scholarly journals CRISPR-edited CART with GM-CSF knockout and auto secretion of IL6 and IL1 blockers in patients with hematologic malignancy

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Yan Yi ◽  
Xiaoshan Chai ◽  
Liping Zheng ◽  
Yongjing Zhang ◽  
Jiankai Shen ◽  
...  
Keyword(s):  
Hematologic Malignancy ◽  
Complete Response ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Gm Csf ◽  
Non Hodgkin Lymphoma ◽  
Low Levels ◽  
Multiple Myelomas ◽  
Initial Results

AbstractRevolutionary CART therapy still faces the challenge of severe cytokine release syndrome (CRS). While IL6 and IL1 have been demonstrated as essential contributors, GM-CSF is one of the most abundant inflammatory cytokines secreted by CART and has also been suggested in contributing to CRS. To minimize GM-CSF production from CART to reduce its associated toxicity, we conducted a pilot study (ChiCTR2000032124) of CRISPR-edited GM-CSF knockout (KO) in CART secreting anti-IL6 scFv and IL1RA, with additional TCR KO for tracing edited CART. The initial results of three patients (1 Non-Hodgkin lymphoma (NHL) and 2 multiple myelomas (MMs)) are summarized as: 3/3 complete response, 2/3 none CRS, 1/3 grade 2 CRS, and 0/3 neurotoxicity. The analysis revealed low levels of GM-CSF, IL6 and IL1B at the time of interferon-gamma (IFNG) peaks, and elevated IL1RA. We also observed significant expansion of CD3– CART during treatment and no aberrant expansion of CD3– CART in the follow-up. Re-expansion of CD3– CART was observed in two patients while recurring CD19+ cells were eradicated in the patient with NHL. In summary, our study supported the safety and durable potency of CRISPR-edited CART in patients, providing a novel platform for developing autologous or allogeneic CART to minimize GM-CSF-associated toxicity in addition to autonomous IL6/IL1 blockade.

Autologous-collected anti-CD19 chimeric antigen receptor T cells (19CARTs) for pediatric acute lymphocytic leukemia (ALL) and non-Hodgkin lymphoma (NHL): Clinical activity and cytokine release without graft versus host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (HSCT).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 10008-10008
Author(s):  
Daniel Warnell Lee ◽  
Nirali Shah ◽  
Maryalice Stetler-Stevenson ◽  
Marianna Sabatino ◽  
Kelly Richards ◽  
...  
Keyword(s):  
T Cells ◽  
Complete Response ◽  
Lymphocytic Leukemia ◽  
Transduction Efficiency ◽  
Clinical Activity ◽  
Cytokine Release ◽  
Hematopoietic Stem ◽  
Gm Csf ◽  
Reactive Protein ◽  
Non Hodgkin Lymphoma

10008 Background: Despite intensive chemotherapy and HSCT, outcomes in relapsed/refractory pediatric B cell ALL and NHL are poor. To treat children with or without prior allogeneic-HSCT and quickly deliver therapy, we developed a Phase I trial of 19CARTs for both HSCT-naive and post-allo-HSCT patients where autologous-collected T cells are manufactured in 11 days. Methods: T cells collected on Day -11 by lymphopheresis were positively selected and activated using anti-CD3/CD28 beads then transduced with the CD19-CAR gene via retrovirus. Cells were infused after 7 additional days of expansion. Patients (Pt) received fludarabine and cyclophosphamide prior to receiving 1e6 19CARTs/kg. Results: A 59-65 fold expansion of 19CARTs with 39-65% transduction efficiency was achieved in Pt 1 and 3 (ALL, NHL). Pt 1 achieved a complete response (CR). Mild cytokine release syndrome was observed (Gr 3 fever, Gr 2 hypotension) correlating with mild elevation in IL6, GM-CSF, INFg and C reactive protein (CRP; Table). No other non-hematologic, CAR-related Gr ≥3 toxicities were observed. Pt 2 (ALL) received 2.8% of the targeted cell dose due to lack of cell expansion likely from recent prior chemotherapy but experienced a transient CR with significant 19CART expansion (15% blood, 5% marrow, 6% CSF). Importantly, 19CARTs were well tolerated without evidence of GVHD in these post-allo HSCT patients. Conclusions: Autologous-collected allogeneic derived 19CART cells can be rapidly manufactured and safely administered to children with ALL and NHL. Clinical activity can be achieved without GVHD despite inflammatory cytokine generation. 19CARTs offer a potentially effective strategy to treat post-HSCT relapse warranting further study. Clinical trial information: NCT01593696. [Table: see text]

Evaluation of R-CHOP and R-CVP in the treatment of elderly patient with non-Hodgkin lymphoma

MedPharmRes ◽  
2019 ◽  
Vol 3 (3) ◽  
pp. 1-6
Author(s):  
Truc Phan ◽  
Tram Huynh ◽  
Tuan Q. Tran ◽  
Dung Co ◽  
Khoi M. Tran
Keyword(s):  
Elderly Patients ◽  
Hodgkin Lymphoma ◽  
B Cell Lymphoma ◽  
Complete Response ◽  
The Elderly ◽  
Free Survival ◽  
Non Hodgkin Lymphoma ◽  
Common Sign ◽  
Related Mortality

Introduction: Little information is available on the outcomes of R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine and prednisone) and R-CVP (rituximab with cyclophosphamide, vincristine and prednisone) in treatment of the elderly patients with non-Hodgkin lymphoma (NHL), especially in Vietnam. Material and methods: All patients were newly diagnosed with CD20-positive non-Hodgkin lymphoma (NHL) at Blood Transfusion and Hematology Hospital, Ho Chi Minh city (BTH) between 01/2013 and 01/2018 who were age 60 years or older at diagnosis. A retrospective analysis of these patients was perfomed. Results: Twenty-one Vietnamese patients (6 males and 15 females) were identified and the median age was 68.9 (range 60-80). Most of patients have comorbidities and intermediate-risk. The most common sign was lymphadenopathy (over 95%). The proportion of diffuse large B cell lymphoma (DLBCL) was highest (71%). The percentage of patients reaching complete response (CR) after six cycle of chemotherapy was 76.2%. The median follow-up was 26 months, event-free survival (EFS) was 60% and overall survival (OS) was 75%. Adverse effects of rituximab were unremarkable, treatment-related mortality accounted for less than 10%. There was no difference in drug toxicity between two regimens. Conclusions: R-CHOP, R-CVP yielded a good result and acceptable toxicity in treatment of elderly patients with non-Hodgkin lymphoma. In patients with known cardiac history, omission of anthracyclines is reasonable and R-CVP provides a competitive complete response rate.

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.

Managing Cytokine Release Syndrome and Neurotoxicity with Step-Up Dosing of Mosunetuzumab in Relapsed/Refractory B-Cell Non-Hodgkin Lymphoma

2019 ◽  
Vol 19 ◽  
pp. S247
Author(s):  
Nancy L. Bartlett ◽  
Laurie H. Sehn ◽  
Sarit Assouline ◽  
Francesc Bosch ◽  
Catherine M. Diefenbach ◽  
...  
Keyword(s):  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Non Hodgkin Lymphoma

scholarly journals The model of cytokine release syndrome in CAR T-cell treatment for B-cell non-Hodgkin lymphoma

2020 ◽  
Vol 5 (1) ◽  
Author(s):  
Jianshu Wei ◽  
Yang Liu ◽  
Chunmeng Wang ◽  
Yajing Zhang ◽  
Chuan Tong ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Car T Cell ◽  
Non Hodgkin Lymphoma ◽  
Car T

Anti-GD2 monoclonal antibody 3F8 plus granulocyte-macrophage colony-stimulating factor (GM-CSF) for primary refractory neuroblastoma (NB) in bone marrow (BM)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9502-9502 ◽  
Author(s):  
B. H. Kushner ◽  
K. Kramer ◽  
S. Modak ◽  
N. V. Cheung
Keyword(s):  
Complete Response ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Post Transplant ◽  
Gm Csf ◽  
Group 3 ◽  
Macrophage Colony Stimulating Factor ◽  
Group 2 ◽  
Macrophage Colony

9502 Background: Despite high-dose chemotherapy, NB in BM often persists and forebodes death. Methods: 3F8/GM- CSF was used in 63 patients (pts) with NB in BM by morphology and/or metaiodobenzylguanidine (MIBG) scan, no prior progressive disease or immunotherapy, and no soft tissue NB; 35 (56%) of the pts had received second-line therapy and 24 (38%) were post-transplant. Treatment was repeated if human anti-mouse antibody (HAMA) titer was low. Results: Of 30 pts with NB in BM but normal MIBG scans (Group 1), 25 (83%) had complete response (CR) after cycle 1 (n=17), cycle 2 (n=5), or cycle 3, 6, or 7 (one pt each), including 13/16 post-transplant pts. Among 15 pts with NB in BM and abnormal MIBG scans (Group 2), 12 (80%) had CR in BM after cycle 1 (n=5), cycle 2 (n=4), cycle 4 (n=2), or cycle 9 (n=1); MIBG scans normalized in 5/11 pts who had multiple abnormal MIBG(+) sites and in 4/4 pts who had one abnormal MIBG(+) site (irradiated in three pts). Of 18 pts who had abnormal MIBG scans but no NB seen in BM tests (Group 3), 14 (78%) had CR or near CR, including eight whose MIBG(+) sites were irradiated. Early HAMA limited treatment in 19 pts, but was prevented by high-dose cyclophosphamide. CR continues in 12 pts (five never transplanted) with long follow-up (20+ -to- 146+ months) and in 10 pts with short follow-up. The only common toxicities of this outpatient treatment were pain and hives; there were no long-term toxicities. Conclusions: 3F8/GM-CSF is well tolerated, achieves a high CR rate against primary refractory NB in BM (including post-transplant), and may prolong disease control in non- transplanted pts. Further experience will show whether it ought to be used for consolidative therapy in place of myeloablative cytoreduction. No significant financial relationships to disclose.

First-line treatment of iNHL or MCL patients with BR or R-CHOP/R-CVP: Results of the BRIGHT 5-year follow-up study.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 7500-7500 ◽  
Author(s):  
Ian Flinn ◽  
Richard van der Jagt ◽  
Julie E. Chang ◽  
Peter Wood ◽  
Tim E. Hawkins ◽  
...  
Keyword(s):  
Progression Free Survival ◽  
Complete Response ◽  
Rank Test ◽  
First Line ◽  
Open Label ◽  
Free Survival ◽  
Non Hodgkin Lymphoma ◽  
Duration Of Response ◽  
Treatment Naïve

7500 Background: BRIGHT, a phase 3, open-label, noninferiority study comparing efficacy and safety of bendamustine plus rituximab (BR) vs rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) or rituximab with cyclophosphamide, vincristine and prednisone (R-CVP) in treatment-naive patients (pts) with indolent non-Hodgkin lymphoma (iNHL) or mantle cell lymphoma (MCL), showed that the complete response rate for first-line BR was statistically noninferior to R-CHOP/R-CVP ( Blood 2014). Pts were monitored for ≥5 years (yr) to assess the overall effect of BR or R-CHOP/R-CVP in a controlled clinical setting. This analysis reports the time-to-event variables of the 5-yr follow-up (FU) study. Methods: Pts with iNHL or MCL randomized to 6-8 cycles of BR or R-CHOP/R-CVP underwent complete assessments at end of treatment, then were monitored regularly. Progression-free survival (PFS), event-free survival (EFS), duration of response (DOR) and overall survival (OS) were compared using a stratified log-rank test. Results: Of 447 randomized pts, 224 received BR, 104 R-CHOP, and 119 R-CVP; 419 entered the FU. The median FU time was 65.0 and 64.1 months for BR and R-CHOP/R-CVP, respectively. The 5-yr PFS rate was 65.5% (95% CI 58.5-71.6) and 55.8% (48.4-62.5), and OS was 81.7% (75.7-86.3) and 85% (79.3-89.3) for BR and R-CHOP/R-CVP, respectively. The hazard ratio (95% CI) for PFS was 0.61 (0.45-0.85; P= .0025), EFS 0.63 (0.46-0.84; P= .0020), DOR 0.66 (0.47-0.92; P= .0134), and OS 1.15 (0.72-1.84; P= .5461) comparing BR vs R-CHOP/R-CVP. Similar results were found in iNHL [PFS 0.70 (0.49-1.01; P= .0582)] and MCL [PFS 0.40 (0.21-0.75; P= .0035)], with the strongest effect in MCL. Use of R maintenance was similar, 43% in BR and 45% in R-CHOP/R-CVP. B was included as second-line in 27 (36%) of the 75 pts requiring therapy who originally received R-CHOP/R-CVP. Comparable safety profiles with expected adverse events were observed in the FU study in BR vs R-CHOP/R-CVP. Conclusions: The long-term FU of the BRIGHT study has confirmed that PFS, EFS, and DOR were significantly better for BR, and OS was not statistically different between BR and R-CHOP/R-CVP. The safety profile was as previously reported. Clinical trial information: NCT00877006.

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