Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 677-677

Abstract: Background: Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive B-NHL. While 50-80% of patients with DLBCL are cured with standard induction therapy, a large fraction of patients either relapse or have primary refractory (rel/ref) disease. High-dose therapy followed by autologous stem cell transplantation (HDT-ASCT) is the established standard of care for these patients. Despite this, approximately half of all rel/ref patients that are chemosensitive to salvage therapy are cured with this approach. Relapse is the major cause of treatment failure, and ultimately death, in these patients. Our group has demonstrated encouraging activity with 19-28z chimeric antigen receptor modified T cells (19-28z CAR-T) directed against CD19 in rel/ref ALL. We hypothesize that biologic optimization of cellular therapy with 19-28z CAR-T can be met immediately post-HDT-ASCT given: lymphoproliferative cytokine availability through lymphodepletion post-HDT, depletion of prohibitive regulatory cellular elements post-HDT and achievement of minimal residual disease prior to 19-28z CAR-T consolidation. Herein, we report safety data on the first 6 patients of the phase I MSKCC #12-117: 19-28z CAR-T post HDT-ASCT for poor-risk rel/ref aggressive B-NHL. Methods: Eligibility for this study includes rel/ref aggressive B-NHL appropriate for HDT-ASCT as defined by chemosensitivity to salvage therapy and poor risk features including: 1) FDG-PET positivity following 2 cycles of salvage therapy or 2) bone marrow involvement of B-NHL at the time of rel/ref clinical restaging. Patients underwent separate apheresis for CD34+ progenitor cells and CD3+ T cells. T cells were transduced with a retrovirus encoding a CAR construct composed of anti-CD19 scFV linked to CD28 and CD3ζ signaling domains (19-28z). Patients were admitted for BEAM conditioned HDT and ASCT occurred day 0. Pegfilgrastim was administered on day+1 and 19-28z CAR-T dose per phase I study was split on days +2 and +3. Results: This analysis includes the first six patients, all male, on the phase I study. The median age is 61 (range 34-68) years at the time of HDT-ASCT. Diagnoses included: n=2 relapsed and transformed follicular lymphoma (one with double-hit biology), n=3 relapsed DLBCL (one CD5+) and one subject with relapsed and transformed marginal zone lymphoma involving the bone marrow. Five patients were treated at dose level #1 (5 x106 19-28z CAR-T/kg) with no dose-limiting toxicity (DLT) observed. Four of the five patients at dose level #1 experienced grade 3 febrile neutropenia and one patient met-criterion for non-severe cytokine-release syndrome (nCRS) effectively treated with tocilizumab 4 mg/kg x1. One patient was treated at dose-level #2, 1 x107 CAR-T/kg, and experienced a DLT of grade 4 severe CRS (sCRS) manifested with acute kidney injury, hypotension and mental status changes effectively treated and fully recovered with tocilizumab in combination with dexamethasone. Peak CRP in all patients was observed at a median of 3.5 days (range 3-4 days) post-19-28z CAR-T infusion (median peak CRP= 17 mg/dL, range: 5-43.1 mg/dL), with CRP 〉 20 mg/dL identified in the two patients that experienced CRS (nCRS=27 mg/dL, sCRS=43 mg/dL). Previously associated serum cytokine elevations (Davila et al Sci Trans Med, 2014) were observed in the two patients that experienced CRS (Figure). All patients engrafted neutrophils at a median of 10 days (range: 9-10 days) post-ASCT, and achieved a complete remission at first post-HDT-ASCT restaging. No sequelae of autoimmune phenomenon were observed. At a median follow-up of six months, with 2 patients 〉 one year post HDT-ASCT, all patients remain alive and in remission. Conclusions: This is the first report of 19-28z CAR-T cells in conjunction with consolidative HDT-ASCT for poor-risk rel/ref aggressive B-NHL. No DLTs have been observed at dose level #1, 5 x106 19-28z CAR-T/kg, while sCRS was observed in n=1 at 1 x107 CAR-T/kg resulting in a DLT. CRS was associated with pro-inflammatory serum cytokine elevation. CRS was aborted with tocilizumab with (sCRS=1) or without (nCRS=1) dexamethasone. All patients engrafted neutrophils at the expected time point. The use of 19-28z CAR T cells is a promising approach in this small group of poor-risk PET+ NHL patients undergoing autologous transplant. This is an ongoing trial and updated data will be presented. Figure 1 Figure 1. Disclosures Riviere: Juno Therapeutics: Consultancy, scientific co-founders Other. Sadelain:Juno Therapeutics: Consultancy, Scientific co-founder and Stock holder Other. Brentjens:Juno Therapeutics: Consultancy, scientific co-founder Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.677.677

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 959-959

Abstract: Introduction: BCMA targeted CAR T cell therapy has shown promising results in patients with relapsed/refractory multiple myeloma (MM). Herein, we report on the safety and efficacy of MCARH171, a second generation, human derived BCMA targeted autologous 4-1BB containing CAR T cell therapy, including a truncated epidermal growth factor receptor safety system (Smith EL. Mol Ther 2018). Methods: This is a phase I first in human, dose escalation trial of MCARH171. Patients received conditioning chemotherapy with cyclophosphamide (Cy) 3 gm/m2 as a single dose or fludarabine 30 mg/m2 daily and Cy 300 mg/m2 daily for 3 days followed by MCARH171 infusion in 1-2 divided doses. The trial followed a standard 3+3 design with 4 dose levels where patients received the following mean doses per cohort: (1) 72x106, (2) 137x106, (3) 475x106, (4) 818x106 viable CAR+ T cells. The primary objective was to demonstrate safety, and secondary objectives included efficacy and expansion, and persistence of CAR T cells using PCR from the peripheral blood. The last accrued patient received MCARH171 on Dec 6, 2017 and the data cut-off is July 16, 2018. The study is closed to accrual. Results: 11 patients with relapsed and/or refractory MM were treated. Median number of prior lines of therapy was 6 (range: 4-14), and all patients received prior therapy with a proteasome inhibitor, IMiD, anti-CD38 monoclonal antibody, and high dose melphalan/stem cell transplant. Nine (82%) patients had high-risk cytogenetics and 9 (82%) were refractory to their immediate prior line of treatment. One patient was not evaluable for DLTs given the need for early radiation and steroids for impending spinal cord compression by tumor. There are no DLTs reported. Cytokine release syndrome (CRS) grade 1-2 occurred in 4 patients (40%), grade 3 occurred in 2 (20%), and there was no grade 4-5 CRS. Grade 2 encephalopathy occurred in 1 patient (10%) in the setting of high fevers which resolved in less than 24 hours. There was no grade 3 or higher neurotoxicity observed. Tocilizumab was administered to 3 patients; 2 in cohort 2, and 1 in cohort 3. Laboratory values correlating with CRS reaching grade 3 or requiring Tocilizumab (N=4) compared to those with no or milder CRS (N=6) included peak CRP (mean: 28.5 vs 4.6 mg/dL, p 〈 0.001), IFNg (mean peak fold increase: 271 vs 11-fold, p 〈 0.0001), and peak IL6 before Tocilizumab, as IL6 elevation artificially increases after use (mean: 435 vs 68.7 pg/mL, p 〈 0.005). No significant change was seen in ferritin or fibrinogen compared to baseline. Overall response rate was 64% and the median duration of response was 106 days (range: 17 to 235 days). The peak expansion and persistence of MCARH171 as well as durable clinical responses were dose dependent. Patients who were treated on the first two dose cohorts (≤150 X106 CAR T cells) had a lower peak expansion in the peripheral blood (mean 14,098 copies/µL; N=6), compared to patients who were treated on the third or fourth dose cohort 3-4 (≥450 X106 CAR T cells; N=5), where the mean peak expansion was 90,208 copies/µL (p 〈 0.05). Among the 5 patients who received higher doses (450 X106), 5/5(100%) patients responded. The duration of responses was also related to the cell dose, with 3 of 5 patients (60%) treated in the cohorts receiving ≥450 X106 had clinical responses lasting 〉 6 months compared to only 1 of 6 (16.7%) patients who received lower doses. Two patien have ongoing responses (VGPR) at 7.5+ and 10+ months of follow up. To normalize for dose administered we compared the pharmacokinetics of only patients treated at dose levels 3-4 ( ≥450 X106 CAR T cells). Here, we demonstrate that peak expansion correlated to clinical efficacy, with the 3 durable responders all having peak expansion 〉 85,000 copies/µL (mean: 131,732 copies/µL); compared to transient responders, where the maximum peak expansion was 33,213 copies/µL (mean: 27,922; Figure 1). Conclusions: MCARH171 has an acceptable safety profile with no DLTs reported. A dose-response relationship with toxicity was not clearly observed, as noted by distribution of tocilizumab use across dose cohorts. However, a dose-response relationship was observed with promising clinical efficacy at dose levels of ≥450 X106 CAR T cells. Controlling for dose level, peak expansion correlated with durability of response. These results further support the development of CAR T cells for heavily pre-treated patients with relapsed and refractory MM. Disclosures Mailankody: Janssen: Research Funding; Takeda: Research Funding; Juno: Research Funding; Physician Education Resource: Honoraria. Korde:Amgen: Research Funding. Lesokhin:Takeda: Consultancy, Honoraria; Squibb: Consultancy, Honoraria; Janssen: Research Funding; Genentech: Research Funding; Serametrix, inc.: Patents & Royalties: Royalties; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Hassoun:Oncopeptides AB: Research Funding. Park:Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Shire: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Palomba:Pharmacyclics: Consultancy; Celgene: Consultancy. Riviere:Fate Therapeutics Inc.: Research Funding; Juno Therapeutics, a Celgene Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding. Brentjens:Juno Therapeutics, a Celgene Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-119717

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. 26 ( 2019-12-26), p. 2361-2368

Abstract: Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high-dose (3 g/m2) cyclophosphamide (HD-Cy) for 17 patients and low-dose (≤1.5 g/m2) cyclophosphamide (LD-Cy) for 8 patients. Fifteen patients had pretreatment minimal residual disease (MRD; & lt;5% blasts in bone marrow), and 10 patients had pretreatment morphologic evidence of disease (≥5% blasts in bone marrow). All toxicities were reversible, including severe cytokine release syndrome in 16% (4 of 25) and severe neurotoxicity in 28% (7 of 25) of patients. Treated patients were assessed for response, and, among the evaluable patients (n = 24), response and peak CAR T-cell expansion were superior in the HD-Cy/MRD cohorts, as compared with the LD-Cy/morphologic cohorts without an increase in toxicity. Our data support the safety of CD19-specific CAR T-cell therapy for R/R B-ALL. Our data also suggest that dose intensity of conditioning chemotherapy and minimal pretreatment disease burden have a positive impact on response without a negative effect on toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01860937.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2019001641

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 130, No. Suppl_1 ( 2017-12-07), p. 742-742

Abstract: Patients with relapsed/refractory MM (RRMM) rarely obtain durable remissions with available therapies. Clinical use of BCMA targeted CAR T cell therapy was first reported in 12/2015 for RRMM, and based on small numbers, preliminary results appear promising. Given that host immune anti-murine CAR responses have limited the efficacy of repeat dosing (Turtle C. Sci Trans Med 2016), our goal was to develop a human BCMA targeted CAR T cell vector for clinical translation. We screened a human B cell derived scFv phage display library containing 6x1010 scFvs with BCMA expressing NIH 3T3 cells, and validated results on human MM cell lines. 57 unique and diverse BCMA specific scFvs were identified containing light and heavy chain CDR's each covering 6 subfamilies, with HCDR3 length ranges from 5-18 amino acids. 17 scFvs met stringent specificity criteria, and a diverse set was cloned into CAR vectors with either a CD28 or a 4-1BB co-stimulatory domain. Donor T cells transduced with BCMA targeted CAR vectors that conveyed particularly desirable properties over multiple in vitro assays, including: cytotoxicity on human MM cell lines at low E:T ratios ( & gt;90% lysis, 1:1, 16h), robust proliferation after repeat antigen stimulation (up to 700 fold, stimulation q3-4d for 14d), and active cytokine profiling, were selected for in vivo studies using a marrow predominant human MM cell line model in NSG mice. A single IV injection of CAR T cells, either early (4d) or late (21d) after MM engraftment was evaluated. In both cases survival was increased when treated with BCMA targeted CAR T cells vs CD19 targeted CAR T cells (median OS at 60d NR vs 35d p & lt;0.05). Tumor and CAR T cells were imaged in vivo by taking advantage of luciferase constructs with different substrates. Results show rapid tumor clearance, peak ( & gt;10,000 fold) CAR T expansion at day 6, followed by contraction of CAR T cells after MM clearance, confirming the efficacy of the anti-BCMA scFv/4-1BB containing construct. Co-culture with primary cells from a range of normal tissues did not activate CAR T cells as noted by a lack of IFN release. Co-culture of 293 cells expressing this scFv with those expressing a library of other TNFRSF or Ig receptor members demonstrated specific binding to BCMA. GLP toxicity studies in mice showed no unexpected adverse events. We generated a retroviral construct for clinical use including a truncated epithelial growth factor receptor (EGFRt) elimination gene: EGFRt/hBCMA-41BBz. Clinical investigation of this construct is underway in a dose escalation, single institution trial. Enrollment is completed on 2/4 planned dose levels (DL). On DL1 pts received cyclophosphamide conditioning (3g/m2 x1) and 72x106 mean CAR+ T cells. On DL2 pts received lower dose cyclophosphamide/fludarabine (300/30 mg/m2 x3) and 137x106 mean CAR+ T cells. All pts screened for BCMA expression by IHC were eligible. High risk cytogenetics were present in 4/6 pts. Median prior lines of therapy was 7; all pts had IMiD, PI, high dose melphalan, and CD38 directed therapies. With a data cut off of 7/20/17, 6 pts are evaluable for safety. There were no DLT's. At DL1, grade 1 CRS, not requiring intervention, occurred in 1/3 pts. At DL2, grade 1/2 CRS occurred in 2/3 pts; both received IL6R directed Tocilizumab (Toci) with near immediate resolution. In these 2 pts time to onset of fever was a mean 2d, Tmax was 39.4-41.1 C, peak CRP was 25-27mg/dl, peak IL6 level pre and post Toci were 558-632 and 3375-9071 pg/ml, respectively. Additional serum cytokines increased & gt;10 fold from baseline in both pts include: IFNg, GM CSF, Fractalkine, IL5, IL8, and IP10. Increases in ferritin were limited, and there were no cases of hypofibrinogenemia. There were no grade 3-5 CRS and no neurotoxicities or cerebral edema. No pts received steroids or Cetuximab. Median time to count recovery after neutropenia was 10d (range 6-15d). Objective responses by IMWG criteria after a single dose of CAR T cells were observed across both DLs. At DL1, of 3 pts, responses were 1 VGPR, 1 SD, and 1 pt treated with baseline Mspike 0.46, thus not evaluable by IMWG criteria, had & gt;50% reduction in Mspike, and normalization of K/L ratio. At DL2, 2/2 pts had objective responses with 1 PR and 1 VGPR (baseline 95% marrow involvement); 1 pt is too early to evaluate. As we are employing a human CAR, the study was designed to allow for an optional second dose in pts that do not reach CR. We have treated 2 pts with a second dose, and longer follow up data is pending. Figure 1 Figure 1. Disclosures Smith: Juno Therapeutics: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: BCMA targeted CAR T cells, Research Funding. Almo: Cue Biopharma: Other: Founder, head of SABequity holder; Institute for Protein Innovation: Consultancy; AKIN GUMP STRAUSS HAUER & FELD LLP: Consultancy. Wang: Eureka Therapeutics Inc.: Employment, Equity Ownership. Xu: Eureka Therapeutics, Inc: Employment, Equity Ownership. Park: Amgen: Consultancy. Curran: Juno Therapeutics: Research Funding; Novartis: Consultancy. Dogan: Celgene: Consultancy; Peer Review Institute: Consultancy; Roche Pharmaceuticals: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Liu: Eureka Therpeutics Inc.: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Brentjens: Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V130.Suppl_1.742.742

Language: English

Publisher: American Society of Hematology

Publication Date: 2017

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 382-382

Abstract: Background: Relapsed adult acute lymphoblastic leukemia (ALL) is associated with high reinduction mortality, chemotherapy resistance, and dismal prognosis with a median overall survival (OS) 〈 6 months and 5-year OS ≤10%. We have previously reported a high anti-tumor activity of autologous T cells genetically modified to express 19-28z chimeric antigen receptor (19-28z CAR) targeting CD19 in adult patients with CLL and ALL (Brentjens R et al. Blood 2011; Davila M et al. Sci Transl Med2014). Herein, for the first time, we further report the long-term outcome of our phase I clinical trial in adults with relapsed/refractory (R/R) ALL (NCT01044069) with analysis on potential predictive markers of response and neurological toxicities. Patients and Methods: Adult patients with R/R B-ALL were enrolled. Eligible patients underwent leukapheresis, and T cells were transduced with a retrovirus encoding a CAR construct composed of anti-CD19 scFV linked to CD28 and CD3ζ signaling domains (19-28z). All patients received lymphodepleting chemotherapy followed 2 days later by 1x106 – 3x10619-28z CAR T cells/kg. The primary objective of the study was to evaluate the safety and anti-tumor activity of 19-28z CAR T cells in ALL. Post-treatment minimal residual disease (MRD) was assessed at day 14-28 by multiparameter flow cytometry and deep sequencing in the bone marrow (BM) samples (Adaptive Biotech Corp.) Results: 24 patients have been treated. The median age was 56 years (range, 23-74). 6 patients (25%) had Ph+ B-ALL (T315I mutation in 2 patients), 6 patients (25%) had prior allogeneic hematopoietic stem cell transplant (allo-HSCT), and 11 patients (46%) had 3 or more prior lines of ALL therapy before receiving the 19-28z CAR T cell therapy. Of the 24 patients, 22 patients were evaluable for response. At the time of 19-28z CAR T cell infusion, 12 of 22 patients had morphologic disease (6 to 97% blasts in the BM) and the remaining 10 patients had MRD. Twenty out of 22 patients (91%) were in complete remission (CR) after 19-28z CAR T-cell infusion, and 18 of these 20 patients (90%) achieved an MRD-negative CR. Ten of the 13 transplant eligible patients (77%) successfully underwent allo-HSCT following the 19-28z CAR T cell therapy. As of July 1, 2014, the median follow-up was 7.4 months (range 1-34), with 13 patients having at least 6 months of follow-up. Responses appear durable with 6 patients remaining disease-free beyond 1 year (range 12.6 – 34 months). Median overall survial (OS) is 9 months. 5 patients relapsed during the follow-up, including 1 patient with CD19 negative relapse. Three of the relapsed patients were treated again with the 19-28z CAR T cells, and two patients achieved a second CR. Comparing responders to non-responders, no association was observed between response and age ( 〈 60 vs. ≥60), prior allo-HSCT, number of prior therapies, or pre-treatment blast percentage. While none of the 10 patients with MRD at the time of T cell infusion developed cytokine release syndrome (CRS), 9 of 13 patients with morphologic disease at the time of the T cell infusion developed CRS with or without neurological symptoms that required intervention with an IL-6R antagonist or corticosteroid. A detailed analysis of serum cytokines demonstrated a consistent peak of IL-6 (22.2 to 553-fold increase) immediately prior to the development of neurological toxicities. Based on these data, we have developed a multi-disciplinary CRS management algorithm for patients at high risk in order to reduce the severity of CRS and improve safety of the 19-28z CAR T cell therapy. Conclusions: While longer follow-up is needed to confirm the durability of the observed responses, the potent induction of MRD-negative responses and successful long-term outcomes, including subsequent allo-HSCT without apparent additional post-transplant toxicities, strongly support the use of 19-28z CAR T cells in adult patients with B-ALL. A temporal relationship between serum IL-6 levels and neurological toxicities indicates that early intervention with IL-6 directed therapy may be more effective in ameliorating neurological toxicities in patients with morphologic disease at the time of T-cell infusion. These findings will need to be evaluated systematically and confirmed in a larger phase 2 trial. Disclosures Park: Juno Therapeutics: Research Funding. Riviere:Juno Therapeutics: Consultancy, scientific co-founders Other. Sadelain:Juno Therapeutics: Consultancy, Scientific co-founder and Stock holder Other. Brentjens:Juno Therapeutics: Consultancy, Scientific co-founder and Stock holder Other.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.382.382

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 134, No. 7 ( 2019-08-15), p. 626-635

Abstract: High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or primary refractory (rel/ref) chemorefractory diffuse large B-cell lymphoma. Only 50% of patients are cured with this approach. We investigated safety and efficacy of CD19-specific chimeric antigen receptor (CAR) T cells administered following HDT-ASCT. Eligibility for this study includes poor-risk rel/ref aggressive B-cell non-Hodgkin lymphoma chemosensitive to salvage therapy with: (1) positron emission tomography–positive disease or (2) bone marrow involvement. Patients underwent standard HDT-ASCT followed by 19-28z CAR T cells on days +2 and +3. Of 15 subjects treated on study, dose-limiting toxicity was observed at both dose levels (5 × 106 and 1 × 107 19-28z CAR T per kilogram). Ten of 15 subjects experienced CAR T-cell–induced neurotoxicity and/or cytokine release syndrome (CRS), which were associated with greater CAR T-cell persistence (P = .05) but not peak CAR T-cell expansion. Serum interferon-γ elevation (P  & lt; .001) and possibly interleukin-10 (P = .07) were associated with toxicity. The 2-year progression-free survival (PFS) is 30% (95% confidence interval, 20% to 70%).  Subjects given decreased naive-like (CD45RA+CCR7+) CD4+ and CD8+ CAR T cells experienced superior PFS (P = .02 and .04, respectively). There was no association between CAR T-cell peak expansion, persistence, or cytokine changes and PFS. 19-28z CAR T cells following HDT-ASCT were associated with a high incidence of reversible neurotoxicity and CRS. Following HDT-ASCT, effector CD4+ and CD8+ immunophenotypes may improve disease control. This trial was registered at www.clinicaltrials.gov as #NCT01840566.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.2018883421

Language: English

Publisher: American Society of Hematology

Publication Date: 2019

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 2533-2533

Abstract: T cells can be genetically modified to target tumor antigens through the expression of a chimeric antigen receptor (CAR). CAR T cells targeting the CD19 antigen is a novel therapeutic approach for patients with relapsed B cell acute lymphoblastic leukemia (B-ALL). We have previously demonstrated that CAR T cells have a significant clinical benefit in adult patients with relapsed B-ALL. The primary objective of this study (NCT01860937) is to extend the use and test the safety of CD19 specific CAR T cells in a multicenter trial for children and young adults with relapsed CD19+ B-ALL. To date, 24 patients with very high risk (VHR) or relapsed B-ALL have been enrolled on protocol with a median age of 12 years (range 2-20 years) at time of T cell collection. We have treated 9 patients with relapsed B-ALL with a median age 15 years (range 3-22 years) using patient derived T cells expressing a CD19 specific CAR (19-28z). Patients received a dose of 1-3 x 10^6 CAR T cells/kg and complete response (complete remission or complete remission with incomplete count recovery) occurred in 5/9 (55%) patients. Significantly, correlations with response included lower disease burden (as assessed by bone marrow cellularity; p 〈 0.02) and fold expansion following CD3/28 bead activation during the generation of CAR T cells (p 〈 0.02). Specifically, BM cellularity ≤50% and fold expansion (average 〉 150 vs 〈 40 fold expansion) was seen in responders compared to non-responders. Pre-collection peripheral blood absolute lymphocyte count, lymphocyte proliferative response (phytohemagglutinin proliferation assay), and CD3 absolute count did not correlate with response in this small sample size. Development of fever and cytokine release syndrome (CRS) occurred in responders including grade I-II (n=2) and grade III-IV (n=3). Systemic immunosuppressants (corticosteroids or anti-IL6 receptor antibody tocilizumab) abrogated clinical symptoms of CRS. Elevated serum cytokines of IFN-g ( 〉 20 fold), fractalkine ( 〉 20 fold), Flt-3L ( 〉 55 fold), IL-5 ( 〉 15 fold), IL-6 ( 〉 100 fold), and IL-10 ( 〉 15 fold) were demonstrated in patients with CRS. Monitoring of bone marrow demonstrated peak 19-28z CAR T cell detection within 1-2 weeks following infusion with gradual contracture over 1-2 months. These early results demonstrate the feasibility and significant clinical impact of this approach in patients with relapsed B-ALL. In an effort to more rapidly generate statistically relevant data, demonstrate the "exportability" of this technology between academic institutions, and offer this therapeutic option to a broader number of pediatric patients with chemo-refractory B-ALL we have expanded this trial to include a collaborating institution. The objective of our trial is not to provide an intent-to-treat cohort, but rather demonstrate the tolerability of this technology in patients with relapsed B-ALL. Furthermore, patients meeting disease eligibility were not pre-screened for lymphocyte function prior to collection and/or treatment. Subsequent cohorts of patients will receive 19-28z CAR T cells and will be evaluated for toxicity, persistence of CAR T cells, and for anti-leukemic efficacy. Disclosures Curran: Juno Therapeutics: Consultancy. Off Label Use: CAR T cells for B-ALL. Riviere:Juno Therapeutics: Other: Co-founder, stockholder and consultant. Prockop:Atara Biotherapeutics: Other: I have no financial disclosures, but Atara Biotherapeutics has exercised a licensing agreement with Memorial Sloan Kettering Cancer Center and MSKCC and some investigators at MSKCC have a financial interest in Atara.. Park:Actinium Pharmaceuticals, Inc.: Research Funding; Juno Therapeutics: Consultancy. O'Reilly:Atara Biotherapeutics: Research Funding. Sadelain:Juno Therapeutics: Other: Co-founder, stockholder and consultant. Brentjens:Juno Therapeutics: Other: Co-founder, stockholder and consultant.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.2533.2533

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

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detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 1429-1429

Abstract: Background: Patients with diffuse large B cell lymphoma (DLBCL) who do not achieve a complete response (CR) following CD19-targeted Chimeric Antigen Receptor T cell (CAR T) therapy are less likely to obtain durable benefit. Greater tumor burden pre-CAR T has been shown to predict lower CR rate and shorter survival. Recently, patterns of failure studies have identified baseline lesion characteristics including size, SUV, and extranodal location as associated with increased risk of post-CAR T failure. It is not yet known how bridging radiotherapy (BRT) prior to CAR T can alter subsequent patterns of failure. Methods: We reviewed DLBCL patients treated from 2017 to 2021 with BRT for any intent in the period from 30d pre-leukapheresis to CAR T infusion. Comprehensive BRT fields were defined as no avidity above liver mean outside of the BRT field. Bulky disease was defined as a max diameter of ≥7.5cm in any dimension. PET response was evaluated by Lugano criteria. Pattern of failure analysis was performed to identify failure sites as pre-existing (present pre-CAR T) vs. new and as in-field, marginal, or distant with respect to BRT. Marginal was defined as failure outside of the area receiving prescription dose but within 1cm of BRT field edge. One patient with a cutaneous target was excluded from size-based analyses. Significance was assessed by Fisher's exact test or T-test. Results: Thirty-five patients were identified with a median age of 66. Most were advanced stage (74%) at BRT with a median of 3 prior lines of systemic therapy. Twelve (35%) had bulky disease at any site pre-BRT (median max diameter 5.9 cm; range 1.1 - 24) with highest overall SUV median 19.8 (range 3.4 - 47); 83% (n=29) had ≥1 extranodal site (bone: n=13; CNS: n=4). Most common BRT sites were head/neck (n=10), pelvis (n=6), and extremity (n=5). BRT targeted the largest lesion in 85% (median 5.8 cm; 32% bulky) and the site of highest SUV in 81% (median 18.7); 49% (n=17) of targets were extranodal. BRT fields were comprehensive in 39%; median radiation treatment volume was 751cc (range 18 - 5856). Twenty-four patients (63%) received ≥30 Gy (median 30 Gy; range 20 - 54). Systemic therapy was given during the bridging period to 31% (n=11). Patients received axicabtagene (n=20), tisagenlecleucel (n=11), lisocabtagene (n=3), or experimental CAR T (n=1). On PET after BRT and pre-infusion (median 12d from BRT), 85% (n=23) had achieved partial response (PR) or better in-field (CR: n=7) though 63% had kinetically active disease with out-of-field progression (PD) and 19% (n=5) had marginal PD. Despite short interval restaging, there was a significant reduction in patients with bulky disease after BRT both within the irradiated field (p=0.007) and at any site (p=0.01). (Fig 1a) A median 81% SUV reduction in the irradiated site was noted with a significant decrease in max SUV in both the irradiated (p & lt;0.001) and any (p=0.03) site. Following CAR T, 82% (n=26) achieved in-field CR and 68% (n=21) overall CR. With median post CAR T follow up of 11.5 mo (range 1.5 - 40), 20 patients (57%) ultimately failed at any site. Most failures (18/20) involved sites distant to the BRT field, however the predominant failure pattern remained within lesions that were present prior to CAR T (16/20). (Fig 1b) Eight patients failed in-field and 8 patients failed marginally; the majority (7/8 in both cases) also experienced distant failure. Comprehensive BRT was not significantly associated with decreased risk of pre-existing site failure. In the subset of patients with a bulky lesion irradiated (n=11; median lesion size 11cm), 73% (n=8) achieved a CR in-field post CAR T and of those 8, only one progressed in-field at 22 mo post CAR T. Conclusion: BRT significantly reduced the number of patients with bulky disease at any site at time of CAR T and significantly reduced the overall highest lesional SUV. Marginal failure rates of 19% and 23% at interim scan post-BRT and after CAR T, respectively in conjunction with the pattern of post CAR T failure predominantly in pre-existing sites, may suggest a need for more generous fields when a BRT approach is used in this population with rapidly proliferating disease. Further work and larger sample sizes are needed to evaluate the impact of dose on local control in bulky lesions as well as to investigate whether comprehensive BRT affects outcomes or patterns of failure. Figure 1 Figure 1. Disclosures Palomba: Juno: Patents & Royalties; Notch: Honoraria, Other: Stock; Novartis: Consultancy; Kite: Consultancy; PCYC: Consultancy; Wolters Kluwer: Patents & Royalties; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Magenta: Honoraria; Ceramedix: Honoraria; WindMIL: Honoraria; Nektar: Honoraria; Rheos: Honoraria; Priothera: Honoraria; BeiGene: Consultancy; Lygenesis: Honoraria; Pluto: Honoraria. Shouval: Medexus: Consultancy. Batlevi: Kite Pharma: Consultancy; Viatris: Current holder of individual stocks in a privately-held company; Dava Oncology: Honoraria; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Regeneron: Current holder of individual stocks in a privately-held company; TouchIME: Honoraria; Juno/Celgene: Consultancy; Medscape: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Seattle Genetics: Consultancy; Life Sciences: Consultancy; Pfizer: Current holder of individual stocks in a privately-held company; Karyopharm: Consultancy; Moderna: Current holder of individual stocks in a privately-held company; Memorial Sloan Kettering Cancer Center: Current Employment; Bayer: Research Funding; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Brentjens: Gracell Biotechnologies, Inc: Consultancy, Ended employment in the past 24 months; BMS: Consultancy, Patents & Royalties, Research Funding; sanofi: Patents & Royalties; Caribou: Patents & Royalties. Dahi: Kite / Gilead: Membership on an entity's Board of Directors or advisory committees. Giralt: JAZZ: Membership on an entity's Board of Directors or advisory committees; AMGEN: Membership on an entity's Board of Directors or advisory committees; JENSENN: Membership on an entity's Board of Directors or advisory committees; PFIZER: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; SANOFI: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; CELGENE: Membership on an entity's Board of Directors or advisory committees; Actinnum: Membership on an entity's Board of Directors or advisory committees. Park: BMS: Consultancy; Kite Pharma: Consultancy; Innate Pharma: Consultancy; Novartis: Consultancy; Minerva: Consultancy; Servier: Consultancy; Kura Oncology: Consultancy; PrecisionBio: Consultancy; Amgen: Consultancy; Intellia: Consultancy; Artiva: Consultancy; Curocel: Consultancy; Autolus: Consultancy; Affyimmune: Consultancy. Scordo: Angiocrine Bioscience: Consultancy, Research Funding; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; i3 Health: Other: Speaker; Omeros Corporation: Consultancy; McKinsey & Company: Consultancy. Sauter: Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Perales: Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Cidara: Honoraria; Miltenyi Biotec: Honoraria, Other; Kite/Gilead: Honoraria, Other; Equilium: Honoraria; Incyte: Honoraria, Other; Medigene: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria; Servier: Honoraria; NexImmune: Honoraria; Novartis: Honoraria, Other; Nektar Therapeutics: Honoraria, Other; Sellas Life Sciences: Honoraria; Omeros: Honoraria; MorphoSys: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-149702

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 138, No. Supplement 1 ( 2021-11-05), p. 96-96

Abstract: Background: CD19 CAR T cells have demonstrated high response rates in patients (pts) with relapsed or refractory (R/R) lymphoma, but these therapies are associated with high rates of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), often requiring prolonged hospital stay including transfer to the intensive care unit (ICU). Real-world data and early and prophylactic corticosteroid trials with axicabtagene in R/R large cell lymphoma have reported lower rates of severe CRS to & lt;10%, but severe ICANS remains elevated at 13-31% (Nastoupil L et al. J Clin Oncol2020; Oluwole O et al. BJH 2021). We have previously reported that elevated interleukin-1 (IL-1) in cerebrospinal fluid (CSF) was associated with ICANS (Santomasso B et al. Cancer Discov 2018), and IL-1 inhibition prevented development of severe ICANS and CRS in the in vivo preclinical model (Giavridis T et al. Nat Med 2018). Based on these data, we initiated a phase II study of IL-1 receptor inhibitor, anakinra (SOBI), in adult pts receiving commercial CD19 CAR T cells for prevention of CRS and ICANS (NCT04148430). Methods: Adult pts with R/R large B-cell lymphoma (LBCL) and mantle cell lymphoma (MCL) receiving commercially available CD19 CAR T cells were enrolled. Pts received anakinra 100mg subcutaneous every 12 hours starting either on day 2 of CAR T cell infusion or after 2 documented fevers of ≥38.5 prior to day 2, whichever was earlier. Anakinra was continued for a minimum of 10 days, and the dose could be increased to 100mg every 6 hours and continued beyond 10 days in the case of persistent or progressing CRS and ICANS. Pts received tocilizumab and/or corticosteroids after anakinra initiation for persistent or worsening CRS or ICANS. CRS and ICANS were assessed per the ASTCT consensus grading. Disease response was assessed per the Lugano criteria. The primary objective was to determine the rate of severe ICANS within the first 28 days of CAR T cell infusion. Secondary objectives included assessment of severe CRS, all grades of CRS and ICANS, disease response and serum and CSF cytokines. Results: A total of 31 pts (LBCL=27, MCL=4) were enrolled to the study. The median age of the pts at the time of T cell infusion was 62 (range, 30-77). CD19 CAR products included axicabtagene (23 pts; 74%), tisagenlecleucel (4 pts; 13%) and brexucabtagene (4 pts; 13%). 17 pts (55%) received bridging therapy prior to T cell infusion. All pts started anakinra at 100mg q12h; 25 pts started on day 2 and 6 pts prior to day 2 for grade 1 CRS. Anakinra dose was increased to 100mg q6h in 13 pts (42%). The median duration of anakinra administration was 10 days (range, 10-27). CRS of all grades was observed in 21 pts (68%) with severe CRS (grade 3-4) in 2 pts (6%) (1 with axicabtagene and 1 with brexucabtagene) (Table). Median CRS duration was 5.5 days (range, 1-21). ICANS of all grades was observed in 4 pts (13%), with severe ICANS in 2 pts (6%) (both grade 3; 1 with axicabtagene and 1 with brexucabtagene). No pt experienced grade 5 CRS or ICANS. Tocilizumab and corticosteroids were used in 9 pts (29%) and 6 pts (19%), respectively. Three pts (10%) required ICU transfer (2 with brexucabtagene and 1 with axicabtagene). In LBCL pts treated with axicabtagene (n=23), both severe CRS and ICANS were observed in 4% with tocilizumab and steroid use in 22% and 13%, respectively (Table). With a median follow-up of 104 days (range, 21-363), overall disease response rate at month 1 was 74% for all pts, with CR rate at 1 and 3 months of 58% and 52%, respectively. Conclusion: Early use of IL-1 receptor inhibitor anakinra appears to be safe and feasible, and reduces the rates of both severe CRS and ICANS with the comparable response rates in adult pts with R/R B-cell lymphoma receiving CD19 CAR T cells. The overall severe CRS and ICANS rates were 6% each with relatively low utilization of tocilizumab (29%) and corticosteroids (19%). In pts receiving axicabtagene, the rate of severe ICANS was 4%. A longer follow-up is needed to assess durability of remission, but the study provides strong support for continued investigation of IL-1 inhibition in prevention of severe ICANS. Further exploratory analysis is planned to address the impact of anakinra on changes in serum and CSF cytokines. Figure 1 Figure 1. Disclosures Park: BMS: Consultancy; Servier: Consultancy; Minerva: Consultancy; Curocel: Consultancy; Autolus: Consultancy; PrecisionBio: Consultancy; Intellia: Consultancy; Kite Pharma: Consultancy; Amgen: Consultancy; Artiva: Consultancy; Kura Oncology: Consultancy; Novartis: Consultancy; Affyimmune: Consultancy; Innate Pharma: Consultancy. Sauter: Gamida Cell: Consultancy; GSK: Consultancy; Bristol-Myers Squibb: Research Funding; Precision Biosciences: Consultancy; Kite/Gilead: Consultancy; Celgene: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharmaceuticals: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding. Palomba: Juno: Patents & Royalties; Seres: Honoraria, Other: Stock, Patents & Royalties, Research Funding; Notch: Honoraria, Other: Stock; Novartis: Consultancy; Kite: Consultancy; Wolters Kluwer: Patents & Royalties; PCYC: Consultancy; Ceramedix: Honoraria; Lygenesis: Honoraria; Magenta: Honoraria; BeiGene: Consultancy; WindMIL: Honoraria; Rheos: Honoraria; Nektar: Honoraria; Priothera: Honoraria; Pluto: Honoraria. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding. Dahi: Gilead sciences: Membership on an entity's Board of Directors or advisory committees; Kite pharma: Membership on an entity's Board of Directors or advisory committees. Scordo: Angiocrine Bioscience: Consultancy, Research Funding; Omeros Corporation: Consultancy; Kite - A Gilead Company: Membership on an entity's Board of Directors or advisory committees; i3 Health: Other: Speaker; McKinsey & Company: Consultancy. Batlevi: Kite Pharma: Consultancy; TouchIME: Honoraria; Seattle Genetics: Consultancy; Juno/Celgene: Consultancy; Karyopharm: Consultancy; TG Therapeutics: Consultancy; ADC Therapeutics: Consultancy; Medscape: Honoraria; BMS: Current holder of individual stocks in a privately-held company; Moderna: Current holder of individual stocks in a privately-held company; Regeneron: Current holder of individual stocks in a privately-held company; Viatris: Current holder of individual stocks in a privately-held company; Pfizer: Current holder of individual stocks in a privately-held company; Dava Oncology: Honoraria; Life Sciences: Consultancy; Memorial Sloan Kettering Cancer Center: Current Employment; Bayer: Research Funding; GLG Pharma: Consultancy; Xynomic: Research Funding; Roche/Genentech: Research Funding; Novartis: Research Funding; Epizyme: Research Funding; Janssen: Research Funding; Autolus: Research Funding. Perales: Merck: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Equilium: Honoraria; Servier: Honoraria; Miltenyi Biotec: Honoraria, Other; MorphoSys: Honoraria; Takeda: Honoraria; Medigene: Honoraria; Incyte: Honoraria, Other; Cidara: Honoraria; Karyopharm: Honoraria; Kite/Gilead: Honoraria, Other; Nektar Therapeutics: Honoraria, Other; Sellas Life Sciences: Honoraria; NexImmune: Honoraria; Omeros: Honoraria; Novartis: Honoraria, Other. Santomasso: Janssen: Consultancy; Legend: Consultancy; Kite/Gilead: Consultancy; Celgene/BMS: Consultancy; Incyte: Consultancy; In8bio: Consultancy. Sadelain: Juno Therapeutics: Patents & Royalties; NHLBI Gene Therapy Resource Program: Other: Provision of Services (uncompensated); Minerva Biotechnologies: Patents & Royalties; Mnemo Therapeutics: Patents & Royalties; Fate Therapeutics: Other: Provision of Services (uncompensated), Patents & Royalties; Takeda Pharmaceuticals: Other: Provision of Services, Patents & Royalties; St. Jude Children's Research Hospital: Other: Provision of Services; Ceramedix: Patents & Royalties; Atara Biotherapeutics: Patents & Royalties. Brentjens: BMS: Consultancy, Patents & Royalties, Research Funding; Gracell Biotechnologies, Inc: Consultancy, Ended employment in the past 24 months; sanofi: Patents & Royalties; Caribou: Patents & Royalties. OffLabel Disclosure: Anakinra for prevention of CRS and ICANS associated with CD19 CAR

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2021-150431

Language: English

Publisher: American Society of Hematology

Publication Date: 2021

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Nature Reviews Clinical Oncology, Springer Science and Business Media LLC, Vol. 19, No. 5 ( 2022-05), p. 342-355

Type of Medium: Online Resource

ISSN: 1759-4774 , 1759-4782

URL: Article

DOI: 10.1038/s41571-022-00607-3

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2022

detail.hit.zdb_id: 2491410-1

detail.hit.zdb_id: 2491414-9