scholarly journals CD20-Specific Chimeric Antigen Receptor-Expressing T Cells As Salvage Therapy in Rituximab-Refractory CD20(+) B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2845-2845
Author(s):  
Xin Li ◽  
Qian Cheng ◽  
Rui Liu ◽  
Liqing Kang ◽  
Nan Xu ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Median Time ◽  
Salvage Therapy ◽  
Car T Cells ◽  
Non Hodgkin Lymphoma ◽  
Car T ◽  
Cd20 Antibody

Abstract Background: CD20 antibody-based chemotherapy has been verified as a valid strategy and prolonged the overall survival (OS) of CD20(+) B-cell Non-Hodgkin Lymphoma (B-NHL) patients. However, over 40% of these patients finally would be relapsed or refractory(R/R) to CD20 antibody rituximab. Treatment of these R/R B-NHL patients has not been standardized yet. Furthermore, it is still a question that whether CD20-specific CAR T-cells could provide an alternative therapy in rituximab-relapsed/refractory B-NHL patients. Methods: Here, we conducted a prospective single-center study on patients with relapsed/refractory to CD20 antibody(No.ChiCTR2000036350). The aim of this study aims was to evaluate the efficacy and in vivo persistence of CART-20 cells in subjects with rituximab R/R CD20(+) B-NHL patients. Between October 2017 to December 2020, 15 patients with R/R B-NHL patients (including 14 DLBCL patents and 1 MCL patient) received anti-CD20 specific CAR T cell therapy. The efficacy of CAR T-cells therapy was evaluated at different assessment points by CT scan or 18FDG-PET. CAR-T expansion in blood was monitored regularly by real-time quantitative PCR (qPCR). Results: In this study, the clinical characteristic of these enrolled patients was a median age at 48 years (range 30 to 66), male n=7(47%). 10 (67%) patients were relapsed and 5 patients (33%) were refractory to rituximab-based chemotherapy.(Table 1) All of these patients were at advanced stage III/IV and 7 (47%) of them were diagnosed with bulky disease. The median time from latest rituximab utilization is 70 days (rang 31-471 days) before CAR T-20 cells infusion. The median number of lines of previous treatments was 4 (2-8). 14 patients (93%) received CAR T-20 with a dose of 1*10^7/kg, the median follow-up time for patients was 219 days (32 to 1231). CRS (100%) was observed in all 15 infusion patients: 11 patients grade I-II and 4 patients' grade ≥III. ICANS was recorded only in 1 patient (grade I). At 30 days after the infusion, the clinical response of all 15 infusion patients could be assessed: 4 (27%) CR, 11 (73%) PR, and ORR 100%.(Figure 1) 5 patients who were in PR at 30 days converted to CR, with a median time of 116 (6-858), and continued follow-up without relapse; 6 patients (40%) had relapse, with a median relapse time of 136 days (48- 1050), this might be related to the short time of rituximab before the CAR-T infusion.Although the cases are limited, we can still draw a preliminary conclusion that the use of rituximab within three months may not affect the efficacy of CD20-CAR-T, but may lead to early recurrence. Furthermore, the persistence time of CART-20 cells were comparably longer than that CART-19 cell infusions. Conclusions: In conclusion，these findings suggest that the use of CAR T-20 can be served as a salvage therapy in Rituximab-refractory CD20(+) B-cell Non-Hodgkin Lymphoma and raises the possibility of using CAR T-20 in an early disease stage. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Efficacy and Safety of JWCAR029 in Adult Patients with Relapsed and Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4187-4187 ◽  
Author(s):  
Zixun Yan ◽  
Wen Wang ◽  
Zhong Zheng ◽  
Ming Hao ◽  
Su Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Dose Level ◽  
Car T Cells ◽  
Car T Cell ◽  
Non Hodgkin Lymphoma ◽  
Car T

Abstract Introduction JWCAR029 is a novel CD19-directed 4-1BB stimulated chimeric antigen receptor T (CAR-T) cell type, which is different from JWCAR017 with independent production of CD4 and CD8 T cells and transfusion in non-fixed ratio. We conducted a single arm, open-label, dose escalation Phase I trial of JWCAR029 in relapsed and refractory B-cell non-Hodgkin lymphoma (NCT03355859). Methods From January to July 2018, 10 patients have been enrolled in this trial, including eight diffused large B cell lymphoma (DLBCL) and two MALT lymphoma, with median age of 47 years (range 32 to 59 years). All the patients received immunochemotherapy as induction and more than two lines of salvage treatment. Two patients received bridging chemotherapy after T-cell collection due to rapid tumor progression, followed by re-evaluation before CAR-T cell infusion. Lymphodepletion preconditioning was accomplished by fludarabine 25mg/m2/d and cyclophosphamide 250mg/m2/d on Day-4 to D-2, followed by CAR-T cell infusion on Day0. JWCAR029 was administrated as a single infusion in escalation dose levels, from 2.5×107 CAR-T cells (dose level 1, DL1) to 5.0×107 CAR-T cells (dose level 2, DL2) and to 1.0×108 CAR-T cells (dose level 3, DL3) according to mTPI-2 algorithm. Circulating blood count, serum biochemistry, and coagulation status were follow-up after infusion. Cytokines were assessed on a Luminex platform. Tumor evaluation was performed on Day 29 by PET-CT. PK data were detected by flow cytometry and real-time quantitative polymerase chain reaction system. All the adverse events were recorded. The study was approved by the Shanghai Rui Jin Hospital Review Board with informed consent obtained in accordance with the Declaration of Helsinki. Results The demographic characteristics of the patients were demonstrated in Table 1. Among six evaluable patients (3 of DL1 and 3 of DL2), the ORR was 100% on Day 29, including four complete remission and 2 partial remission. Cytokine release syndrome (CRS) was 100% in Gr 1, with main symptoms as fever (<39.0 degrees), fatigue, and muscle soreness. No neurotoxicity was observed. Four of the six patients with fever >38.0 degrees used prophylactic IL-6 Inhibitor (8mg/kg, ACTEMRA, two patients administered twice). No patients received steroids. The CRS showed no difference between dose level groups (p>0.99). Adverse effects included leukopenia (Gr 3-4: 83.3%, Gr 1-2: 16.7%), hypofibrinogenemia (Gr 1: 16.7%, Gr 2-4: 0%), liver dysfunction (Gr 1: 33.3%, Gr 2-4: 0%), elevated CRP (Gr 1: 83.3%, Gr 2-4: 0%), ferritin (Gr 1-2: 83.3%, Gr 2-4: 0%), or IL-6 (Gr 1-2:100%, Gr 3-4: 0%, Table 2). Conclusion Although long-term follow-up was needed, the preliminary data of six patients in this trial have demonstrated high response rates and safety of JWCAR029 in treating relapsed and refractory B-cell non-Hodgkin lymphoma. Disclosures Hao: JW Therapeutics: Employment, Equity Ownership.

scholarly journals Chimeric Antigen Receptor T Cell Targeting to CD19 and CD22 Combined with Anti-PD-1 Antibody Induce High Response in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1730-1730
Author(s):  
Ying Zhang ◽  
Jiaqi Li ◽  
Xiangping Zong ◽  
Jin Zhou ◽  
Sixun Jia ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Chimeric Antigen Receptor ◽  
Car T Cells ◽  
Car T Cell ◽  
Non Hodgkin Lymphoma ◽  
Car T

Abstract Objective: Despite the remarkable success of chimeric antigen receptor modified T (CAR-T) cell therapy for refractory or relapsed B cell non-Hodgkin lymphoma (R/R B-NHL), high rates of treatment failure and relapse after CAR-T cell therapy are considerable obstacles to overcome. Preclinical models have demonstrated that anti-PD-1 antibody is an attractive option following CAR-T therapy to reverse T cell exhaustion. Thus, we investigated their combination in R/R B-NHL. Methods: We performed a prospective, single-arm study of CAR-T cell combined with anti-PD-1 antibody treatment in R/R B-NHL (NCT04539444). Anti-PD-1 antibody was administrated on day 1 after patients received sequential infusion of anti-CD19 and anti-CD22 second-generation CAR-T cells, and the efficacy and safety of the combination treatment were evaluated. Results: From August 1, 2020 to June 30, 2021, a total of 11 patients were enrolled and completed at least 3 months follow-up. The median follow-up time is 5.8 months. Overall response was achieved in 9 of 11 patients (81.8%), and the complete response (CR) was achieved in 8 of 11 patients (72.7%). All 8 patients achieving CR still sustained remission at the last follow-up. The progression-free survival (PFS) and overall survival (OS) rates at 6 months were 80.8% and 100.0%, respectively. Cytokine release syndrome (CRS) occurred in only 4 patients (all were grade 1), and no neurotoxicity were observed. Conclusion: This study suggests that CAR-T cells combined with anti-PD-1 antibody elicit a safe and durable response in R/R B-NHL. Keywords: chimeric antigen receptor modified T cell, anti-PD-1 antibody, CD19/CD22, refractory or relapsed B cell non-Hodgkin lymphoma Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: We use the T cells were transduced with a lentivirus encoding the CD19-4-1BB-CD3 z and CD22-4-1BB-CD3 ztransgene to produce CAR-T cells. The main purpose of our study is to improve the response rate in patients with R/R B-NHL.

scholarly journals Auto Hematopoietic Stem Cell Transplantation Combined with Another Target Humanized CAR-T Cells for Refractory/Relapsed B-Cell Non-Hodgkin Lymphoma after Failure of Murinized CD19-CAR-T Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 657-657
Author(s):  
Kai Hu ◽  
Fan Yang ◽  
Rui Liu ◽  
Teng Xu ◽  
Peihao Zheng ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cell Transplantation ◽  
B Cell ◽  
Hematopoietic Stem Cell ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Non Hodgkin Lymphoma ◽  
Car T

Abstract Background: The prognosis of refractory/relapsed aggressive B-cell non-Hodgkin lymphoma (r/r B-NHL) is extremely poor especially for the patients who failed to CD19-Specific chimeric antigen receptor-T (CAR-T) cells therapy.Even sequentially autologous hematopoietic stem cell transplantation(ASCT) could not maintain a durable remission in most patients. Aims: To prolong relapse-free survival, we combined ASCT and another target humanized CAR-T cells to treat r/r B-NHL patients failed to murinized CD19-CAR-T cells therapy with either CD22 or CD20 antigen expression on tumor cell.The safety and efficacy will be evaluated. Methods: From December 2019 to March 2021, 12 patients were enrolled. The median age was 38 (16-68) years old. The diagnosis included DLBCL (n=8) ,BL(n=3) and PMBCL (n=1). The median IPI score was 3 (range,2-4).There were 9 patients(9/12,75%) with extranodal lesions. Six cases(6/12,50%) were with TP53 mutations. The disease status was progressive disease in all patients who failed to multi-line therapies and murinized CD19-CAR-T cells therapy.In order to further reduce the tumor burden, all patients were treated with combined chemotherapy before transplantation. Before the trial, the expression of CD20 and CD22 antigen in tumor tissue was positive confirmed by immunohistochemistry,and the target was selected according to the antigen expression. Conditioning with BEAM-based regimen was applied. The kinetics and function of CAR-T cells was monitored by quantitative PCR and flow cytometry. The efficacy was evaluated by PET-CT every 3 month after transplantation. Results: The autologous peripheral blood stem cells were infused with the median CD34 + cells 3.91(range,0.46-9.46)×10 6/kg.Humanized CAR-T cells with the median 1.85 (range,0.13-3.26)×10 6/kg were infused 2 day after stem cells,including target antigen CD20(7/12,58.3%) and CD22(5/12,41.7%). Cytokine release syndrome (CRS) occurred in 11 cases with 5 cases in grade I, 3 case in grade II and 3 cases in grade III.One case developed immune effector cell-associated neurotoxicity syndrome (ICANS) in grade IV. The peak of cytokine IFN-γ and IL-6 post baseline in patients with grade III CRS were significantly higher than those in patients with grade I-II CRS,especially in ICANS patient.Six cases with grade II and III were relieved with glucocorticoid. The neutrophil and platelets engraftment was achieved in all cases on median days 14 (range,9-22) and 14(range,8-35) respectively post-transplant .Seven cases of bacterial enteritis were seen. Pneumonia occurred in 7 cases.For CAR-T cells expansion,the peak time in vivo was on median 11(range,7-28) days after CAR-T cells infusion.The median peak lever of CAR-T cells was 20.3 (range,0.13-60.4)×10 6/L, which was positively correlated with the number of CART infused. The tumor burden before transplantation was not significantly associated with CAR-T cells expansion.The median duration of CAR-T cells in vivo was 30 days, and the longest lasting time was 139 days post-transplant so far. B-cell aplasia was documented in all cases(7/7,100%) of CD20-CART group and two cases(2/5,40%) of CD22-CART group during the follow-up. With the median follow-up 266 (range,118-565) days, 9/12(75%) patients survived,seven cases(7/12,58.3%) achieved complete remission(CR),2 cases(2/12,16.7%) achieved PD and survival with tumor.Kaplan-Meier survival analysis showed that OS and PFS rates were 71.3% and 66.6% respectively at 9 months after transplantation.Two cases(2/12,16.7%) with BL and one with DLBCL (1/12,8.3%)died of PD.Significantly lower levels of Cumulative CAR T cell levels (AUC) during the first 1 month post transplantation were observed in patients with disease progression compared with those who had durable responses (P&lt;0.0001). Conclusion: CRS is manageable and has no influence on hematopoiesis reconstitution.With current protocol, complication was mild and encouraging disease control was found. ASCT combined with another target humanized CAR-T therapy is a safe and effective salvage strategy for r/r B-NHL after failure of murinized CD19-CAR-T. Long-term follow-up is needed. [Key words] refractory/relapsed B-cell non-Hodgkin lymphoma; failure of CD19-CAR-T; another target CAR-T cell; autologous hematopoietic stem cell transplantation Disclosures No relevant conflicts of interest to declare.

scholarly journals Allogeneic Hematopoietic Stem Cell Transplantation with Conditioning Including Donor Humanized CAR-T Cells for Refractory/Relapsed B-Cell Non-Hodgkin Lymphoma and Multiple Myeloma

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 557-557
Author(s):  
Fan Yang ◽  
Hui Shi ◽  
Yang Lei ◽  
Ruiting Li ◽  
Teng Xu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Tumor Burden ◽  
Car T Cells ◽  
Car T Cell ◽  
Non Hodgkin Lymphoma ◽  
Car T

Abstract Background: The prognosis of refractory/relapsed aggressive B-cell non-Hodgkin lymphoma (r/r B-NHL) and multiple myeloma (r/r MM) is extremely poor, especially for the patients who failed to CAR-T cells therapy and/or ASCT. Aims: Forr/r B-NHLand r/r MM, a clinical trial using Allo-HSCT with conditioning including donor humanized CAR-T cells from the same donor (allo-CAR-T) has been registered, and the safety and efficacy will be evaluated. Methods: From September 2020 to May 2021, 11 patients were enrolled.The median age was 41 (26-64) years old. The diagnosis included high grade B-cell lymphoma (n=9) and Multiple myeloma (n=2). Seven cases were with TP53 mutations.All patients was progressive disease (PD) who failed to multi-line therapies, including chemotherapy (n=11), ASCT (n=4), autologous CAR-T (n=11).In order to further reduce the tumor burden, all patients were treated with combination therapy before transplantation. Before the trial, the expression of CD19 and/or CD22 or CD20 antigen in tumor tissue of r/r B-NHL and BCMA antigen in r/r MM patients was positive confirmed by immunohistochemistry.There were matched sibling identical donor in 1 case,matched unrelated donor in 1 case and haploidentical donor in 9 cases；Conditioning with busulfan, fludarabine-based regimen combined with allo-CAR-T was applied. Tacrolimus, mycophenolate mofetil, a short-term methotrexate and antithymocyte globulin were used for GVHD prophylaxis. The kinetics and function of CAR-T cells was monitored by quantitative PCR and flow cytometry. The efficacy was evaluated by PET-CT in r/r NHL as well as bone marrow puncture and immunofixation electrophoresis in r/r MM every 2 month after CAR-T infusion. Results: The median allo-CAR-T cells infused were 4 (range,0.78-4.88)×10 6/kg. CRS occurred in all cases with 6 cases in grade I, 1 case in grade II and 4 cases in grade III.The peak of cytokine IFN-γ and IL-6 in grade III CRS were significantly higher than those with grade I-II.No ICANS was noted. Four cases with grade III CRS were relieved with methylprednisolone. G-CSF-mobilized PBSC were infused 7 days after allo-CAR-T with the median CD34 + cells 6 (range,3-8.19)×10 6/kg. The neutrophil and platelets engraftment was achieved in all cases on median days 13 (range,11-24) and 16 (range,14-85) respectively post-transplant .All cases were donor type by STR analysis.Three cases of grade II acute GVHD were seen. CMV viremia occurred in 7 cases.For allo-CAR-T cell expansion,the peak time in vivo was on median 14(range,7-28) days after infusion.The median peak lever was 221 (range,0.191-1502)×10 6/L, which positively correlated with the number of allo-CAR-T infused. The tumor burden before transplantation was not significantly associated with allo-CAR-T expansion.Levels of allo-CAR-T cells were very low after the first 2 months of HSCT which detected persistently in 9/11(81.8%) patients, and the longest lasting time was 239 days post-transplant so far. B-cell aplasia was documented in 8/9 cases of r/r B-NHL during the follow-up. With the median follow-up 171 (range,100-295) days, 7/11(63.6%) patients survived,five cases(5/11,45.5%) achieved CR,one cases(1/11,9.1%) obtained PR, and 1 case(1/11,9.1%) of MM achieved SD and survival with tumor .Three cases(3/11,27.3%) with DLBCL died of PD whose disease status before transplantation were SD or PD, one patient(1/11,9.1%) died of infection.Significantly lower levels of Cumulative CAR T cell levels (AUC) during the first 2 month post transplantation were observed in patients who relapsed compared with those who had durable responses (P=0.0001).aGVHD were not associated directly with in vivo CAR T-cell expansion(P=0.193). Conclusion: Our preliminary results have shown that CRS is manageable and has no influence on hematopoiesis reconstitution. Allo-CAR-T cells still exist persistently post-transplant in majority of patients, which may contribute a long-term anti-lymphoma effect.With current protocol, aGVHD and viral reactivation was mild. Allo-HSCT with conditioning including allo-CAR-T cells is a safe and effective strategy for r/r B-NHL and MM. The Poor clinical efficacy was associated with high tumor burden before transplantation. [Key words] refractory/relapsed B-cell non-Hodgkin lymphoma; refractory/relapsed multiple myeloma;allogeneic CAR-T cell; allogeneic hematopoietic stem cell transplantation Disclosures No relevant conflicts of interest to declare.

scholarly journals CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma

Blood ◽  
2019 ◽  
Vol 134 (7) ◽  
pp. 626-635 ◽  
Author(s):  
Craig S. Sauter ◽  
Brigitte Senechal ◽  
Isabelle Rivière ◽  
Ai Ni ◽  
Yvette Bernal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
B Cell Lymphoma ◽  
Car T Cells ◽  
Poor Risk ◽  
Car T Cell ◽  
Non Hodgkin Lymphoma ◽  
Car T

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.

scholarly journals Development and clinical evaluation of non-viral genome specific targeted CAR T cells in relapsed/refractory B-cell non-Hodgkin lymphoma

2020 ◽  
Author(s):  
Jiqin Zhang ◽  
Yongxian Hu ◽  
Jiaxuan Yang ◽  
Wei Li ◽  
Yue Tian ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Viral Genome ◽  
Great Promise ◽  
Adoptive Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Non Hodgkin Lymphoma ◽  
Car T

In recent years, chimeric antigen receptor (CAR) T cell therapy has shown great promise in treating hematological malignancies. However, using virus in manufacture of CAR T cells brings about several problems. The application of CRISPR/Cas9 genome editing technology emerges in constructing novel CAR T cells by disrupting endogenous genes. Here we successfully develop a two-in-one approach to generate non-viral genome specific targeted CAR T cells through CRISPR/Cas9. By targeting a CAR in AAVS1 safe harbor locus, we demonstrated that these CAR T cells behave comparable to those conventionally produced by lentivirus. Furthermore, PD1-knockin anti-CD19 CAR T cells show a superior ability to eradicate tumor cells with high PD-L1 expression. In the adoptive therapy for relapsed/refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL), we observed durable responses without serious adverse events and complete remission (CR) in patients treated with these PD1 knockout CAR T cells. Collectively, our results prove the safety and feasibility of non-viral genome specific integrated CAR T cells, thus providing a new potential strategy for cancer treatment using these novel CAR T cells.

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