microenvironment, a considerable proportion of patients relapse after CAR-T cell therapy. Thus, in this review, we focus on the progress and challenges of CAR-T cell therapy in hematological malignancies, such as attractive therapeutic targets, CAR-T related toxicities, and resistance to CAR-T cell therapy, and provide some practical recommendations.

Efficacy of Chimeric Antigen Receptor T Cell in the Treatment of Refractory/Recurrent B Acute Lymphocytic Leukemia in Children

To observe the efficacy of chimeric antigen receptor T cell (CAR-T) in the treatment of children with refractory/recurrent B acute lymphocytic leukemia (B-ALL). Thirty-two patients with r/r B-ALL were treated by CAR-T, the recurrence and death respectively were the end point events to evaluate the efficacy and safety of CAR-T. The median age of the patients was 7.5 (2-17.5) years old; 40 times CAR-T were received in all patients and the median number of CAR-T was 0.9×107/kg; efficacy evaluation showed that 2 cases died before the first evaluation. Thirty patients showed that 3, 6, and 9-moth RFS was (96.3±3.6)%, (81.4±8.6)% and (65.3±12.5)%, respectively, while 3, 6, and 9-month OS was all 100%, and 12, 24-month OS was (94.7±5.1)% and (76±12.8)%. BM blasts≥36% before reinfusion and ferritin peak≥2 500 ng/ml within two weeks of CAR-T cell reinfusion were associated with recurrence. Adverse reactions mainly included cytokine release syndrome (CRS) and CART-cell-related encephalopathy syndrome (CRES), CRS appeared in 26 patients within a week of CAR-T cell reinfusion. CRES reaction was detected in 12 patients. Eighteen patients received intravenous drip of tocilizumab, among them, 12 combined with glucocorticoid. CRS and CRES reactions were relieved within one week after treatment. Hormone dosage was related to the duration of remission in patients, and the cumulative dose of methylprednisolone≥8 mg/kg showed a poor prognosis. CAR-T is a safe and effective treatment for r/r B-ALL, most CRS and CRES reactions are reversible. BM blasts ≥36% before reinfusion and cumulative dose of methylprednisolone ≥8 mg/kg after reinfusion both affect the therapeutic effect. Ferritin≥2 500 ng/ml within two weeks after reinfusion is related to disease recurrence and is an independent prognostic risk factor.

Unity brings strength: Combination of CAR-T cell therapy and HSCT

With the rapid revolution of therapies, hemopoietic stem cell transplantation (HSCT) has become a widely promoted treatment for hematological malignancies. High-dose chemotherapy (HDCT) followed by autologous blood cell (ABC) transplantation is a standard procedure for patients with primary relapse B-cell non-Hodgkin lymphoma (NHL) and multiple myeloma (MM), and allogeneic HSCT is one of the few treatments for patients with acute leukemia. However, refractory and recurrent disease has a negative impact on disease-free survival (DFS) for patients after HSCT. Furthermore, complications such as GVHD and infection significantly impair the quality of life and life expectancy of patients who receive allogeneic HSCT. The promising efficacy of chimeric antigen receptor T (CAR-T) cell therapy for relapsed or refractory B-cell acute lymphoblast leukemia (ALL) has offered hope for patients with R/R hematological malignancies. However, the long-term survival of patients after CAR-T cell therapy is also threatened by recurrent disease, and relapse occurs in half of patients who achieve remission. In addition, the rapid proliferation of CAR-T cells will cause damage to the balance of the immune system, leading to cytokine release syndrome (CRS) and CAR-T cell-related encephalopathy syndrome (CRES). Although therapeutic regimens such as IL-6 pathway blockers have obvious impacts on the side effects related to CAR-T cell therapy, there are still reports of patient deaths in past clinical trials. Based on the characteristics of HSCT and CAR-T cell therapy, it is unclear whether there is a better combination of cutting-edge immune cell therapy and traditional transplantation to improve the prognosis of patients. This review focuses on the possible ways to take full advantage of each therapy in the treatment of hematological malignancies.

Integrated Analysis of B-Cell Maturation Antigen-Specific CAR T Cells (CT053) in Relapsed and Refractory Multiple Myeloma Subjects By High-Risk Factors

Background: For relapsed and refractory multiple myeloma (RRMM), various clinical trials of B-cell maturation antigen-targeted chimeric antigen receptor (CAR) T-cell clinical trials are under way. For one such treatment, CT053, the Phase 1 investigator-initiated CG studies (NCT03380039, NCT03716856, NCT03302403) and the Phase 1 LUMMICAR STUDY 1 (NCT03975907) demonstrated deep and durable responses in heavily pretreated subjects with RRMM. Here we report integrated efficacy and safety of CT053 in Chinese subjects with RRMM based on high-risk factors.Methods: All subjects had received ≥2 prior therapies, including at least an immunomodulatory drug and a proteasome inhibitor. Subjects also could have had exposure to an anti-CD38 antibody. All subjects were refractory to the last therapy per International Myeloma Working Group criteria. After lymphodepletion, subjects received a dose of 0.5 (n=1), 1.0 (n=4), 1.5 (n=32), or 1.8 (n=1) ×10 8 CAR+ T cells. We performed an integrated subgroup analyses of efficacy and safety in subjects stratified by high-risk characteristics, including extramedullary disease (EMD), high-risk cytogenetics [del(17p), t(4;14), t(14;16), t(14;20) and gain 1q], and International Staging System (ISS) stage III.Results: A total of 38 subjects (LUMMICAR STUDY 1: n=14; CG studies: n=24) were treated with CT053 in Phase I studies in China. Of these, 31.6% subjects (12/38) had EMD, 47.4% (18/38) had high-risk cytogenetics, and 28.9% (11/38) had ISS stage III disease. After a median follow-up of 13.9 months, the objective response rate (ORR), complete response (CR) rate, median duration of response (mDOR) and median progression-free survival (mPFS) were 92.1%, 78.9%, 24.0 months [95% CI 13.3 months-not reached (NR)] and 22.7 months (95% CI 13.3 months-NR), respectively.The ORRs for subjects with EMD, high-risk cytogenetics, and ISS stage III were 91.7% (95% CI 0.62-1.00), 83.3% (95% CI 0.59-0.96), and 81.8% (95% CI 0.48-0.98), respectively. A lower CR rate and poorer mDOR and mPFS were observed in subjects with EMD compared to subjects without EMD (58.3% vs 88.5%, 9.2 months vs 24.0 months, and 9.3 months vs 25.0 months, respectively). Although high-risk cytogenetics and ISS stage III disease at baseline did not substantially affect the CR rate, they seemed to negatively impact the DOR and PFS. The mDOR and mPFS were 14.8 months (95% CI 8.5 months-NR) and 15.6 months (95% CI 6.2-25.0 months) respectively for subjects with high-risk cytogenetics, and 13.3 months (95% CI 7.6 months-NR) and 13.3 months (95% CI 0.9 months-NR), respectively for subjects with ISS stage III. The median DOR and median PFS had not been reached in subjects without these two high-risk factors (Figure 1).No dose limiting toxicity or CT053 treatment-related death occurred. The incidence of Grade 1/2 cytokine release syndrome (CRS) was 73.7%, and no ≥Grade 3 CRS occurred. Generally, CRS cases fully resolved after supportive care or tocilizumab. Only one subject with ISS stage III and EMD developed Grade 3 CAR T-cell-related encephalopathy syndrome (CRES), which fully resolved after methylprednisolone treatment. No other grade of CRES was observed in the studies.Conclusions: The results demonstrate that CT053 represents a promising treatment option for subjects with RRMM, including those with high-risk disease. Phase 2 trials are actively enrolling. [Display omitted] DisclosuresLI: CARsgen Therapeutics Co. LtD: Current Employment, Current equity holder in publicly-traded company. Wang: CARsgen Therapeutics Corp: Current Employment. Zhao: CARsgen Therapeutics Corp: Current Employment.

Inclusion of the Inducible Caspase 9 Suicide Gene in CAR Construct Increases Safety of CAR.CD19 T Cell Therapy in B-Cell Malignancies.

T cells engineered with chimeric antigen receptor (CAR-T cells) are an effective treatment in patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia or B-cell non-Hodgkin lymphoma. Despite the reported exciting clinical results, the CAR-T cell approach needs efforts to improve the safety profile, limiting the occurrence of adverse events in patients given this treatment. Besides the most common side effects, such as cytokine release syndrome and CAR-T cell–related encephalopathy syndrome, another potential issue involves the inadvertent transduction of leukemia B cells with the CAR construct during the manufacturing process, thus leading to the possibility of a peculiar mechanism of antigen masking and treatment resistance. In this study, we investigated whether the inclusion of the inducible caspase 9 (iC9) suicide gene in the CAR construct design could be an effective safety switch to control malignant CAR+ B cells, ultimately counteracting this serious adverse event. iC9 is a suicide gene able to be activated through binding with an otherwise inert small biomolecule, known as AP1903. The exposure of iC9.CAR.CD19-DAUDI lymphoma and iC9.CAR.CD19-NALM-6 leukemia cells in vitro to 20 nM of AP1903 resulted into the prompt elimination of CAR+ B-leukemia/lymphoma cell lines. The results obtained in the animal model corroborate in vitro data, since iC9.CAR.CD19+ tumor cells were controlled in vivo by the activation of the suicide gene through administration of AP1903. Altogether, our data indicate that the inclusion of the iC9 suicide gene may result in a safe CAR-T cell product, even when manufacturing starts from biological materials characterized by heavy leukemia blast contamination.

Efficacy and safety of humanized CD19 CAR-T as a salvage therapy for recurrent CNSL of B-ALL following murine CD19 CAR-T cell therapy.

The present study aimed to compare the differences between the humanized CD19 chimeric antigen receptor (CAR)-T cell therapy and the murine CD19 CAR-T therapy in recurrent B-acute lymphoblastic leukemia (B-ALL). A 62-year-old male patient who had B-ALL (BCR/ABL+) for 4 years was diagnosed with relapsed central nervous system leukemia (CNSL). After several courses of high dose methotrexate combined with intrathecal chemotherapy, the patient received murine CD19 CAR-T therapy and achieved complete response (CR). The patient was diagnosed with relapsed CNSL again 15 months after his murine CD19 CAR-T therapy, and was therefore enrolled in the humanized CD19 CAR-T therapy. Subsequently, the present study aimed to compare murine and humanized CD19 CAR-T cells against Nalm-6 cells in vitro and in mice. The patient initially achieved CR from his murine CD19 CAR-T therapy with Grade 1 cytokine-release syndrome (CRS) and Grade 1 CAR-T cell-related encephalopathy syndrome (CRES). The patient then achieved CR again from his humanized CD19 CAR-T therapy with Grade 1 CRS and Grade 2 CRES. Peak levels of CD19 CAR-T cells were higher in humanized CD19 CAR-T therapy than those in murine CD19 CAR-T therapy 7 days after infusion in the peripheral blood, in bone marrow and in cerebrospinal fluid (CSF). The cytokine levels were higher in humanized CD19 CAR-T therapy than those in murine CD19 CAR-T therapy in the peripheral blood and in CSF. The cytotoxicity to Nalm-6 cells was higher in humanized CD19 CAR-T cells than that in murine CD19 CAR-T cells in vitro. In Nalm-6 BALB/c mice, the median survival time of mice in the murine CD19 CAR-T group was 35 days, while it was 43 days in the humanized CD19 CAR-T group. In conclusion, humanized CD19 CAR-T cell therapy had a better curative effect than that of murine CD19 CAR-T therapy, and may be used as a salvage treatment for recurrent B-ALL after treatment with murine CD19 CAR-T therapy.

Promoter usage regulating the surface density of CAR molecules may modulate the kinetics of CAR-T cells in vivo

Although chimeric antigen receptor T (CAR-T) cell therapy achieves high remission rates, challenges (e.g., toxicity management and relapse prevention) remain. The major risks are cytokine release syndrome and related neurological toxicity. The influence of the CAR surface density on the efficacy/safety of CAR-T cell therapy and the factors determining CAR density were not elucidated comprehensively. Here, we discovered that the use of the MND promoter increased the transduction rate and reduced the CAR surface density. Additionally, MND-driven CAR-T cells had prolonged antileukemia activity in a mouse model. In an initial dual-armed anti-CD19 CAR-T cell pilot study (ClinicalTrials.gov: NCT03840317), eight and six subjects were infused with MND and EF1α promoter-driven autologous CAR-T cells (3 × 105 CAR-T cells/kg), respectively. MND subjects developed mild fever and lower interferon gamma (IFN-γ) concentrations than in the EF1A19 group. All but one subject in each cohort reached minimal residual disease (MRD)-negative complete remission after the first month of evaluation. These results represent the first comprehensive study on the promoter-driven modulation of CAR-T cell functionality. These findings encourage further evaluation of the potential of the MND promoter to drive CAR-T cells as a broadly applicable cellular product for anticancer immunotherapy.

1105. The Burden of Infections Prior to Chimeric Antigen Receptor (CAR) Modified T-cell Therapy Predicts Post-CAR T-cell Infectious Complications

BackgroundCAR T -cell therapy (CTT) is a novel treatment for B-cell cancers. CTT patients (pt) are at risk of infection due to neutropenia, cytokine release syndrome (CRS), and CAR T-cell related encephalopathy syndrome (CRES), which are treated with steroids and tocilizumab (anti-IL-6). This is a single-center study evaluating the risk factors for infection after CTT.MethodsA retrospective review was conducted of 60 consecutive CTT recipients between 7/17/17 and 9/5/19. Data was collected from 6 months (mo) pre- and at least 6 mo post-CTT. Data was censored for death, additional chemotherapy, or loss to follow up. Cox proportional hazard and Poisson regression were used.ResultsMedian age was 66 (23-84) years; 48% (29) were female. The most common cancer was non-Hodgkin lymphoma (89%, 54). 25% (15) had a prior stem cell transplant (SCT). 73% (44) and 45% (27) of pts developed CRS and CRES, respectively. 43% (26) received steroids; 65% (39) received tocilizumab. In the 6 mo pre-CTT, 39 infections occurred in 45% (27) of pts. 103 infections occurred in 66% (40) after CTT; 33 (55%) had an infection within 6 mo. Infections were bacterial (52%; 54/103), viral (30%; 37/103), fungal (10%; 10/103), mycobacterial (1%; 1/103), protozoal (1%; 1/103). Cumulative incidence of infection in the first 6 mo are shown in Fig 1. All-cause and infection-related mortality were 32% (19) and 15% (9), respectively. Mortality among pts with fungal infections was 20% (2/10). Infection density was 1.28 and 0.58 infections per 100 pt-days between days 0-30 and 30-89, respectively. Factors associated with infection post CTT were number (no.) of infections in the 6 mo prior to infusion (HR 1.62, CI [1.1-2.38]; p=0.015), no. of lines of therapy in the 6 mo pre-CTT (HR 1.52, CI [1.01-2.27]; p=0.04), prior allogeneic SCT (HR 5.96, CI [1.34-26.47]; p=0.019), and no. of tocilizumab doses. Grade 1 CRS and grade 2 CRES were risk factors between days 0-30 and 0-180, respectively (HR 4.67, CI [1.02 -21.4], p = 0.047; HR 2.48, CI [1.17-5.23], p = 0.02).Fig 1: Cumulative Incidence of Infection 6 Months Post CAR T-cell Therapy ConclusionInfections after CTT are common. Infection before CTT was associated with risk of infection after CTT. Pt selection may ameliorate this risk. Mortality due to fungal infections was high. Randomized-controlled trials of antifungal prophylaxis in high-risk pts are needed.Disclosures All Authors: No reported disclosures

Optimized tandem CD19/CD20 CAR-engineered T cells in refractory/relapsed B-cell lymphoma

AbstractChimeric antigen receptor (CAR) T cells targeting CD19 have achieved breakthroughs in the treatment of hematological malignancies, such as relapsed/refractory non-Hodgkin lymphoma (r/rNHL); however, high rates of treatment failure and recurrence after CAR T-cell therapy are considerable obstacles to overcome. In this study, we designed a series of tandem CARs (TanCARs) and found that TanCAR7 T cells showed dual antigen targeting of CD19 and CD20, as well as formed superior and stable immunological synapse (IS) structures, which may be related to their robust antitumor activity. In an open-label single-arm phase 1/2a trial (NCT03097770), we enrolled 33 patients with r/rNHL; 28 patients received an infusion after conditioning chemotherapy. The primary objective was to evaluate the safety and tolerability of TanCAR7 T cells. Efficacy, progression-free survival, and overall survival were evaluated as secondary objectives. Cytokine release syndrome occurred in 14 patients (50%): 36% had grade 1 or 2 and 14% had grade 3. No cases of CAR T-cell–related encephalopathy syndrome (CRES) of grade 3 or higher were confirmed in any patient. One patient died from a treatment-associated severe pulmonary infection. The overall response rate was 79% (95% confidence interval [CI], 60-92%), and the complete response rate was 71%. The progression-free survival rate at 12 months was 64% (95% CI, 43-79%). In this study, TanCAR7 T cells elicited a potent and durable antitumor response, but not grade 3 or higher CRES, in patients with r/rNHL.

Efficacy and safety of CD19 chimeric antigen receptor T cells in the treatment of 11 patients with relapsed/refractory B-cell lymphoma: a single-center study.

BackgroundNo effective treatment exist for patients with relapsed and refractory B-cell lymphoma, until the advent of anti-CD19 chimeric antigen receptor (CAR) T-cells. Therefore, this study aimed to explore the factors affecting the efficacy of anti-CD19 CAR T-cell and the adverse reactions of the therapy.MethodsWe recruited 11 patients with relapsed and refractory B-cell lymphoma. The number of anti-CD19 CAR T-cells, proliferation, and adverse reactions were recorded in detail, to explore the relationship between the factors affecting the efficacy of anti-CD19 CAR T-cell and the long-term survival of patients.ResultsThe 11 patients in our study had a total overall response rate of 100%, after receiving anti-CD19 CAR T-cells. The median follow-up was 253 days (range, 130–1,017 days). The median overall survival (OS) and median progression-free survival (PFS) were not reached. After 3 months of treatment, the complete remission (CR) rate was 63.6% (7/11). As of December 7, 2019, 5 patients had maintained CR for a period exceeding 1 year, including 2 patients who had maintained CR for more than 1,000 days. The patients who received 3 or 4 lines of chemotherapy were more likely to have sustained remission than the patients who received <2 or >4 lines of chemotherapy. Each of the 4 patients in the study who had diffuse large B cell lymphoma (DLBCL) progression all had high myc protein expression (positive incidence: 30–80%). The incidence of Grade 2 cytokine release syndrome (CRS) was 36.4% (4/11), and Grade 3 CAR T-cell-related encephalopathy syndrome (CRES) was experienced by 1 patient. The occurrence of adverse reactions was not significantly related to the infusion dose, peak amplification time, or maximum copy amount. The immunoglobulin levels of the four patients who died showed a significant downward trend. Interleukin-1β (IL-1β), interferon-γ (IFN-γ), interleukin-10 (IL-10), and interleukin-17A (IL-17A) appeared to be associated with the occurrence of CRS and CRES.ConclusionsAnti-CD19 CAR T-cell treatment is a new therapy for patients with relapsed and refractory B-cell lymphoma. Among the small sample size in this study, it demonstrated high efficiency and safety.

Safety and efficacy of CD19-targeted CAR-T cells in 14 patients with refractory/relapsed Philadelphia chromosome-positive acute B-precursor lymphoblastic leukemia

目的研究靶向CD19的嵌合抗原受体T细胞（CAR-T细胞）治疗复发难治Ph染色体阳性急性B淋巴细胞白血病（R/R Ph+ B-ALL）的安全性及有效性。方法对2016年11月至2019年4月采用CD19 CAR-T细胞治疗的14例R/R Ph+ B-ALL患者的临床资料进行回顾性分析。结果14例患者中，男7例，女7例，中位年龄33（7~66）岁。输注CAR-T细胞后第28天近期疗效：总反应率（ORR）为100.0%（14/14），其中完全缓解（CR）率为92.9%（13/14）；部分缓解（PR）率为7.1%（1/14）。CAR-T细胞治疗后有12例（85.7%）发生细胞因子释放综合征（CRS），其中1级1例、2级4例、3级6例、4级1例；1例（例3）发生CAR-T细胞相关脑病综合征（CRES）；全部14例患者均有Ⅲ~Ⅳ级血液学不良反应；13例CR患者均发生B细胞发育不全。上述不良反应均可控。中位随访441（182~923）d，中位总生存期、无进展生存期分别515（95% CI 287~743）d、207（95% CI 123~301）d。结论CD19 CAR-T细胞治疗复发难治性Ph+ B-ALL安全有效，短期疗效显著，长期疗效有待进一步提高。

Safety and efficacy of optimized tandem CD19/CD20 CAR-engineered T cells in patients with relapsed/refractory non-Hodgkin lymphoma.

3034 Background: Chimeric antigen receptor T (CAR T) cells targeting CD19 have been used to achieve breakthroughs in the treatment of hematological malignancies, however, a high recurrence rate is the main obstacle to durable remission following CAR T cell therapy. Methods: As an open-label and single-arm phase I/IIa trial (ClinicalTrials.gov number, NCT03097770), we screened 99 patients with r/r B-NHL—including DLBCL, PMBCL, CLL/SLL, MCL, TFL and FL—according to the 2008 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissue, and a total of 87 patients received an infusion of one dose tandem CD19/CD20 CAR-engineered T cells on day 0 in the range of 0.5×106-10×106 cells per kilogram of body weight after conditioning chemotherapy. The primary objective was to evaluate the safety and tolerability of CAR T cells. Efficacy, progression-free survival (PFS) and overall survival (OS) were evaluated as secondary objectives. Our clinical trials is registered with ClinicalTrials.gov, NCT03097770. Safety was assessed by CTCAE Version 5.0, and clinical response by PET-CT referred to standard international criteria. The trial remains open, and recruitment to extension cohorts with alternative endpoints is underway. Results: Between May 11, 2017, and Jan 31, 2020, 99 patients were enrolled and 87 received tandem CD19/CD20 CAR-engineered T cells across phases I/IIa. As of the cutoff date, 74 assessable patients were followed up for a median of 13.5 months (IQR 33.2 - 3.3), 62 (84%) had an objective response, and 55 (74%) had a complete response. The median progression-free survival and overall survival were all not reached. Cytokine release syndrome (CRS) occurred in 62 patients (71%), with 61% grade 1 or 2 and 10% grade 3 or more. CAR-T-cell-related encephalopathy syndrome (CRES) of grade 3 occurred in 2 patients (2%) . Three treatment-related deaths (2 in pulmonary infection and 1 in deposition of CART cells in pulmonary alveoli). Conclusions: In this study, optimized tandem CD19/CD20 CAR-engineered T cells induced a potent and durable anti-tumour response with controllable CRS and CRES. Clinical trial information: NCT03097770 .

Oncologic Emergencies: Immune-Based Cancer Therapies and Complications.

Cancer therapies have undergone several recent advancements. Current cancer treatments include immune-based therapies comprised of checkpoint inhibitors, and adoptive immunotherapy; each treatment has the potential for complications that differ from chemotherapy and radiation. This review evaluates immune-based therapies and their complications for emergency clinicians. Therapy complications include immune-related adverse events (irAE), cytokine release syndrome (CRS), autoimmune toxicity, and chimeric antigen receptor (CAR) T-cell-related encephalopathy syndrome (CRES). Immune-related adverse events are most commonly encountered with checkpoint inhibitors and include dermatologic complications, pneumonitis, colitis/diarrhea, hepatitis, and endocrinopathies. Less common irAEs include nephritis, myocardial injury, neurologic toxicity, ocular diseases, and musculoskeletal complications. CRS and CRES are more commonly associated with CAR T-cell therapy. CRS commonly presents with flu-like illness and symptoms resembling sepsis, but severe myocardial and pulmonary disease may occur. Critically ill patients require resuscitation, broad-spectrum antibiotics, and hematology/oncology consultation.

The Risk of Hepatitis B Reactivation Is Controllable in Patients with Concomitant Hepatitis B Virus Infection during Chimeric Antigen Receptor T-Cell Therapy

Background: Among patients with non-Hodgkin lymphoma (NHL) and concomitant chronic or resolved hepatitis B virus (HBV) infection, HBV reactivation is an identified risk associated with chemotherapy, especially after rituximab-based immunochemotherapy. Chimeric antigen receptor (CAR) T-cell targeting CD19 can also cause B-cell aplasia as seen in patients receiving rituximab, and the risk of HBV reactivation during CAR T-cell therapy is still unknown. We performed a retrospective study to explore the risk of HBV reactivation in patients with concomitant HBV infection who had received anti-CD19 CAR T therapy at our hospital. Methods: Patients with relapse or refractory B-cell lymphoma who were treated with CNCT19 (second-generation anti-CD19 CAR T-cell provided by Juventas) at Blood Disease Hospital were retrospectively analyzed. All patients were screened for hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb) and hepatitis B core antibody (HBcAb) at the time of evaluation for CNCT19 therapy, and those with positive HBsAg or positive HBcAb were eligible for this retrospective study. This study was approved by Blood Diseases Hospital Internal Review Board. Results: Between June 2017 and May 2019, 17 patients with relapsed or refractory B-cell lymphoma and concomitant HBV infection who were treated with CNCT19 therapy alone (n=14) or CNCT19 therapy following high-dose chemotherapy and autologous stem cell transplantation (HDT/ASCT, n=3) were included in this study. The median age was 53 years (range: 31-71years), with 53% were male. 6 patients (35%) had chronic HBV infection, defined as positive HBsAg, 11 patients (65%) had resolved HBV infection, defined as negative HBsAg and positive HBcAb. At the time of CNCT19 infusion, HBV DNA levels of all patients were lower than the normal limit (&lt;1000IU/ml). All 6 patients with chronic HBV infection received prophylactic anti-HBV nucleos(t)ide therapy (NAT) of entecavir, 5/11(45%) patients with resolved HBV infection received prophylactic NAT of entecavir or lamivudine, and the other 6/11(55%) patients with resolved HBV infection did not receive any prophylactic anti-HBV therapy. With median follow-up of 8 months (range: 1-24 months) from CNCT19 infusion, including 9 patients who had been followed up for more than 6 months, no HBV reactivation occurred (defined as HBV-DNA level exceeding 1000IU/ml). 6 patients with chronic HBV infection remained on NAT at the time of last follow-up, and among the 5 patients with resolved HBV infection who had received prophylactic NAT during CNCT19 therapy, 1 patient was still on NAT at 3 months after CNCT19 infusion following HDT/ASCT, 4 patients stopped NAT at 1, 2, 6, 6months after CNCT19 infusion, respectively. Cytokine release syndrome (CRS) occurred in 59% of patients and CAR-T-cell-related encephalopathy syndrome (CRES) occurred in 12% of patients, with 2 patients received short term of corticosteroids for grade 4 CRES. Conclusions: Our results showed that CAR T therapy could be safely administered in patients with chronic or resolved HBV infection. Considering the small sample size and the retrospectively analysis, the risk of HBV reactivation and the recommendation for prophylactic anti-HBV NAT during CAR T therapy should be further evaluated in large and prospective studies. Disclosures Lv: Juventas Cell Therapy Ltd.: Employment.

Interim Results from the Phase I Deplethink Trial Evaluating the Infusion of a NKG2D CAR T-Cell Therapy Post a Non-Myeloablative Conditioning in Relapse or Refractory Acute Myeloid Leukemia and Myelodysplastic Syndrome Patients

CYAD-01 cells are engineered T-cells expressing a chimeric antigen receptor (CAR) based on the natural full-length human natural killer group 2D (NKG2D) receptor fused to the intracellular domain of CD3ζ. NKG2D binds to 8 ligands (MICA, MICAB, and ULBP1-6) over-expressed by a large variety of malignancies, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Phase I DEPLETHINK study (NCT03466320) evaluates the safety and preliminary efficacy of a single CYAD-01 infusion (inf.) after lymphodepletion with cyclophosphamide and fludarabine in patients with relapsed or refractory (r/r) AML and MDS. A second cycle of 3 CYAD-01 infusions without preconditioning could be administered in absence of progressive disease (PD) following the 1st infusion. Three dose-levels (DLs; 1x108, 3x108 and 1x109 cells/inf.) are evaluated in the dose escalation segment. The first DL is also evaluated at two different intervals between preconditioning and CYAD-01 infusion (T7: seven days interval; T3: three days interval) in order to mitigate for any potential increased toxicity due to the administration of lymphodepletion. As of end of July 2019, 6 patients (4 AML and 2 MDS) were enrolled in the first 2 cohorts which evaluated DL1 (1x108 cells/inf. at T3 or T7) and 3 patients (3 AML) were enrolled in the cohort 3 evaluating DL2 (3x108 cells/inf. at T3). The blasts in the bone marrow of 8 out of 9 patients ranged between 3% and 48% at baseline. Of the 6 patients treated at DL1 (with lymphodepletion administered up to 7 or 3 days before first CYAD-01 infusion), 3 patients experienced grade (G) 1 toxicity (cytokine release syndrome or CRS and diarrhea), or G2 CRS (uncleaned database). The patient with G2 CRS following the first infusion also experienced G4 CRS and G3 CAR T-cell-related encephalopathy syndrome (CRES) during the second inf. at 3x109 cells/inf. One other patient experienced G1 CRS during the second cycle. At DL2, only 1 patient experienced G1 related AEs (diarrhea and CRS) after the first CYAD-01 infusion. Another patient experienced G3 CRS during the second cycle. All patients recovered with treatment including tocilizumab and, when indicated, steroids. At DL1, two out of 5 evaluable patients reached a stable disease (SD) at day (d) 36, allowing the initiation of the 2nd cycle. At DL2, one patient out of 3 reached SD. The DEPLETHINK study is currently enrolling at DL3 (T3). Preliminary correlative studies show that the area under the curve at d36 (AUC D1-D36) after a single infusion of CYAD-01 with prior lymphodepletion is better than without preconditioning. Furthermore, the T3 interval between the preconditioning and CYAD-01 provides better engraftment than the T7 interval. In conclusion, to date, the results demonstrate the safety and tolerability for CYAD-01 doses 1x108 and 3x108 cells/infusion with a prior lymphodepletion in patients with r/r AML and MDS. The T3 interval was therefore chosen for further CYAD-01 evaluations. The improved persistence of CYAD-01 with lymphodepletion, in particular 3 days before infusion, could lead to improved clinical responses. The study is ongoing and further data will be provided at the meeting. Disclosures Al-Homsi: Celyad: Membership on an entity's Board of Directors or advisory committees. Abdul-Hay:Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Pollyea:Diachii Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celyad: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forty-Seven: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lequertier:Celyad: Employment. Alcantar-Orozco:Celyad: Employment. Borghese:Celyad: Employment. Lonez:Celyad: Employment. Braun:Celyad: Employment. Renard:Celyad: Employment. Flament:Celyad: Employment.