Refraktäres/rezidiviertes Multiples Myelom: CAR-T-Zell-Therapie zeigt beträchtliche Wirksamkeit

2021 ◽  
pp. 1-2
Author(s):  
Tobias Holderried
Keyword(s):  
Overall Response Rate ◽  
Response Rate ◽  
Multiples Myelom ◽  
Complete Response ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Single Chain Variable Fragment ◽  
Single Chain ◽  
Car T ◽  
International Myeloma Working Group

KarMMa ist eine offene, einarmige, multizentrische, multinationale Phase-II-Studie zur Bewertung der Wirksamkeit und Sicherheit von Idecabtagen Vicleucel (ide-cel) bei erwachsenen Patienten mit rezidiviertem und refraktärem Multiplem Myelom (RRMM) in Nordamerika und Europa. Der primäre Endpunkt der Studie ist die Gesamtansprechrate (Overall Response Rate, ORR), die von einem unabhängigen Prüfungsausschuss (IRC) gemäß den Kriterien der International Myeloma Working Group (IMWG) bewertet wird. Ein wichtiger sekundärer Endpunkt ist ein komplettes Ansprechen (complete Response, CR) oder besser. Bei ide-cel handelt es sich um eine BCMA-gerichtete, genetisch modifizierte autologe CAR-T-Zell-Immuntherapie. Ide-cel besteht aus einem murinen extrazellulären einkettigen variablen Fragment (single-chain variable fragment, scFv), das spezifisch für die Erkennung von BCMA ist und an eine humane CD8-α-Gelenk- und Transmembrandomäne gebunden ist. Diese ist im Tandem mit den zytoplasmatischen T-Zell-Signaldomänen CD137 4–1BB und CD3-ζ-Kette fusioniert. Ide-cel erkennt und bindet an BCMA auf der Oberfläche von multiplen Myelom-Zellen, was zur Proliferation von CAR-T-Zellen, zur Ausschüttung von Zytokinen und zur anschließenden zytolytischen Abtötung von BCMA-exprimierenden Zellen führt. Ide-cel führte bei der Mehrheit der stark vorbehandelten Patienten mit refraktärem und rezidivierendem Myelom zu einem Ansprechen; ein MRD-negativer Status wurde bei 26% der behandelten Patienten erreicht. Bei fast allen Patienten traten toxische Wirkungen des Grades 3 oder 4 auf, am häufigsten hämatologische toxische Wirkungen und Zytokin-Freisetzungssyndrome (Cytokine-release syndrome, CRS). (ClinicalTrials.gov Identifier: NCT03361748)

scholarly journals Efficacy-enhanced and cytokine release syndrome-attenuated anti-CD7 universal chimeric antigen receptor-T cell therapy for relapsed/refractory CD7-positive hematological malignancies: A phase I clinical study

2021 ◽  
Author(s):  
He Huang ◽  
Yongxian Hu ◽  
Yali Zhou ◽  
Mingming Zhang ◽  
Houli Zhao ◽  
...  
Keyword(s):  
T Cell ◽  
Chimeric Antigen Receptor ◽  
Objective Response ◽  
Antigen Receptor ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Single Chain ◽  
Antitumor Effects ◽  
Car T ◽  
T Cell Malignancies

Abstract Chimeric antigen receptor-T cell (CAR-T) therapy in T cell malignancies faces fratricide, T cell aplasia, and product contamination. Here, we successfully developed a universal anti-CD7 CAR-T product (RD13-01). RD13-01 contains a bbzg-CAR comprising an anti-CD7 single-chain variable fragment, a 4-1BB costimulatory domain, a CD3ζ signaling domain, the intracellular domain of the common γ chain, and a natural killer cell inhibitory molecule (E-cadherin). TRAC, CD7 and HLA-II were disrupted to avoid graft versus host disease (GvHD), fratricide and rejection. Bbzg-CAR-T exerted antitumor effects superior to those of conventional CAR-T, while exhibiting reduced cytokine production. Among 11 evaluable relapsed/refractory (r/r) patients, no dose-limited toxicity, GvHD, immune effector cell-associated neurotoxicity or severe cytokine release syndrome (grade≥3) occurred. Nine (82%) showed objective response. For r/r leukemia and NHL, complete response rates were 75% and 33.3% respectively. Outstanding safety and efficacy of this universal CAR-T product was achieved in CD7+ T cell malignancies.

scholarly journals T Cells Expressing Anti B-Cell Maturation Antigen Chimeric Antigen Receptors for Plasma Cell Malignancies

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1013-1013 ◽  
Author(s):  
Chunrui Li ◽  
Qiuxiang Wang ◽  
Hui Zhu ◽  
Xia Mao ◽  
Ying Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Plasma Cell ◽  
Response Rate ◽  
Disease Free Survival ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cells ◽  
Car T ◽  
Expression Rate

Abstract Introduction: Chimeric antigen receptor (CAR) modified T cells targeting B-cell maturation antigen (BCMA) have shown activity in a case series of patients with relapsed or refractory Multiple Myeloma (MM), but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define the duration of disease, number of treatment lines, treatment course, extramedullary plasma cell tumor, hematopoietic stem cell transplantation, FISH abnormal gene number, risk (combined FISH and second-generation sequencing analysis) ,feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in patients with malignant plasma cell disease treated with BCMA-CAR T cells. This trial is registered with ChiCTR, number ChiCTR-OPC-16009113. Methods: Between March 10, 2017, and March 27, 2018, 28 patients (including 26 patients with relapsed or refractory MM, 1 patient with Plasma cell leukemia and 1 patient with POEMS) were enrolled and infused with BCMA-CAR T cells. The CAR-BCMA chimeric antigen receptor was encoded by the lentiviral vector and contained a murine anti-BCMA single-chain variable fragment, a CD8a hinge, the CD28 transmembrane regions and intracellular domain and CD3-ζ T-cell activation domain. Peripheral blood mononuclear cells were collected from the patient by leukapheresis, and whole peripheral blood mononuclear cells were cultured and transduced. Patients received a target dose of 5.4 ~ 25.0×106 anti-BCMA CAR T cells per kilogram of body weight after a conditioning chemotherapy regimen of cyclophosphamide and fludarabine. MM response assessment was conducted according to the International Uniform Response Criteria for MM. Cytokine-release syndrome (CRS) was graded as Lee DW et al. described (Current concepts in the diagnosis and management of cytokine release syndrome. Blood. 2014;124(2):188-195.) Results: Twenty-six of 28 treated patients obtained remission. According to the expression rate of BCMA on the surface of plasma cells, all patients were divided into BCMA strong expression group (22 cases, BCMA expression rate ≥ 50%) and BCMA weak expression group (6 cases, BCMA expression rate <50%). The overall response rate for BCMA strong expression group was 87%, with 73% complete response. The overall response rate for the BCMA weak expression group was 100%, with 33% very good partial response or complete response (Figure a-d). The overall survival of the two groups was undefined (a strong group) and 206.5 days (a weak group) respectively (P=0.0468). The median disease-free survival of the two groups was 296 days (strong group, 20 responded cases) and 64 days (weak group,6 cases) respectively (P=0.0069) (Figure e, f). Patients with longer duration have shorter overall survival time. Patients with soft-tissue plasmacytomas have short disease-free survival (155 days vs. 327 days) (Figure g, h). All toxicities were fully reversible, with the most severe being grade 3 cytokine release syndrome that occurred in four of 28 patients. High peak blood CAR+ cell levels were associated with anti-MM responses. Blood CAR-BCMA T cells were predominantly highly differentiated CD8+ T cells after infusion. Conclusions: BCMA-CAR T cell therapy is feasible, safe, and mediates potent anti-tumor activity in relapsed/refractory Multiple Myeloma. All toxicities were reversible Our results should encourage additional development of CAR T-cell therapies for other plasma cell malignancies such as plasma cell leukemia and POEMS. Figure Figure. Disclosures No relevant conflicts of interest to declare.

177 A severe cytokine release syndrome with respiratory failure in recurrent mesothelioma induced by EpCAM CAR-T cells infusion: a case report

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A191-A191
Author(s):  
Sitong Wang ◽  
Juemin Fang ◽  
Hui Wang ◽  
Qing Xu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Pulmonary Edema ◽  
Inflammatory Factors ◽  
Close Monitoring ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Single Chain ◽  
Car T Cells ◽  
Car T

BackgroundWith the development and maturity of chimeric antigen receptor T (CAR-T) cells therapy-related technologies, the application of CAR-T therapy has progressed from blood tumors to solid tumors, and its potential risks and side effects have been more widely recognized. As the most common complication of CAR-T therapy, cytokine release syndrome (CRS) is an inflammatory syndrome caused by the activation and proliferation of T-cell and the increased levels of multiple cytokines. Epithelial cell adhesion molecule (EpCAM) is overexpressed in a variety of tumors and has been used as one of the targets of CAR-T therapy. Case reports of severe CRS due to the use of anti-EpCMA CAR-T cell therapy are very rare.MethodsA 45-year-old malignant mesothelioma woman with EpCAM-positive whose disease progressed after chemotherapy was enrolled into our study (ChiCTR2000030274). The patient received a total of 1.8×107 autologous T cells which contained sequences encoding single-chain variable fragments (scFv) specific for EpCAM after cyclophosphamide lymphodepletion. After the infusion of CAR-T cells, the patient developed typical CRS reactions such as fever, hypoxemia, pulmonary edema, and elevated inflammatory factors. The patient‘s condition did not improve after the use of anti-inflammatory and antipyretic drugs. After administration of tocilizumab (4 mg/kg, day 6 and day 17) combined with glucocorticoid (40 mg q12h, decreasing gradually), the patient‘s general condition gradually improved, and chest computed tomography (CT) showed that pulmonary edema was absorbed.ResultsThe patient‘s CRS was successfully eliminated after the use of IL-6 inhibitor tocilizumab combined with glucocorticoid.ConclusionsAlthough EpCAM CAR-T is safe in general, serious complications still happen possibly requiring close monitoring and timely treatment. Our findings suggest that tocilizumab combined with glucocorticoid can be an effective therapeutic method for severe CRS caused by CAR-T cells therapy in solid tumor.

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

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

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

Myelopathy Due to CAR-T Related Neurotoxicity Treated with Siltuximab

2021 ◽  
pp. 10.1212/CPJ.0000000000001078
Author(s):  
Yasmin Aghajan ◽  
Alison Yu ◽  
Caron A. Jacobson ◽  
Austin I. Kim ◽  
Leslie Kean ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Hematologic Malignancy ◽  
Case Series ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T ◽  
Large Case Series ◽  
Large Case

Chimeric antigen receptor T (CART) cell therapy is highly effective for relapsed/refractory hematologic malignancy [1,2]; however, cytokine release syndrome (CRS) and neurotoxicity are observed in up to 77% of patients [3]. In large case series, the most common presentations of neurotoxicity were encephalopathy (57%), headache (42%), tremor (38%) and aphasia (35%). CART mediated spinal cord toxicity is not well characterized. Structural neurologic damage (stroke and intracranial hemorrhage) was only observed in 1-2% and seizures were seen in 1%-8% of cases [3, 4]. Neuroimaging findings in patients with neurotoxicity are rare and not specific.

The Efficacy of Orgotein in the Treatment of Acute Toxicity Due to Radiotherapy on Head and Neck Tumors

2002 ◽  
Vol 88 (5) ◽  
pp. 385-389 ◽  
Author(s):  
Javier Valencia ◽  
Carmen Velilla ◽  
Angel Urpegui ◽  
Ignacio Alvarez ◽  
M Angeles Llorens ◽  
...  
Keyword(s):  
Acute Toxicity ◽  
Head And Neck ◽  
Overall Response Rate ◽  
Response Rate ◽  
Complete Response ◽  
Tumor Location ◽  
Head And Neck Tumors ◽  
Secondary Effects ◽  
Neck Tumors ◽  
Head And Neck Radiotherapy

Aims and background To assess the efficacy of orgotein in the treatment of acute secondary effects of radiotherapy on head and neck tumors. Material and methods Data were collected on 41 patients who received radiotherapy for tumors of the head and neck. Radiotherapy was the exclusive treatment in 19.5% of cases, with surgery in 24.4%, chemotherapy in 48.8%, and with both in 7.3%. The toxicity requiring use of orgotein was: oropharynx mucositis (26.8%), dysphagia (34.2%), or both (39%), in grade 2 or more according to the RTOG scale. Orgotein (8 mg im) was administered every 48 hrs until radiotherapy was finished. Results The overall response rate was 92.5%; a complete response was obtained in 12 patients (30%) and partial in 25 (62.5%). The reduction in toxicity at the end of radiotherapy was one grade in 18 patients (45%), 2 grades in 16 (40%), 3 in 2 patients (5%), and 4 grades in the only patient with grade 4 acute toxicity. A statistically significant influence was shown in obtaining complete response: laryngeal tumor location (P = 0.037), duration of radiotherapy of more than 53 days (P = 0.002), discontinuation for non-toxic reasons (P = 0.008). Conclusions We consider that orgotein is highly effective in dealing with acute secondary effects of radiotherapy on the head and neck area.

scholarly journals Phase 1/2a study of 177Lu-lilotomab satetraxetan in relapsed/refractory indolent non-Hodgkin lymphoma

2020 ◽  
Vol 4 (17) ◽  
pp. 4091-4101
Author(s):  
Arne Kolstad ◽  
Tim Illidge ◽  
Nils Bolstad ◽  
Signe Spetalen ◽  
Ulf Madsbu ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Overall Response Rate ◽  
Response Rate ◽  
Phase 1 ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
Hematologic Toxicity ◽  
Overall Response ◽  
Non Hodgkin Lymphoma ◽  
Anti Cd20

Abstract For patients with indolent non-Hodgkin lymphoma who fail initial anti-CD20–based immunochemotherapy or develop relapsed or refractory disease, there remains a significant unmet clinical need for new therapeutic approaches to improve outcomes and quality of life. 177Lu-lilotomab satetraxetan is a next-generation single-dose CD37-directed radioimmunotherapy (RIT) which was investigated in a phase 1/2a study in 74 patients with relapsed/refractory indolent non-Hodgkin B-cell lymphoma, including 57 patients with follicular lymphoma (FL). To improve targeting of 177Lu-lilotomab satetraxetan to tumor tissue and decrease hematologic toxicity, its administration was preceded by the anti-CD20 monoclonal antibody rituximab and the “cold” anti-CD37 antibody lilotomab. The most common adverse events (AEs) were reversible grade 3/4 neutropenia (31.6%) and thrombocytopenia (26.3%) with neutrophil and platelet count nadirs 5 to 7 weeks after RIT. The most frequent nonhematologic AE was grade 1/2 nausea (15.8%). With a single administration, the overall response rate was 61% (65% in patients with FL), including 30% complete responses. For FL with ≥2 prior therapies (n = 37), the overall response rate was 70%, including 32% complete responses. For patients with rituximab-refractory FL ≥2 prior therapies (n = 21), the overall response rate was 67%, and the complete response rate was 24%. The overall median duration of response was 13.6 months (32.0 months for patients with a complete response). 177Lu-lilotomab satetraxetan may provide a valuable alternative treatment approach in relapsed/refractory non-Hodgkin lymphoma, particularly in patients with comorbidities unsuitable for more intensive approaches. This trial was registered at www.clinicaltrials.gov as #NCT01796171.

scholarly journals Cytokine release syndrome and neurological event costs in lisocabtagene maraleucel–treated patients in the TRANSCEND NHL 001 trial

2021 ◽  
Vol 5 (6) ◽  
pp. 1695-1705
Author(s):  
Jeremy S. Abramson ◽  
Tanya Siddiqi ◽  
Jacob Garcia ◽  
Christine Dehner ◽  
Yeonhee Kim ◽  
...  
Keyword(s):  
Health Care ◽  
T Cell ◽  
B Cell Lymphoma ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
System Perspective ◽  
Cell Therapies ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

Abstract Chimeric antigen receptor (CAR) T-cell therapies have demonstrated high response rates in patients with relapsed/refractory large B-cell lymphoma (LBCL); however, these therapies are associated with 2 CAR T cell–specific potentially severe adverse events (AEs): cytokine release syndrome (CRS) and neurological events (NEs). This study estimated the management costs associated with CRS/NEs among patients with relapsed/refractory LBCL using data from the pivotal TRANSCEND NHL 001 trial of lisocabtagene maraleucel, an investigational CD19-directed defined composition CAR T-cell product with a 4-1BB costimulation domain administered at equal target doses of CD8+ and CD4+ CAR+ T cells. This retrospective analysis of patients from TRANSCEND with prospectively identified CRS and/or NE episodes examined relevant trial-observed health care resource utilization (HCRU) associated with toxicity management based on the severity of the event from the health care system perspective. Cost estimates for this analysis were taken from publicly available databases and published literature. Of 268 treated patients as of April 2019, 127 (47.4%) experienced all-grade CRS and/or NEs, which were predominantly grade ≤2 (77.2%). Median total AE management costs ranged from $1930 (grade 1 NE) to $177 343 (concurrent grade ≥3 CRS and NE). Key drivers of cost were facility expenses, including intensive care unit and other inpatient hospitalization lengths of stay. HCRU and costs were significantly greater among patients with grade ≥3 AEs (22.8%). Therefore, CAR T-cell therapies with a low incidence of severe CRS/NEs will likely reduce HCRU and costs associated with managing patients receiving CAR T-cell therapy. This clinical trial was registered at www.clinicaltrials.gov as #NCT02631044.

scholarly journals Cytokine Release Syndrome Is an Independent Risk Factor Associated With Platelet Transfusion Refractoriness After CAR-T Therapy for Relapsed/Refractory Acute Lymphoblastic Leukemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Yadan Liu ◽  
Bin Liang ◽  
Yan Liu ◽  
Guoqing Wei ◽  
Wenjun Wu ◽  
...  
Keyword(s):  
Risk Factor ◽  
Acute Lymphoblastic Leukemia ◽  
Platelet Transfusion ◽  
Independent Risk Factor ◽  
Lymphoblastic Leukemia ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T ◽  
Grade 3 ◽  
Platelet Transfusions

Background: Chimeric antigen receptor T cell (CAR-T) therapy is successful in improving treatment outcomes for relapsed/refractory acute lymphoblastic leukemia (R/R ALL). However, toxicities associated with CAR-T therapy are being increasingly identified. Pancytopenia is one of the most common complications after CAR-T therapy, and platelet transfusions are an essential part of its supportive care.Study Design and Methods: This study aimed to assess the effectiveness of platelet transfusions for R/R ALL patients at our single center and identify associated risk factors. Overall, 44 R/R ALL patients were enrolled in this study, of whom 26 received CAR-T therapy and 18 received salvage chemotherapy.Result: Patients in the CAR-T group had a higher incidence of platelet transfusion refractoriness (PTR) (15/26, 57.7%) than those in the chemotherapy group (3/18, 16.7%) (p = 0.007). For patients receiving CAR-T therapy, multivariate analysis showed that the grade of cytokine release syndrome (CRS) was the only independent risk factor associated with PTR (p = 0.007). Moreover, higher peak serum IL-6 and IFN-γ levels suggested a higher risk of PTR (p = 0.024 and 0.009, respectively). Patients with PTR received more platelet infusion doses than those without PTR (p = 0.0426). Patients with PTR had more grade 3–4 bleeding events than those without PTR (21.4 vs. 0%, p = 0.230), and the cumulative incidence of grade 3–4 bleeding event was different (p = 0.023).Conclusion: We found for the first time that PTR is associated with the CRS grade. Improved knowledge on the mechanisms of PTR after CAR-T therapy is needed to design a rational therapeutic strategy that aims to improve the efficiency of transfusions.

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