Cytokine Release Syndrome (CRS) after Chimeric Antigen Receptor (CAR) T Cell Therapy for Relapsed/Refractory (R/R) CLL

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1983-1983 ◽  
Author(s):  
David L. Porter ◽  
Simon F. Lacey ◽  
Wei-Ting Hwang ◽  
Pamela Shaw ◽  
Noelle V. Frey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Research Funding ◽  
Grading System ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T ◽  
Life Threatening ◽  
Guide Intervention

Abstract CTL019 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) consisting of an external anti-CD19 domain with the CD3z and 4-1BB signaling domains, and mediate potent anti-tumor effects in patients (pts) with advanced, R/R CLL, ALL and NHL. CRS is the most serious toxicity of CTL019 therapy; symptoms can include fevers, nausea, myalgias, capillary leak, hypoxia, and hypotension. Standard CRS grading criteria are not applicable to CAR T cell therapies. To better capture clinical manifestations of CRS and guide intervention after CTL019, we devised a novel CRS grading scale. that was applied to 40 pts treated with CTL019 for R/R CLL; 14 pts on an initial pilot and 26 pts on an ongoing dose-optimization trial (reported separately). Our new CRS grading system is shown below. Pts were 80% male, a median age of 65 (range 51-78) and received a median of 4 prior therapies (range 1-10). 41% had known mutation at p53. 83% of 24 pts tested had unmutated IgVH. Response rate to CTL019 (CR+PR) was 42%. CRS was the major toxicity and occurred in 57% (23/40) of pts. CRS was gr 1 in 10%, gr 2 in 17%, gr 3 in 15% and gr 4 in 15%. Development of CRS correlated with response; 13/23 (57%) pts with CRS responded versus 4/17 (24%) pts without CRS responded (p=0.05). CRS was associated with elevations in IL-6, IFN-g, and other cytokines; details for 33 pts will be presented. Peak fold-increase over baseline for IL-6 was a median of 10.6x (range 0.28–649) and for IFN- g a median of 32.9x (1–7243x). For pts with CRS, this increase in IL-6 was a median of 23.5x compared to 1.86x in pts without CRS (p=0.001); and in IFN- g was a median of 97.2xin pts with CRS compared to 24.2x without (p=0.018). Increasing CRS severity was associated with peak fold change in IL-6 (p< 0.0001) and IFN- g (p=0.015). Notably, unlike cytokine changes associated with sepsis, TNF-a did not markedly increase during CRS. CRS occurred with a consistent and often dramatic increase in ferritin, C reactive protein (CRP), and hemophagocytosis, suggesting concurrent macrophage activation syndrome (MAS). Increasing CRS severity was associated with an increasing trend for peak ferritin (log scale, p<0.001) and peak CRP (p<0.001). The median peak ferritin was 13,463 ng/ml in pts with CRS compared to 378 in pts without (p<0.001). Median peak CRP was 16 mg/dl in pts with CRS compared to 3.86 in pts without (p=0.002). CRS required intervention in 8 pts. 1 pt was successfully treated with corticosteroids. Given marked increases in IL-6, 7 patients received the IL6-receptor antagonist tocilizumab with or without corticosteroids with resolution of CRS. Tocilizumab was given to 1/7 pts with gr 2 CRS, 1/6 pts with gr 3 and 5/6 pts with gr 4. Several pts also received corticosteroids and/or etanercept. All pts had resolution of CRS signs with no TRM from CRS. CRS is the most significant complication of CTL019 and can be life threatening. A novel CRS grading system was needed to identify CRS severity more accurately guide intervention timing. CTL019-related CRS is associated with a unique cytokine profile and has been manageable with anti-cytokine therapy in pts with R/R CLL. CRS appears to correlate with response of CLL to CTL019. Further study is needed to develop reliable methods to predict severity and minimize CRS toxicity without inhibiting anti-leukemia activity of CTL019. New CRS Grading System for CTL019 Abstract 1983. Table Grade 1 Grade 2 Grade 3 Grade 4 Mild: Treated with supportive care such as anti-pyretics, anti-emetics Moderate: Requiring IV therapies or parenteral nutrition; some signs of organ dysfunction (i.e. gr 2 Cr or gr 3 LFTs) related to CRS and not attributable to any other condition. Hospitalization for management of CRS related symptoms including fevers with associated neutropenia. More severe: Hospitalization required for management of symptoms related to organ dysfunction including gr 4 LFTs or gr 3 Cr related to CRS and not attributable to any other conditions; this excludes management of fever or myalgias. Includes hypotension treated with IV fluids or low-dose pressors, coagulopathy requiring FFP or cryoprecipitate, and hypoxia requiring supplemental O2 (nasal cannula oxygen, high flow 02, CPAP or BiPAP). Pts admitted for management of suspected infection due to fevers and/or neutropenia may have gr 2 CRS. Life-threatening complications such as hypotension requiring “high dose pressors”, hypoxia requiring mechanical ventilation. Disclosures Porter: Novartis: Patents & Royalties, Research Funding; Genentech (spouse employment): Employment. Off Label Use: Use of genetically modified T cells (CTL019) to treat CLL and use of tocilizumab to treat cytokine release syndrome.. Lacey:Novartis: Research Funding. Hwang:NVS: Research Funding. Frey:Novartis: Research Funding. Chew:Novartis: Patents & Royalties, Research Funding. Chen:Novartis: Research Funding. Kalos:Novartis: Patents & Royalties, Research Funding. Gonzalez:Novartis: Research Funding. Melenhorst:Novartis: Research Funding. Litchman:Novartis: Employment. Shen:Novartis: Employment. Quintas-Cardamas:Novartis: Employment. Wood:Novartis Pharma: Employment. Levine:Novartis: Patents & Royalties, Research Funding. June:Novartis: Patents & Royalties, Research Funding. Grupp:Novartis: Research Funding.

scholarly journals B-Cell Maturation Antigen (BCMA)-Specific Chimeric Antigen Receptor T Cells (CART-BCMA) for Multiple Myeloma (MM): Initial Safety and Efficacy from a Phase I Study

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1147-1147 ◽  
Author(s):  
Adam D. Cohen ◽  
Alfred L. Garfall ◽  
Edward A Stadtmauer ◽  
Simon Francis Lacey ◽  
Eric Lancaster ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Depth Of Response ◽  
Car T ◽  
Equity Ownership ◽  
Grade 3

Abstract Background : BCMA is expressed on MM cells, and CAR T cells targeting BCMA have pre-clinical anti-MM activity. CART-BCMA is an autologous T cell product engineered by lentiviral transduction to express a fully human BCMA-specific CAR with CD3ζ and 4-1BB signaling domains, and then expanded ex vivo using CD3/CD28 beads. Methods: In this ongoing, 3+3 dose-escalation study, relapsed/refractory MM patients (pts) receive CART-BCMA cells as split-dose infusions (10% on day 0, 30% on day 1, and 60% on day 2). Three cohorts are planned: 1) 1-5 x 108 CART cells alone; 2) cyclophosphamide (CTX) 1.5 g/m2 + 1-5 x 107 CART cells; and 3) CTX 1.5 g/m2 + 1-5 x 108 CART cells. Pts need serum creatinine (Cr) <2.5 mg/dL or Cr clearance≥30 ml/min, and adequate hepatic, cardiac, and pulmonary function. BCMA expression on MM cells is analyzed by flow cytometry, though no pre-specified level is required for eligibility. CART-BCMA frequency and activation status are assessed in blood and marrow by flow cytometry. Levels of CAR-transduced cells are also measured by qPCR using a transgene-specific primer/probe pair. Soluble BCMA, BAFF and APRIL levels in serum are assessed by ELISA. Bioactivity of the infusion product and CART-related cytokine release syndrome are analyzed by Luminex. Responses are assessed by IMWG criteria. Results: To date, 11 pts have been screened, and 6 treated in cohort 1. Reasons for not receiving treatment were screen fail (n=2), rapid MM progression/renal failure (n=2), and pt/MD choice (n=1). The 6 treated pts were all IMID/PI-refractory with high risk cytogenetics and median 9 lines of therapy (Table). All expressed BCMA on MM cells, and achieved the minimum target dose of 1x108 CART-BCMA cells. All but 2 received 100% of planned dose, with 2 (pts 01and 03) receiving 40% (3rd infusions held for fever). Cytokine release syndrome (CRS) occurred in 5 patients: 2 grade 3 requiring tocilizumab (pts 01 and 03), 1 grade 2, and 2 grade 1. High-grade CRS was associated with elevated levels of IL-6, IFNg, MCP1, MIG, IL2Ra, and IL-10, as seen in our acute lymphoblastic leukemia CTL019 trial (Teachey et al, 2016). There was 1 DLT: grade 4 PRES (posterior reversible encephalopathy syndrome) in pt 03, with severe delirium, recurrent seizures, obtundation, and cerebral edema on MRI. This resolved after anti-epileptics, high-dose methylprednisolone and cyclophosphamide, without long-term neurologic sequelae. Other grade 3/4 toxicities to date include hypophosphatemia (n=3 pts), hypocalcemia (n=2), and anemia, neutropenia, lymphopenia, thrombocytopenia, hypofibrinogenemia, fatigue, pneumonia, UTI, elevated Alk phos and AST, hypokalemia, hypertension, and pleural effusion (n=1 each). CART-BCMA cells were detected in blood and marrow by CAR-specific PCR in all 6 pts, and in 4/6 by flow cytometry, with 2 pts, 01 and 03, having massive CART expansion peaking at 90% and 76% of peripheral CD3+ T cells, respectively. CART-BCMA cells during peak expansion were predominantly CD8+ and highly activated. Pt 01 has ongoing CART-BCMA persistence, with ongoing stringent CR at 7 months and MRD-negative bone marrow by flow cytometry. Pt 03, who had pleural and possible dural MM involvement, had CART-BCMA cells found in pleural fluid and CSF, and achieved VGPR (IF+ only) with resolution of extramedullary disease on PET/CT scan. She progressed at 5 months, associated with significant reduction of CART-BCMA cells and loss of BCMA expression on her MM cells by flow cytometry, suggestive of antigen escape. Two pts (02, 11) had modest CART-BCMA expansion, with 1 minimal response (MR) lasting 2 months, and 1 ongoing MR 1 month post-infusion. Two pts (09, 10) had minimal expansion and no response. Soluble BCMA levels, which were elevated in all pts at baseline, declined in parallel with CART-BCMA expansion and correlated with depth of response, with an accompanying increase in previously suppressed BAFF and APRIL levels in serum. Conclusions: CART-BCMA cells can be manufactured from heavily-pretreated MM pts, and demonstrate promising in vivo expansion and clinical activity, even without lymphodepleting conditioning. Depth of response correlates with degree of CART-BCMA expansion and CRS. Toxicities to date include CRS and in 1 pt, severe reversible neurotoxicity, as described in other CAR T cell studies. Expanded accrual in cohort 1, as well as in cohorts with CTX conditioning, is ongoing, with updated data to be presented at the meeting. Table Table. Disclosures Cohen: Bristol-Meyers Squibb: Consultancy, Research Funding; Janssen: Consultancy. Garfall:Bioinvent: Research Funding; Novartis: Consultancy, Research Funding; Medimmune: Consultancy. Stadtmauer:Novartis: Consultancy; Takada: Consultancy; Amgen: Consultancy; Celgene: Consultancy; Teva: Consultancy; Janssen: Consultancy. Lacey:Novartis: Research Funding. Lancaster:Janssen: Consultancy; Medimmune, Inc.: Consultancy; Grifols, Inc.: Other: Teaching courses. Vogl:Millennium: Consultancy, Research Funding; Celgene: Consultancy; Karyopharm: Consultancy; Teva: Consultancy; Acetylon: Research Funding; Glaxo Smith Kline: Research Funding; Calithera: Research Funding; Constellation: Research Funding. Ambrose:Novartis: Research Funding. Plesa:Novartis: Patents & Royalties, Research Funding. Kulikovskaya:Novartis: Research Funding. Weiss:Prothena: Other: Travel, accommodations, Research Funding; Novartis: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy, Other: Travel, accommodations, Research Funding; Millennium: Consultancy, Other: Travel, accommodations. Richardson:Novartis: Employment, Patents & Royalties, Research Funding. Isaacs:Novartis: Employment. Melenhorst:Novartis: Patents & Royalties, Research Funding. Levine:Novartis: Patents & Royalties, Research Funding. June:Novartis: Honoraria, Patents & Royalties: Immunology, Research Funding; University of Pennsylvania: Patents & Royalties; Tmunity: Equity Ownership, Other: Founder, stockholder ; Johnson & Johnson: Research Funding; Celldex: Consultancy, Equity Ownership; Immune Design: Consultancy, Equity Ownership; Pfizer: Honoraria. Milone:Novartis: Patents & Royalties, Research Funding.

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

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

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

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

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

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

scholarly journals Suppressed Fibrinolytic Activity Demonstrated By Simultaneous Thrombin and Plasmin Generation Assay during Cytokine Release Syndrome after CD19 Chimeric Antigen Receptor-Modified T-Cell Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4807-4807
Author(s):  
Takashi Ishihara ◽  
Yasuyuki Arai ◽  
Makiko Morita ◽  
Tomoko Onishi ◽  
Hanako Shimo ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Research Funding ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Time Points ◽  
Car T ◽  
D Dimer ◽  
Coagulation And Fibrinolysis

Abstract Introduction: Infusion T cells engineering to express CD19-specific chimeric antigen receptor T cells (CAR-T) following lymphodepleting chemotherapy has shown promising efficacy in patients with relapsed and/or refractory CD19-positive B-cell malignancies including B-cell acute lymphoblastic leukemia (B-ALL), and diffuse large B-cell lymphoma (DLBCL). CAR-T therapy can often be associated with cytokine release syndrome (CRS), which has been reported to present severe coagulopathy. Conventional coagulation and fibrinolysis parameters have been reported to worsen in correlation with CRS grading [Hay KA et al. Blood 2017]. In the present study, we hypothesized that the change of balance between coagulation and fibrinolysis due to coagulopathy is associated with CRS after CAR-T therapy. To clarify our hypothesis, we investigated the global coagulation and fibrinolytic function of patients receiving CD19 CAR-T therapy using simultaneous thrombin and plasmin generation assay (T/P-GA). Patients: We enrolled 13 consecutive patients aged 23-69 years (8 males and 5 females, DLBCL; n = 11, B-ALL; n = 2) receiving CD19 CAR-T therapy from May 2020 to December 2020 at a single center in Japan. Due to a history of internal jugular venous thrombosis, one patient received edoxaban, an anticoagulant. Methods: We evaluated the global functions of coagulation and fibrinolysis using T/P-GA [Matsumoto et al. TH 2013]. This clotting was initiated by the mixture of recombinant human tissue factor (Innovin ®, f.c. 1 pM), phospholipid vesicles (f.c. 4 μM), and tissue-type plasminogen activator (f.c. 3.2 nM). We simultaneously monitored thrombin and plasmin generation using thrombin- and plasmin-specific fluorogenic substrate (Z-Gly-Gly-Arg-AMC and BOC-Glu-Lys-Lys-MAC, respectively) in separate microtiter wells. The first derivatives (velocity) of thrombin and plasmin generation were utilized to derive the parameters, lag time (LT), endogenous potential (EP), peak levels (Peak), and time to peak (ttPeak). In this study, EP of thrombin generation (T-EP) and plasmin-peak (P-Peak) were selected as parameters for evaluation. We calculated the ratio of T-EP and P-Peak of patients' plasmas to those of control normal plasma. A ratio &gt; 1.0 was defined as high coagulation or fibrinolytic potential relative to normal. Using fibrinogen (Fbg), D-dimer, and antithrombin (AT), we also monitored the conventional laboratory markers of hemostasis. Soluble IL-2 receptor (sIL-2R) was also measured as a marker of inflammatory cytokines. Day 0 was defined as the day of CAR-T infusion. Plasmas were collected at T0; pre-lymphodepleting chemotherapy, T1; Days -2-0, T2; Days 1-3, T3; Days 4-6, T4; Days 7-9, T5; Days 10-12, T6; Days 13-18, and T7; Days 19-23. Results: All patients had Grade ≤ 2 CRS. Two cases developed CRS-associated coagulopathy, one of whom required fresh frozen plasma transfusion and cryoprecipitate for low Fbg level, and the other required tranexamic acid for hemorrhagic cystitis. The median values of AT remained within the reference value (RV). The median Fbg values were 229-525 mg/dL, and which were significantly greater at T0-T3 than at T5-T7 (p &lt; 0.05). The median D-dimer values were 0.45-3.9 µg/mL, which were within or above the RV with no significant change between time points. The median values of sIL-2R were 819-3,953 U/mL, and which were significantly increased at T3-T4 than at T0-T1 (p &lt; 0.05). T-EP/P-Peak revealed a median of 1,877/21.9, 1,659/18.6, 1,731/19.8, 1,856/15.0, 1,931/16.3, 1,758/18.5, 1,600/19.1, 1,634/20.3, and 1,594/17.4 nM for T0-T7 and control plasma, respectively, indicating the reduced P-Peak ratios (Fig. 1). T-EP ratios showed consistently maintaining &gt; 1 with no significant difference between time points, while P-Peak ratios were significantly lower at T3 and T4 than at T0 (p &lt; 0.01) (median ratios of T-EP/P-peak; T0; 1.23/1.22, T1; 1.08/1.05, T2; 1.12/1.09, T3; 1.23/0.81, T4; 1.27/0.91, T5; 1.19/1.11, T6; 1.07/1.12, and T7; 1.20/1.15, respectively). Conclusion: The results of T/P-GA showed that hemostatic kinetics in patients with Grade ≤ 2 CRS were likely to shift to hypercoagulable states throughout the entire period and that they were likely to experience hypofibrinolytic activity during the CRS phase. These results suggest that the imbalance of coagulation and fibrinolysis might cause organ disorder due to thrombotic tendency associated with CRS after CAR-T therapy. Figure 1 Figure 1. Disclosures Takaori-Kondo: Bristol-Myers K.K.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Research Funding; Celgene: Research Funding. Nogami: Chugai Pharmaceutical Co., Ltd.: Consultancy, Research Funding.

scholarly journals Anakinra Targeting Cytokine Release Syndrome Associated with Chimeric Antigen Receptor T-Cell Therapies

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2812-2812
Author(s):  
Sandy W. Wong ◽  
Shambavi Richard ◽  
Yi Lin ◽  
Deepu Madduri ◽  
Carolyn C. Jackson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cell ◽  
Receptor Antagonist ◽  
Chimeric Antigen Receptor ◽  
Research Funding ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T

Abstract Introduction: Cytokine release syndrome (CRS) is a common toxicity associated with chimeric antigen receptor (CAR) T-cell therapies. Corticosteroids and steroid-sparing therapies such as tocilizumab, an interleukin-6 receptor antagonist, and anakinra, an interleukin-1 receptor antagonist, have been used to reduce the incidence and severity of these toxicities. Preclinical and clinical case studies of anakinra, administered subcutaneously or intravenously at various doses, have shown promising results in the management of CRS and systemic inflammatory responses resembling hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS). In CARTITUDE-1, CRS occurred in 95% of heavily pretreated patients with relapsed/refractory multiple myeloma (RRMM) receiving ciltacabtagene autoleucel (cilta-cel), a CAR T-cell therapy with 2 B-cell maturation antigen-targeting single-domain antibodies (Berdeja et al. Lancet 2021). Per protocol, tocilizumab was required to manage CRS with option to give steroids and/or anakinra per investigator discretion. Here, we report the institutional experiences of anakinra use in the management of CRS in patients who have received cilta-cel as part of the CARTITUDE-1 study. Methods: Eligible patients had MM and received ≥3 prior therapies or were refractory to a proteasome inhibitor (PI) and immunomodulatory drug (IMiD), and had received a PI, IMiD, and anti-CD38 antibody (Berdeja et al. Lancet 2021). After apheresis, bridging therapy was permitted. Patients received a single cilta-cel infusion (target dose: 0.75×10 6 CAR+ viable T cells/kg; range 0.5-1.0×10 6) 5-7 days after lymphodepletion (300 mg/m 2 cyclophosphamide, 30 mg/m 2 fludarabine daily for 3 days). Lee et al (Blood 2014) grading criteria for CRS were mapped to the ASTCT criteria for CRS. Post-hoc analysis of data revealed use of anakinra at some sites in patients who failed to respond to the initial management of CRS with tocilizumab +/- dexamethasone or in clinical settings where rise of ferritin and/or liver function tests were indicative for continued HLH/MAS-like manifestations (Kennedy et al. ASH 2020). Results: Of 97 patients in CARTITUDE-1, CRS occurred in 92 (95%) patients; 4% were grade 3/4. The median time to onset was 7 days (range 1-12) and median duration was 4 days (range 1-14). Supportive measures to treat CRS were administered to 91% of patients, most commonly tocilizumab (69%; 4 patients received ≥3 doses), corticosteroids (22%), and anakinra (18 patients, 19%). CRS resolved in 99% of patients. Anakinra was administered after initial tocilizumab and within the first 48 hours (range 0-6 days) of CRS onset for the majority of patients as part of effective management of CRS. Anakinra was administered at a dose of 100-200 mg every 8-12 hours over a median of 2.5 days (range 1-15 days). CRS uniformly resolved following anakinra use in CARTITUDE-1, apart from one patient who died from sepsis (grade 5 outcome) due to HLH/MAS considered related to treatment (Table). Conclusions: CRS events in cilta-cel-treated patients in CARTITUDE-1 were common, generally low-grade, and successfully managed with standard tocilizumab +/- dexamethasone. The use of anakinra should be considered in patients with persistent CRS/inflammatory symptoms despite tocilizumab use, and in particular in patients with HLH/MAS-like symptoms/phenotype occurring following CRS or in the absence of prior CRS. Figure 1 Figure 1. Disclosures Wong: Amgen: Consultancy; Genentech: Research Funding; Fortis: Research Funding; Janssen: Research Funding; GloxoSmithKlein: Research Funding; Dren Biosciences: Consultancy; Caelum: Research Funding; BMS: Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees. Richard: Karyopharm, Janssen: Honoraria. Lin: Juno: Consultancy; Legend: Consultancy; Merck: Research Funding; Bluebird Bio: Consultancy, Research Funding; Sorrento: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy, Research Funding; Novartis: Consultancy; Celgene: Consultancy, Research Funding; Takeda: Research Funding; Gamida Cell: Consultancy; Vineti: Consultancy. Madduri: Janssen: Current Employment. Jackson: Janssen: Current Employment; Memorial Sloan Kettering Cancer Center: Consultancy. Zudaire: Janssen: Current Employment. Romanov: Janssen: Current Employment. Trigg: Janssen: Current Employment. Vogel: Janssen Global Services, LLC: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company, Divested equity in a private or publicly-traded company in the past 24 months. Garrett: Legend Biotech USA: Current Employment. Nesheiwat: Legend Biotech USA: Current Employment. Martin: Oncopeptides: Consultancy; Sanofi: Research Funding; Janssen: Research Funding; GlaxoSmithKline: Consultancy; Amgen: Research Funding. Jagannath: Bristol Myers Squibb: Consultancy; Legend Biotech: Consultancy; Karyopharm Therapeutics: Consultancy; Janssen Pharmaceuticals: Consultancy; Takeda: Consultancy; Sanofi: Consultancy. OffLabel Disclosure: At the time of abstract submission, cilta-cel is being investigated for the treatment of multiple myeloma but is not yet approved

CAR-T Therapy for Lymphoma with Prophylactic Tocilizumab: Decreased Rates of Severe Cytokine Release Syndrome without Excessive Neurologic Toxicity

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 30-31 ◽  
Author(s):  
Paolo F Caimi ◽  
Ashish Sharma ◽  
Patricio Rojas ◽  
Seema Patel ◽  
Jane Reese ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Advisory Board ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T Cell ◽  
Significant Difference ◽  
Car T

INTRODUCTION: Anti-CD19 chimeric antigen receptor T (CAR-T) cells have demonstrated activity against relapsed/refractory lymphomas. Cytokine release syndrome (CRS) and CAR-T related encephalopathy syndrome (CRES/ICANS) are well-known complications of CAR-T cell therapy. Tocilizumab, a humanized monoclonal antibody targeting the interleukin 6 (IL-6) receptor, is approved for treatment of CRS. Our institutional standard was modified to administer prophylactic tocilizumab before infusion CAR-T cell products. We present the outcomes of subjects treated with locally manufactured antiCD19 CAR-T cells (TNFRSF19 transmembrane domain, CD3Zeta/4-1BB costimulatory signaling) with and without prophylactic tocilizumab. METHODS: Relapsed / refractory (r/r) lymphoma patients (pts) treated with anti-CD19 CAR-T cells at our institution were included. Baseline demographic and clinical characteristics, as well as laboratory results were obtained from our Hematologic Malignancies and Stem Cell Therapy Database. Prior to institution of prophylactic tocilizumab, pts received this agent only if they presented evidence of CRS grade 2 or higher. In May 2019, our institutional practice changed to provide tocilizumab 8mg/kg, 1 hour prior to infusion of CAR-T cell product. CRS was measured according to the ASTCT Consensus Grading, whereas CRES was measured using the CARTOX-10 criteria. Comparisons between groups were done with the Mann-Whitney U test for continuous variables and Fisher's exact test for categorical variables. RESULTS: Twenty-three relapsed / refractory lymphoma pts were treated with antiCD19 CAR-T cells; 15 pts received prophylactic tocilizumab. Median follow up was 312 days (range 64 - 679) days. Baseline characteristics are listed in table 1. Both groups were similar: There were no statistically differences in the rate of bulky, refractory disease, prior ASCT or number or prior lines of therapy. Baseline lymphocyte counts, C - reactive protein (CRP) and were also comparable between groups (Table 2). We did not observe immune adverse reactions to tocilizumab infusion. There were no differences in the incidence of cytopenias or infectious complications between groups. CRS of any grade was observed in 6/8 (75%) of pts without prophylactic tocilizumab vs. 6/15 (40%) in pts treated with prophylactic tocilizumab (p = 0.23), whereas CRS grade &gt;1 was observed in 5 pts (62.5%) without prophylactic tocilizumab and in 3 pts (20%) treated with prophylactic tocilizumab (p = 0.02). There was no significant difference in the incidence of all grade CRES (no prophylaxis, 3/8 [38%] pts; prophylaxis 5/15 [30%] pts, p = 0.2969). There was a statistically significant difference in the peak CRP and peak ferritin without difference in the peak lymphocyte count after CAR-T infusion (Table 2, Figure 1). Patients given prophylactic tocilizumab had higher IL-6 plasma concentrations on day 2 after infusion (Figure 2). Complete response was observed in 4/8 (50%) pts without prophylactic tocilizumab vs. 12/15 (80%) pts with prophylactic tocilizumab (p = 0.18). All pts had detectable Anti-CD19 CAR-T cells on day 30, both groups had peak CAR-T expansion on day 14, with no statistically significant differences in expansion rates between groups. All evaluable subjects have had CAR-T persistence on days 60, 90, 180, and 365. CONCLUSIONS: Use of prophylactic tocilizumab prior to infusion of antiCD19 CAR-T cells is associated with reduced incidence of severe CRS and decreased levels of clinical laboratory markers of inflammation, despite increases in plasma concentration of IL-6. This decreased rate of grade ≥2 CRS is not associated with impaired disease control and did not result in increased rates of neurologic toxicity. Prophylactic tocilizumab does not appear to affect CAR-T cell expansion or persistence. Figure 1 Disclosures Caimi: ADC therapeutics: Other: Advisory Board, Research Funding; Celgene: Speakers Bureau; Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Kite pharmaceuticals: Other: Advisory Board. Worden:Lentigen, a Miltenyi biotec company: Current Employment. Kadan:Lentigen, a Miltenyi biotec company: Current Employment. Orentas:Lentigen Technology, a Miltenyi Biotec Company: Research Funding. Dropulic:Lentigen, a Miltenyi Biotec Company: Current Employment, Patents & Royalties: CAR-T immunotherapy. de Lima:Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding; Kadmon: Other: Personal Fees, Advisory board; Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board. OffLabel Disclosure: Use of tocilizumab as prophylaxis for CRS is not approved, whereas use for treatment is approved and on label.

scholarly journals Cardiovascular Complications of Chimeric Antigen Receptor T-Cell Therapy: The Cytokine Release Syndrome and Associated Arrhythmias

2020 ◽  
Vol 3 (3) ◽  
pp. 113-120 ◽  
Author(s):  
Cesar Clavijo Simbaqueba ◽  
Maria Patarroyo Aponte ◽  
Peter Kim ◽  
Anita Deswal ◽  
Nicolas L. Palaskas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Tumor Antigens ◽  
Antigen Receptor ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
T Cell Therapy ◽  
Car T

ABSTRACT In recent years, cancer treatment has evolved, and new therapies have been introduced with significant improvement in prognosis. The immunotherapies stand out owing to their efficacy and remission rate. Chimeric antigen receptor (CAR) T-cell therapy is a part of this new era of therapies. Chimeric antigen receptor T-cell therapy is a form of adoptive cellular therapy that uses a genetically encoded CAR in modified human T cells to target specific tumor antigens in a nonconventional, non-major histocompatibility complex (MHC) protein presentation. Chimeric antigen receptor T-cell therapy successfully identifies tumor antigens and through activation of T cells destroys tumoral cells. It has been found to efficiently induce remission in patients who have been previously treated for B-cell malignancies and have persistent disease. As the use of this novel therapy increases, its potential side effects also have become more evident, including major complications like cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Cytokine release syndrome is a major systemic inflammatory process as a result of massive cytokine production by the proliferating and activated CAR T cells in which multiple interleukins and immune cells contribute to the inflammatory response. Cytokine release syndrome has been associated with cardiovascular life-threatening complications including hypotension, shock, tachycardia, arrhythmias, left ventricular dysfunction, heart failure, and cardiovascular death. Arrhythmias, among its major complications, vary from asymptomatic prolonged corrected QT interval (QTc) to supraventricular tachycardia, atrial fibrillation, flutter, and ventricular arrhythmias like Torsade de pointes. This article focuses on the cardiovascular complications and arrhythmias associated with CRS and CAR T-cell therapy.

scholarly journals Nutritional Status Alterations After Chimeric Antigen Receptor T Cell Therapy in Patients With Hematological Malignancies: A Retrospective Study

2021 ◽  
Author(s):  
Shuyi Ding ◽  
Lingxia Cai ◽  
Aiyun Jin ◽  
Xiaoyu Zhou ◽  
Jiali Yan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nutritional Status ◽  
Serum Albumin ◽  
Chimeric Antigen Receptor ◽  
Hematological Malignancies ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T

Abstract Purpose: The influence of innovative chimeric antigen receptor T cell (CAR-T) therapy for hematological malignancies on nutritional status remains unknown. Therefore, we aim to explore the alterations of nutritional status after CAR-T therapy in patients with hematological malignancies.Methods: We retrospectively collected the data of patients with acute leukemia (AL), lymphoma and multiple myeloma (MM), who underwent CAR-T therapy at our hospital from 2018 to 2020. The serum albumin, triglyceride and cholesterol before and 7, 14 and 21 days after CAR-T cells infusion were compared and analyzed.Result: A total of 117 patients were enrolled, consisting of 39 AL, 23 lymphoma and 55 MM patients. The baseline albumin, triglyceride and cholesterol were 37.43±5.08 mg/L, 1.63±0.74 mmol/L and 3.62±1.03 mmol/L, respectively. The lowest albumin level was found at 7 days after CAR-T infusion compared with baseline (P<0.001), while the levels of triglyceride increased at 14 and 21 days (P<0.001, P=0.036). The levels of cholesterol at 7, 14, 21 days after CAR-T infusion were lower than baseline (all P<0.05). Spearman correlation coefficient showed cytokine release syndrome grade was negatively correlated with the levels of albumin at 7 days and cholesterol at 21 days after CAR-T infusion (r=-0.353, P<0.001; r=-0.395, P=0.002).Conclusion: Serum albumin and total cholesterol concentration decreased at the lowest level 7 days after CAR-T cells infusion, while triglyceride increased at 14 and 21 days after infusion. The levels of albumin and total cholesterol after CAR-T cells infusion were negatively correlated with the grade of cytokine release syndrome.

scholarly journals Preemptive mitigation of CD19 CAR T-cell cytokine release syndrome without attenuation of antileukemic efficacy

Blood ◽  
2019 ◽  
Vol 134 (24) ◽  
pp. 2149-2158 ◽  
Author(s):  
Rebecca A. Gardner ◽  
Francesco Ceppi ◽  
Julie Rivers ◽  
Colleen Annesley ◽  
Corinne Summers ◽  
...  
Keyword(s):  
T Cell ◽  
Acute Lymphocytic Leukemia ◽  
Negative Impact ◽  
Lymphocytic Leukemia ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cell ◽  
Car T ◽  
Antileukemic Effect ◽  
Life Threatening

Gardner et al report that early intervention with tocilizumab and steroids at the first signs of mild cytokine release syndrome (CRS) following CD19 chimeric antigen receptor (CAR) T-cell infusion for B-cell acute lymphocytic leukemia reduces the development of life-threatening severe CRS without having a negative impact on antileukemic effect.

scholarly journals Clinical Characterization and Risk Factors Associated with Cytokine Release Syndrome Induced By COVID-19 and Chimeric Antigen Receptor T-Cell Therapy

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 35-36
Author(s):  
Ruimin Hong ◽  
Houli Zhao ◽  
Yiyun Wang ◽  
Yu Chen ◽  
Hongliu Cai ◽  
...  
Keyword(s):  
Risk Factors ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Antigen Receptor ◽  
Tumor Burden ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
T Cell Therapy ◽  
Car T

Background: An excessive immune response during coronavirus disease (COVID-19) can induce cytokine release syndrome (CRS), which is associated with life-threatening complications and disease progression. Methods: This study was aimed to investigate the differences and similarities between CRS induced by COVID-19 and CAR-T therapy, then provide valuable experiences for early identification and controlling CRS progression in COVID-19. We retrospectively evaluated the clinical characteristics of severe CRS (sCRS, grade 3-4) induced by COVID-19 (40 patients) or chimeric antigen receptor T-cell (CAR-T) therapy as a comparator (41 patients). Results: Grade 4 CRS was significantly more common in the COVID-19 group (15/40 [35.7%] vs. 5/41 [12.2%], P=0.008). CAR-T group had more more dramatic increase in cytokine than COVID-19 group (Figure1), including IL-2 (7.3pg/mL [IQR: 2.0-12.7] vs.1.7 [0.7-2.7], P&lt;0.001), IL-6 (7120.6 pg/mL [1066.8-15 136.4] vs. 110.3 [41.7-728.1], P&lt;0.001), IL-10 (174.5pg/mL [61.7, 434.6] vs. 10.1 [6.3-20.6], P&lt;0.001) and IFN-γ (1308.5pg/mL [296.6, 3108.2] vs .35.0 [16.9-60.8], P&lt;0.001). Interestingly, COVID-19 group had significantly higher levels for TNF-α (31.1 pg/ml [16.1-70.0] vs. 3.3 [1.8-9.6], P&lt;0.001).The correlations between viral load/ tumor burden and various cytokine levels were shown in Figure 2. Lg viral loads were correlated with lg IL-6 (R2=0.101; P&lt;0.001) and lg IL-10 (R2=0.105; P&lt;0.001) .In CAR-T group, LDH was a common indicator related to tumor burden among patients with ALL, NHL, and MM. The lg LDH concentration was correlated with the lg serum concentration of IL-6 (R2=0.161; P=0.01). The independent risk factors for COVID-19-related sCRS were hypertension history (OR: 7.167, 95% CI: 2.345-21.903; P=0.001) and minimum platelets &lt;100×109 /L during disease course (OR: 9.237, 95% CI: 2.544-33.546; P=0.001). Conclusion: Our study demonstrated that there were similar processes but different intensity of inflammatory responses of sCRS in COVID-19 and CAR-T group. The diagnose and management of COVID-19 related sCRS can learn lessons from treatment of sCRS induced by CAR-T therapy. Keywords: Cytokine release syndrome, COVID-19, Chimeric antigen receptor T-cell therapy Figure 1 Disclosures No relevant conflicts of interest to declare.

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