scholarly journals CD19-CAR T Cells Treatment for Minimal Residual Disease in B-Cell Lymphoma with a Higher Response Rate and Fewer Adverse Reactions

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3714-3714
Author(s):  
Xia Xiao ◽  
Yanyu Jiang ◽  
Xiaoyuan He ◽  
Xin Jin ◽  
Cao Yaqing ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Response Rate ◽  
Residual Disease ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Car T Cells ◽  
Car T ◽  
Minimal Residual

Abstract Background: Chimeric antigen receptor modified T cells directed against CD19 (CART19) has demonstrated efficacy in relapsed or refractory (r/r) B-cell lymphoma with durable complete remissions (CR). However, there are some patients with minimal residual disease (MRD) also need attention. Persistence or reappearance of minimal residual disease (MRD) after chemotherapy always results in relapse. MRD is an indicator of resistance to chemotherapy. Based on these considerations, a clinical retrospective trials with control and without random study (ChiCTR-ONN-16008911) was conducted to determine the efficacy and safety of CD19-CAR-T cells in MRD positive B-cell lymphoma patients, which is devoted to reduce the risk of recurrence. This paper will discuss the difference of efficacy and safety between minimal residual disease or partial remission and relapsed or refractory patients. The structural features of our CAR-T products include anti-CD19 scFv, a transmembrane domain, and a 4-1BB/CD3ζsignaling domain. Patients and Methods: This study enrolled B cell lymphoma in two cohorts. Cohort1 includes 10 patients with MRD persistence or reappearance after induction and consolidation therapy or patients acquired partial remission(PR). Cohort2 includes 12 patients with relapsed or refractory (r/r) B-cell lymphoma were included. We used autologous T cells expressing a CD19-CAR T cells to treat these patients. Patients were monitored for response to treatment, toxic effects, the expansion and persistence of CD19-CAR T cells. Results: 1. A total of 22 patients with B-cell lymphoma received CD19-CAR T cells, the median dose of CAR-T cells was 5.2×106/kg (2.0~10.0×106/kg). The infusions were safe, and no dose-limiting toxicities occurred. 2.The cohort1 overall response rate was 100%. Complete remission occurred in 8 of 10 patients (80%). The other 2patients with DLBCL were stable after CAR T cells treatment. The cohort2 overall response rate was 75%(9/12). Complete remission occurred in 2 of 12 patients (17%),partial remission occurredin 5 of 12 patients (42%).And another 2 patients got stable disease. 3. CD19-CAR T cells proliferated in vivo and were detectable in the blood of patients. The cohort1 and cohort2 peak time of CAR T cells proliferated was 12(5~19) days and 4.5(1~12) days after treatment respectively. And among peripheral blood cells, CAR-T cells accounted for 10.10% (3.55% ~24.74%)and 4.02% (2.23%~28.60%) of T lymphocytes respectively. 4. The cohort1 patients achieved sustained remissions, and at a median follow-up of 10 months(3 ~18 months). None of all the patients relapsed and the median follow-up time was 10 months (3~18 months). However, 9 of the cohort2 patients who had a response maintain a good condition for 40-90 days. Except for one patient with following hematopoietic stem cell transplantation, the remaining patients developed disease progression in different degrees. 5. Cytokine-release syndrome(CRS) occurred in all patients, which in cohort1 were grade 1-2 CRS and in cohort 2 has one patient developed a grade 3 CRS. Conclusions: CAR-T cell therapy not only plays a role in the rescue treatment of relapsed and refractory patients, but also has a surprising effect in the consolidation and maintenance of B-cell lymphoma, and it is expected to become a treatment that benefits more patients.CD19-CAR T cells might be more effective in the treatment of MRD+/PR B-cell lymphoma patients than in the refractory or relapse patients. High response rate were observed, with fewer adverse reactions. CAR T treatment in MRD-positive B-cells lymphoma patients may be a therapeutic option to put off the progression to relapse and refractory lymphoma. Disclosures No relevant conflicts of interest to declare.

Chimeric Antigen Receptor-Engineered T-Cells - A New Way and Era for Lymphoma Treatment

2020 ◽  
Vol 14 (4) ◽  
pp. 312-323
Author(s):  
Romeo G. Mihăilă
Keyword(s):  
T Cells ◽  
T Cell ◽  
Response Rate ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Car T Cells ◽  
Future Developments ◽  
Car T Cell ◽  
Large B Cell Lymphoma ◽  
Car T

Background: Patients with refractory or relapsed diffuse large B-cell lymphoma have a poor prognosis with the current standard of care. Objective: Chimeric Antigen Receptor T-cells (CAR T-cells) are functionally reprogrammed lymphocytes, which are able to recognize and kill tumor cells. The aim of this study is to make progress in this area. Method: A mini-review was achieved using the articles published in Web of Science and PubMed in the last year and the new patents were made in this field. Results: The responses to CAR T-cell products axicabtagene ciloleucel and tisagenlecleucel are promising; the objective response rate can reach up to 83%, and the complete response rate ranges between 40 and 58%. About half of the patients may have serious side effects, such as cytokine release syndrome and neurotoxicity. Current and future developments include the improvement of CAR T-cell expansion and polyfunctionality, the combined use of CAR T-cells with a fusion protein between interferon and an anti-CD20 monoclonal antibody, with checkpoint inhibitors or small molecule sensitizers that have apoptotic-regulatory effects. Furthermore, the use of IL-12-expressing CAR T-cells, an improved technology for the production of CAR T-cells based on targeted nucleases, the widespread use of allogeneic CAR T-cells or universal CAR T-cells obtained from genetically engineered healthy donor T-cells are future developments actively considered. Conclusion: CAR T-cell therapy significantly improved the outcome of patients with relapsed or refractory diffuse large B-cell lymphoma. The advances in CAR T-cells production technology will improve the results and enable the expansion of this new immunotherapy.

scholarly journals Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE)

BMJ Open ◽  
2020 ◽  
Vol 10 (2) ◽  
pp. e034629 ◽  
Author(s):  
Philip George ◽  
Nathaniel Dasyam ◽  
Giulia Giunti ◽  
Brigitta Mester ◽  
Evelyn Bauer ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
B Cell ◽  
Chimeric Antigen Receptor ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Third Generation ◽  
Car T Cells ◽  
Car T

IntroductionAutologous T-cells transduced to express a chimeric antigen receptor (CAR) directed against CD19 elicit high response rates in relapsed or refractory (r/r) B-cell non-Hodgkin lymphoma (B-NHL). However, r/r B-NHL remissions are durable in fewer than half of recipients of second-generation CAR T-cells. Third-generation (3G) CARs employ two costimulatory domains, resulting in improved CAR T-cell efficacy in vitro and in animal models in vivo. This investigator-initiated, phase I dose escalation trial, termed ENABLE, will investigate the safety and preliminary efficacy of WZTL-002, comprising autologous T-cells expressing a 3G anti-CD19 CAR incorporating the intracellular signalling domains of CD28 and Toll-like receptor 2 (TLR2) for the treatment of r/r B-NHL.Methods and analysisEligible participants will be adults with r/r B-NHL including diffuse large B-cell lymphoma and its variants, follicular lymphoma, transformed follicular lymphoma and mantle cell lymphoma. Participants must have satisfactory organ function, and lack other curative options. Autologous T-cells will be obtained by leukapheresis. Following WZTL-002 manufacture and product release, participants will receive lymphodepleting chemotherapy comprising intravenous fludarabine and cyclophosphamide. A single dose of WZTL-002 will be administered intravenously 2 days later. Targeted assessments for cytokine release syndrome and immune cell effector-associated neurotoxicity syndrome, graded by the American Society Transplantation and Cellular Therapy criteria, will be made. A modified 3+3 dose escalation scheme is planned starting at 5×104 CAR T-cells/kg with a maximum dose of 1×106 CAR T-cells/kg. The primary outcome of this trial is safety of WZTL-002. Secondary outcomes include feasibility of WZTL-002 manufacture and preliminary measures of efficacy.Ethics and disseminationEthical approval for the study was granted by the New Zealand Health and Disability Ethics Committee (reference 19/STH/69) on 23 June 2019 for Protocol V.1.2. Trial results will be reported in a peer-reviewed journal, and results presented at scientific conferences or meetings.Trial registration numberNCT04049513

G-CSF does not worsen toxicities and efficacy of CAR-T cells in refractory/relapsed B-cell lymphoma

2020 ◽  
Vol 55 (12) ◽  
pp. 2347-2349
Author(s):  
Eugenio Galli ◽  
Vincent Allain ◽  
Roberta Di Blasi ◽  
Sophie Bernard ◽  
Laetitia Vercellino ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Car T Cells ◽  
Car T

Direct Comparison of In Vivo Fate of Second and Third-Generation CD19-Specific Chimeric Antigen Receptor (CAR)-T Cells in Patients with B-Cell Lymphoma: Reversal of Toxicity from Tonic Signaling

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1851-1851 ◽  
Author(s):  
Diogo Gomes da Silva ◽  
Malini Mukherjee ◽  
Madhuwanti Srinivasan ◽  
Olga Dakhova ◽  
Hao Liu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
2Nd Generation ◽  
Car T Cells ◽  
Car T ◽  
Equity Ownership

Abstract Although adoptive transfer of T cells with second-generation CD19-specific CARs containing CD28 or 4-1BB costimulatory endodomains shows remarkable clinical efficacy against B cell malignancies, the optimal choice of costimulatory domains in these and other CARs remains controversial. Depending on the precise CAR structure and specificity, individual endodomains may be associated with deleterious ligand-independent tonic signaling in the transduced T cell. Long et al. (Nat Med 2015) established the CD28 co-stimulatory endodomain can have a toxic tonic signaling effect, but it is unclear if tonic 4-1BB signaling may have deleterious consequences as well, and if such effects can be reversed. We therefore modeled tonic CAR signaling in T cells by transducing them with gammaretroviral vectors expressing 2nd-generation CD19.CAR constructs containing either the CD28 or 4-1BB costimulatory endodomain (in addition to the CD3-ζ chain endodomain). Compared to CAR-T cells with the CD28 endodomain alone, those with 4-1BB alone expanded 70% more slowly following transduction. Impaired expansion of 4-1BB CD19.CAR-T cells was coupled with a 4-fold increase in apoptosis and a gradual downregulation of CAR expression, and was a consequence of 4-1BB-associated tonic TRAF2-dependent signaling, leading to activation of NF-κB, upregulation of Fas and augmented Fas-dependent activation-induced T cell death (AICD). Moreover, expression of 4-1BB CAR from a gammaretroviral vector increased tonic signaling through a self-amplifying/positive feedback effect on the retroviral LTR promoter. Because of the toxicity of 4-1BB in our gammaretroviral CAR.CD19 construct (manifest by delayed expansion and increased apoptosis) we could not directly compare the in vivo fate of T cells expressing CAR.CD19 4-1BB with that of co-administered CAR.CD19 CD28 T cells in patients with lymphoma. We found, however, that the adverse effects of tonic 4-1BB costimulation could be overcome in a 3rd-generation CAR.CD19 vector, containing both CD28 and 4-1BB costimulatory molecules in tandem. We thus compared the fate of a 3rd-generation vector containing both CD28 and 4-1BB costimulatory domains with that of a 2nd-generation vector containing CD28 alone. Six patients with refractory/relapsed diffuse large B-cell lymphoma received 2 cell populations, one expressing 2nd and one expressing 3rd generation vectors. To determine whether CD28 alone was optimal (which would suggest 4-1BB is antagonistic) or whether 4-1BB had an additive or synergistic effect contributing to superior persistence and expansion of the CD28-41BB combination, patients were simultaneously infused with 1-20×106 of both 2nd and 3rd generation CAR+ T cells/m2 48-72 hours after lymphodepletion with cyclophosphamide (500 mg/m2/d) and fludarabine (30 mg/m2/d) × 3. Persistence of infused T cells was assessed in blood by CD19.CAR qPCR assays specific for each CAR. Molecular signals peaked approximately 2 weeks post infusion, remaining detectable for up to 6 months. The 3rd-generation CAR-T cells had a mean 23-fold (range 1.1 to 109-fold) higher expansion than 2nd-generation CAR-T cells and correspondingly longer persistence. Two patients had grade 2 cytokine release syndrome, with elevation of proinflammatory cytokines, including IL-6, at the time of peak expansion of T cells. Of the 5 patients evaluable for response, 2 entered complete remission (the longest ongoing for 9 months), 1 has had continued complete remission after autologous stem cell transplantation, 1 had a partial response, and 1 progressed. In conclusion, our data indicate that infusion of T cells carrying a CD19.CAR containing CD28 and 4-1BB endodomains is safe and can have efficacy at every dose level tested. Additionally, in a side-by-side comparison, the 3rdgeneration vector produced greater in vivo expansion and persistence than an otherwise identical CAR-T cell population with CD28 alone. Disclosures Rooney: Cell Medica: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Viracyte: Equity Ownership. Heslop:Celgene: Patents & Royalties, Research Funding; Chimerix: Other: Endpoint adjudication committee; Viracyte: Equity Ownership; Cell Medica: Patents & Royalties: Licensing agreement EBV-specific T cells.

scholarly journals HashClone: a new tool to quantify the minimal residual disease in B-cell lymphoma from deep sequencing data

2017 ◽  
Vol 18 (1) ◽  
Author(s):  
Marco Beccuti ◽  
Elisa Genuardi ◽  
Greta Romano ◽  
Luigia Monitillo ◽  
Daniela Barbero ◽  
...  
Keyword(s):  
B Cell ◽  
Minimal Residual Disease ◽  
Deep Sequencing ◽  
Residual Disease ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Sequencing Data ◽  
Deep Sequencing Data ◽  
Minimal Residual
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