scholarly journals Long-Term Outcomes Following Donor-Derived Anti-CD19 CAR-T Cell Therapy for B-Cell Acute Lymphoblastic Leukemia Patients Relapsed after Allogenic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 53-54
Author(s):  
Rongli Zhang ◽  
Ying Wang ◽  
Dehui Zou ◽  
Erlie Jiang ◽  
Yi He ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
The Other ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Experienced Grade

Background: Patients with B cell acute lymphoblastic leukemia (B-ALL) relapsed after allogenic hematopoietic stem cell transplantation(alloHSCT) have poor prognosis and the median survival after relapse was 4 - 5.5 months, estimated 2-year post-relapse survival rates were 10 - 16%. Donor lymphocyte infusion (DLI) have shown limited success in the setting of relapse by a mere increase in median survival by 6 months and a significant risk of acute and chronic graft-versus-host disease (GVHD) and additional risk of marrow aplasia. The donor chimeric antigen receptor-T cell (CAR-T) for CD19 is a promising treatment for relapsed and refractory B-ALL, but the effectiveness and safety of donor-derived CD19 CAR-T cell infusion for relapsed B-ALL after alloHSCT have not been determined. Methods: Between July 2017 and Nov 2018, 10 adult patients with B-ALL relapsed (4 patients were hematologic relapsed, 3 patients were extramedullary relapse, the other 3 patients were bone marrow MRD-positive, Table) after alloHSCT were enrolled, including 9 sibling-matched stem cell transplantation and 1 haploidentical transplantation. About 100 - 200 ml venous blood form each donor was obtained and the T cells were separated. Then donor's T cells were infected with lentivirus carrying CD19 CAR plasmid which containing CD19 scfv (HI-19 clone) and 4-1BB-CD3ζ signaling domains to generate CAR-T cells. ALL the 10 Patients received FAC (fludarabine: 25-30mg/m2/d*3, cyclophosphamide:350mg/m2/d*2, cytosine arabinoside:100mg/m2/d*4) pretreatment and then a total of 5.01 × 106/kg (range, 3.39 - 6.53 × 106/kg) donor T cells including donor-derived anti-CD19 CAR-T cell (1.82 × 106/kg, (range, 1.26 - 4.67 × 106/kg)) was infused on 2 or 3 consecutive days for each patient. The levels of cytokines including IL-1,IL-2R,IL-6,IL-8,IL-10 and the percentage of the donor anti-CD19 CAR-T cells were monitored serially . Clinical manifest and the severity of cytokine release syndrome (CRS) were recorded and evaluated. The bone marrow examination was performed every 2 weeks after CAR T-cell infusion to assess the response for the first 2 months and then was performed every 1-3 months including bone marrow smear, MRD detection by flow cytometry, fusion gene detection by quantitative real-time polymerase chain reaction (qPCR), donor chimera rate by short tandem repeat(STR). Results: The median transduction efficiency of the final donor-derived CD19 CAR-T cells was 35.8%(range 25 - 70.6%). The peak of donor-derived anti-CD19 CAR-T cell expansion in the recipients was about 7 - 14days after infusion and then decreased rapidly. The serum cytokines levels varied differently: the serum IL-6 and IL-2R levels increased overtly and reached the peak during day 5 - day 7 in most of the patients, whereas the serum levels of IL-1, IL-8 and IL-10 did not vary obviously. one patient experienced Grade 3 CRS, 4 patients experienced Grade 2 CRS and the other 5 patients only experienced Grade 1 CRS. Four patients showed encephalopathy and 2 patients received glucocorticoid treatment. All the 10 patients achieved MRD negative remission and complete donor chimerism within 14days to 42days after donor's CAR-T cells infusion. No patients developed acute or chronic graft-versus-host disease (GVHD). After a median follow-up of 20.6 months (range, 13.4-30.3), 5 patients (including all the 3 patients with extramedullary relapse) relapsed with leukemia cells CD19-dim and 4 of them died due to disease progression. Only one patient received a successful secondary alloHSCT from a haplo-identical donor. The other 5 patients showed persistent complete donor chimerism with MRD negative remission(Figure). The estimated 2-year overall survival and leukemia-free survival were 68.6% and 48.0%, 2.5-year OS and LFS were 51.4% and 48.0%. Conclusion: Donor-derived CD19 CAR-T cell infusion seems to be an effective and safe treatment for B-ALL relapsed after alloHSCT, especially for those without extramedullary disease, which may be confirmed with more clinical studies. Disclosures No relevant conflicts of interest to declare.

scholarly journals Allogeneic CAR-T Cell Therapy for Treatment of Relapse after Allo-HSCT in Patients with Refractory CML Lymphoid Blast Crisis: Significance of HLA Matched Donor/Patient Pair in the Safety/Efficacy of CAR-T Cell Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4275-4275 ◽  
Author(s):  
Kai Sun ◽  
Xuejun Zhang ◽  
Zhen Wang ◽  
Yuqing Chen ◽  
Lei Zhang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Blast Crisis ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Introduction: CD19-specific CAR-T cells have shown promise in the treatment of relapsed or refractory Ph+ ALL. It remains to be established whether allogeneic CAR-T cells have clinical activity in patients with relapsed CML lymphoid blast crisis with a history of allo-HSCT. Here we report our experience in two cases of allogeneic CAR-T cell therapy for treatment of relapse after allo-HSCT in patients with refractory CML lymphoid blast crisis. Methods: For manufacture of allogeneic CAR-T cells, peripheral blood mononuclear cells were collected from the same stem cell donor. Lentiviral construction and generation of CAR-T cells, clinical protocol design, assessment and management of cytokine release syndrome (CRS), were performed as described in our previous report (Leukemia. 2017;31:2587-2593). Fludarabine and cyclophosphamide had been administered for lymphocyte depletion before allogeneic CAR-T cells infusion. Patients: Patient 1 was a 52-year-old woman with refractory CML lymphoid blast crisis, who had a relapse after undergoing allo-HSCT from her daughter (HLA-10/10). Her initial examinations of peripheral blood and bone marrow were consistent with the diagnosis of CML lymphoid blast crisis. Cytogenetics and molecular analysis confirmed the presence of t(9;22)(q34;q11) and BCR-ABL1 210 fusion protein. In February 2017, examination of bone marrow revealed a further increase of lymphoblasts to 83.2%. In addition, ABL1 kinase mutations (Y253H and E255K/V) were identified. The patient underwent HLA 10/10-matched allo-HSCT without acute GVHD. A remission with a negative test for BCR-ABL1 210 and 99.62% donor chimerism had been achieved, then she had a lymphoblastic relapse occurred 2 months after allo-HSCT. Consistently, BCR-ABL1 210 turned positive, and chimerism analysis showed 67.4% donor chimerism. 3 weeks after relapse, allogeneic CAR-T cells were infused at the dose of 5×106 /kg CD19-specific CAR-T cells. Patient 2 was a 39-year-old male patient with relapsed CML lymphoid blast crisis with a history of allo-HSCT. He had received a diagnosis of CML chronic phase 7 years earlier. Bone marrow revealed a karyotype of 46, XY, t(3;9;22)(q27;q34;q11) and BCR-ABL mRNA transcript. From April 2011 to September 2012, the patient was treated with nilotinib. In September 2012, bone marrow examination revealed 78% lymphoblasts, thus the diagnosis of CML lymphoid blast crisis was established. In December 2012, the patient underwent HLA 7/10-matched sibling allo-HSCT (from his brother) without evidence of GVHD and maintained CR for 2 years. In December 2014, the patient developed bone marrow relapse (lymphoblast 9.5%) and extramedullary leukemia (testicular involvement) harboring the BCR-ABL-T315I mutation. During 2014 to 2018, the patient received multiple courses of CIKs, HDMTX and DLI, but failed to achieve CR. In March 2018, the patient received healthy donor derived allogeneic CAR19 T cells (2×105/kg) therapy. Result: Before CAR-T cells infusion, both patients with refractory CML lymphoid blast crisis had a relapse after successful allo-HSCT. Approximately 1 month after CAR-T cells infusion, a persistent morphologic remission, a recovering BM, and complete absence of BCR-ABL mRNA transcripts confirmed morphologic and molecular remission in both patients. Consistent with this, flow cytometry could not detect blasts or CD19+ B lineage cells. Patient 1 did not experience toxicities and allogeneic CAR-T cell therapy was well tolerated. Patient 2 developed severe CRS (Gr 4) including high-grade fevers (>40°C), hypotension, hypoxia, mental status changes, and seizures. These episodes ran for approximately 1 week before they were halted by treatment with steroids plus tocilizumab, and plasma exchange. The toxicity of allogeneic CAR-T cells is correlated with high levels of IL-6, IFN-γ, TNF-a, and CRP. Conclusion: The clinical outcomes from these 2 patients demonstrate the in vivo efficacy of allogeneic CD19-targeted T cells to induce clinical, morphology and molecular remissions as well as B cell aplasia in adults with relapsed CML lymphoid blast crisis with a history of allo-HSCT. The efficacy of allogeneic CAR-T cell therapy may not always be related to the risk of severe CRS. The degree of HLA matching may have a major impact on the prevention of CRS after allogeneic CAR-T cell therapy. Fully HLA-matched-pair may increase the safety and efficacy of the allogeneic CAR-T cell therapy. Disclosures No relevant conflicts of interest to declare.

scholarly journals CAR2.0 Therapy for the Management of Post-Transplantation Relapse of B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 7-7
Author(s):  
Rui Zhang ◽  
Juan Xiao ◽  
Zhouyang Liu ◽  
Yuan Sun ◽  
Sanfang Tu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

BACKGROUND: Allogeneic haematopoietic stem cell transplantation (allo-HCT) is a standard treatment for relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL). However ~30-40% of patients (pts) still relapse after HCT. We report a cohort of 20 r/rB-ALL pts, who relapsed after HCT, and enrolled in the CAR2.0 study receiving one or two types of CAR-T cells targeting various B-ALL antigens. METHOD: Pts with r/r B-ALL who relapsed after allo-HCT and did not have significant active comorbiditeis, were enrolled in the study. The target antigens were determined based on immunostaining of each pt's leukemia cells, and CAR-T infusions included a single, or a combination of CAR-Ts targeting the following antigens: CD19, CD22, CD123 and CD38. T cells were collected from pts (N=4) or their allogeneic donors (N=16) and transduced with an apoptosis-inducible, safety-engineered lentiviral CAR with the following intracellular signaling domains: CD28/CD27/CD3ζ-iCasp9 (4SCAR). Pts received cyclophosphamide/fludarabine lymphodepleting therapy before infusion of 0.2-5.8x106 CAR-T/kg per infusion. In addition to disease response, we carefully monitored the quality of apheresis cells, efficiency of gene transfer, T cell proliferation rate, CAR-T infusion dose, and the CAR-T copy number in peripheral blood. RESULTS: Among the 20 enrolled pts, 11 were <18 years of age, and 7 were BCR- ABL (P190) positive. Before CAR-T treatment, 7 pts had ≤grade 2 active graft-versus-host disease (GVHD), and 13 pts received chemotherapy or targeted therapy after their relapse post HCT. Six pts had extramedullary relapse and 2 of them also had bone marrow relapse. The tumor burden in bone marrow ranged from minimal residual disease (MRD) negative to 66% of blasts, based on flow cytometry before CAR-T therapy. Five pts had >10% blasts in bone marrow, 8 pts had <3% blasts, and 7 pts had MRD negative bone marrow (summarized in the Table below). Based on the GVHD history, chimerism state and the available T-cell sources, 16 pts used allogeneic HCT donor T-cells for CAR-T preparation. All pts were full donor chimeras prior to CAR-T infusion, except one pt who had 41% donor cells in bone marrow. Eleven pts received a single CD19 CAR-T infusion, with a mean dose of 1.6x106 CAR-T/kg, and ten achieved an MRD remission and one had progressive disease (PD) within 60 days by flow cytometry. The remaining 9 pts received 2 CAR-Ts (CD19 plus CD22, CD123 or CD38 CAR-Ts) given on the same day, and resulted in 8 CR and 1 PD within 60 days. After CAR-T infusion, no cytokine release syndrome (CRS) was observed in 8 pts, and 12 pts experienced CRS of grade 1, which was consistent with the previously described low toxicity profile of the 4SCAR design. Acute GVHD ≤ grade 2 developed in 5 pts within one month following CAR-T cell infusion but all responded well to supportive care and/or cyclosporine infusion. The 2 pts who developed PD after CAR-T infusion included the one with 41% donor chimerism and had grade 2 GVHD and active infections before CAR-T infusion. The other pt with PD following CAR-T had severe bone marrow suppression, low leukocyte count, infections and was transfusion dependent before enrollment. This emphasizes the need for controlling comorbidities before infusion of CAR-T cells. In summary, total 18 patients (90%) achieved negative MRD remission within 2 months of therapy with acceptable CRS. Four pts relapsed (after being in remission for 3 months) and 14 pts are in continued remission, 6 of which for > 1 year. None of these 20 pts received a second HCT after CAR-T infusion. GVHD developed in 5/16 (31%) pts after donor source CAR-T cell infusion within one month, but all responded well to treatment. CONCLUSION: This study focuses on CAR-T cell therapy following relapse after HCT. While the expanded study is ongoing, we present results of the first 20 pts. Use of donor-derived or recipient-derived CAR-T products in pts who relapsed after allo-HCT is well tolerated and it may prolong life expectancy of these pts while maintaining good quality of life. Table Disclosures No relevant conflicts of interest to declare.

scholarly journals Local Manufacture of CD19 CAR-T Cells Using an Automated Closed-System: Robust Manufacturing and High Clinical Efficacy with Low Toxicities

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2625-2625
Author(s):  
Olga Molostova ◽  
Larisa Shelikhova ◽  
Dina Schneider ◽  
Rimma Khismatullina ◽  
Yakov Muzalevsky ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Brain Edema ◽  
Transmembrane Domain ◽  
Lymphoblastic Leukemia ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade Iii

Introduction CD19 CAR-T cell products were recently approved as therapy for B-lineage malignancies. We initiated an IIT trial where manufacture of CAR-T cells was performed locally using a unique CD19 CAR with potent anti-leukemic effects. Patients and methods A total of 37 pts with relapsed/refractory B-acute lymphoblastic leukemia (12 female, 25 male, median age 10 y) were screened, 27 pts were enrolled for a trial, 10 were eligible for compassionate use of CD19 CAR-T cell therapy. Sixteen patients had relapsed B-ALL after haploidentical HSCT, 19 pts refractory relapse, 2 induction failure, 13 patients had previous blinatumomab infusion. Eighteen patients had >20% blast cells, median bone marrow leukemia burden for patients with full blown disease was 89%, 19 pts had minimal residual disease (MRD) >0.1% in BM, 3 had skeletal involvement with multiple mass lesions, one had CNS involvement. The CliniMACS Prodigy T cell transduction (TCT) process was used to produce CD19 CAR-T cells. The automated production included CD4/CD8 selection, CD3/CD28 stimulation with MACS GMP T Cell TransAct and transduced with lentiviral vector expressing the CD19CAR gene (second generation CD19.4-1BB zeta with alternate transmembrane domain derived from the TNF superfamily) (Lentigen, Miltenyi Biotec company). T cells were expansion over 10 days in the presence of serum-free TexMACS GMP Medium supplemented with MACS GMP IL-7 and IL-15. Final product was administered without cryopreservation to the patients after fludarabine/cyclophosphamide preconditioning. All patients received prophylactic tocilizumab at 8mg/kg before CAR-T cell infusion. Patients did not receive HSCT as consolidation after CAR-T therapy. Results Thirty-five manufacturing cycles were successful. Median transduction efficacy was 60% (20-80). Median expansion of T cells was x 46 (18-51). CD4:CD8 ratio in the final product was 0.73. The cell products were administered at a dose of 3*106/kg of CAR-T cells in 4 pts, 1*106/kg in 9 pts, 0.5*106/kg in 14 pts, 0.1*106/kg in 8 pts. Two patients received 0.1*106/kg of CAR-T cells produced from haploidentical donors. The cytokine release syndrome (CRS) occurred in 22 (59%) pts and was mostly mild and moderate: grade I - 15 pts, grade II- 4 pts, grade III - 2 pt, grade IV - 1 pt. CAR-T cell related encephalopathy occurred in 15 (40%). Grade I-II neurotoxicity developed in 10 pts, grade III - in 2 pt, grade IV - 1 pt, grade V - 2 pt. In one patient with grade V neurotoxicity concomitant K. pneumonia encephalitis was documented. Severe (grade 3-5) CRS and neurotoxicity were associated exclusively with large leukemia burden (>20% in the bone marrow) at enrollment, p=0,002. Thirty-one patient was evaluable for response at day 28. Four pts had persistent leukemia. In 27 (87%) cases Flow MRD-negative remission was achieved. Disease relapse after initial response was registered in 9 (33%) cases (7 patients had CD19 negative, 2 had CD19 positive relapse). At the moment of reporting, 10 patients have died (3 due to sepsis, 1 due to brain edema, 1 due to brain edema and K. pneumonia encephalitis, 5 due to progression of disease or relapse). Twenty-seven pts are alive, 19 in complete remission with a median follow up of 223 days (41-516 days). Conclusion CliniMACS Prodigy TCT process is a robust CAR-T cell manufacturing platform that enables rapid and flexible provision of CAR-T cells to patients in need. Significant toxicity of CD19 CAR-T cells was associated exclusively with high leukemia burden at enrollment. In the absence of HSCT consolidation relapse rate exceeds 30%. Disclosures Schneider: Lentigen Technology, A Miltenyi Biotec Company: Employment. Preussner:Miltenyi Biotec: Employment. Rauser:Miltenyi Biotec: Employment. Orentas:Lentigen Technology Inc., a Miltenyi Biotec Company: . Dropulic:Lentigen Technology, A Miltenyi Biotec Company: Employment. Maschan:Miltenyi Biotec: Other: lecture fee.

scholarly journals CD4/CD8 T-Cell Selection Enhances CD22 CAR-T Cell Transduction and in-Vivo CAR-T Expansion: Updated Results on Phase I Anti-CD22 CAR Dose Expansion Cohort

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 809-809
Author(s):  
Nirali N Shah ◽  
Steven L Highfill ◽  
Haneen Shalabi ◽  
Bonnie Yates ◽  
Eli Kane ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Complete Remission ◽  
Cell Selection ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
T Cell Selection

Abstract Background: We previously demonstrated that non-T cells in apheresis products collected from patients with cancer, particularly in those with circulating leukemic cells or low CD3 counts, can substantially affect T cell expansion and transduction and, potentially, in vivo efficacy. Flask adhesion and elutriation methods to remove monocytes and granulocytes, and separation using CD3/CD28 activation beads are inefficient at removing tumor and other inhibitory cells. In the context of an ongoing CD22 CAR clinical trial, we introduced magnetic CD4/CD8 selection prior to activation and lentiviral transduction which resulted in enhanced in vivo CAR T-cell potency compared to products generated prior to the introduction of CD4/CD8 T cell selection. Design: Children and young adults with relapsed/refractory CD22+ hematologic malignancies eligible for our phase I dose escalation anti-CD22 CAR protocol were enrolled on study (NCT02315612). All had bone marrow evaluations at baseline, prior to lympho-depleting chemotherapy (Fludarabine 25 mg/m2 x 3 days and Cyclophosphamide 900 mg/m2 x 1 day) and again at day 28 (+/- 4 days) post-CAR infusion. Three dose levels were explored during dose-escalation (3 x 10e5; 1 x 10e6 and 3 x 10e6 transduced CAR T-cells/kg) prior to treating in the expansion phase at the 1 x 10e6 dose level, which is the focus of this report. As a result of a manufacturing failure in an enrolled patient, as of January 2017, the CAR-T manufacturing process was modified to include CD4/CD8 bead selection (TCS) for all subsequent patients. CAR T cell activation, transduction and expansion processes were otherwise unchanged. Results: From December 2014 to July 2017, 30 patients with ALL were treated, of which 22 (73%) were treated at 1 x 10e6 transduced CAR T cells/kg. All patients had active bone marrow involvement at baseline and 18 (82%) had an M2 marrow (>5% blasts) or higher disease burden. Eighteen had a prior transplant and 14 were previously treated with CAR. The first 15 patients were treated using an unselected apheresis product and 7 patients were treated using CD4/CD8 TCS. The first patient treating using TCS initially had a product failure when CAR-T cells were manufactured without TCS, due in part to a low CD3 at the time of collection resulting in substantial numbers of non-T cells in the apheresis product. Following CD4/CD8 TCS, the CD3 T-cell content in the starting product increased from 47% to 90%, T cell proliferation increased from 1.97-fold to 24.2-fold, transduction increased from 2.57% to 33.4% and an MRD negative complete remission was achieved. Following TCS, median transduction efficiencies were significantly higher (33.4% (pre-TCS) vs 40.7%, p=0.02). Cytokine release syndrome (CRS) occurred in 19 of 22 patients and was grade 1 CRS in 12 (4 in the TCS arm); grade 2 in 6 (2 in the TCS arm) and grade 4 in one patient. Amongst those developing CRS, tocilizumab was utilized in 2 of 13 (15%) patients pre-TCS and in 3 of 6 (50%) patients in the TCS arm to prevent higher grade CRS. Steroids were administered to 1 of 13 patients pre-TCS versus 3 of 6 (50%) patients in the TCS arm. Clinical parameters suggestive of a more robust inflammatory response in TCS patients included statistically significantly higher peak IL-6, IL-8, IL-10 and IL-15 levels as well as higher ferritin (Figure), and higher peak CAR-T% (75% vs 82%, p=0.03) with a trend towards higher absolute CAR values. Furthermore, 3 of the 5 responders in the TCS arm had evidence for a secondary expansion with a late rise in ferritin, WBC and CAR-T% with 2 patients having confirmed hemophagocytosis on the bone marrow at day 28, which was not seen in patients enrolled pre-TCS. For the entire cohort, 16 of 21 (76%) patients evaluable for response attained a complete remission (11 of 15 enrolled pre-TCS and 5 of 7 post-TCS). Amongst the TCS group, 5 of 5 who were CD22 CAR naïve attained MRD negative remission; two patients pre-treated with CD22 CAR T at an outside institution experienced poor in vivo CAR expansion possibly due to immune rejection. Conclusion: Ongoing experience on our expansion cohort confirms activity of CD22 CAR T cells resulting in high remission induction rates in relapsed refractory ALL, including responses in patients previously treated with CD19 CAR T cells. T cell selection using CD4/CD8 positive selection led to enhanced in vivo CAR-T expansion resulting in a 100% MRD negative complete remission rate (5 of 5 patients) in CD22 CAR naïve patients. Figure Figure. Disclosures No relevant conflicts of interest to declare.

T Cell Products of Defined CD4:CD8 Composition and Prescribed Levels of CD19CAR/Egfrt Transgene Expression Mediate Regression of Acute Lymphoblastic Leukemia in the Setting of Post-Allohsct Relapse

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3711-3711 ◽  
Author(s):  
Rebecca A Gardner ◽  
Julie R Park ◽  
Karen S Kelly-Spratt ◽  
Olivia Finney ◽  
Hannah Smithers ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Transgene Expression ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Circulating T Cells

Abstract Introduction. ALL relapse following allogeneic HSCT has dismal outcomes due in large part to ineffective therapies. The primary objectives of the Phase 1 portion of this study, which is restricted to the subset of pediatric and young adult patients who relapse following HSCT, is to determine the feasibility of manufacturing products of defined composition and transgene expression, the safety of the cryopreserved T cell product infusion, and to describe the full toxicity profile, including development of clinically significant GVHD. Therapeutic responses are also tracked based on multiparameter flow and IgH deep sequencing. Methods. CD4 and CD8 T cell subsets are immunomagnetically isolated from apheresis products obtained from the research participant. Following anti-CD3xCD28 bead stimulation, T cell lines are transduced with a SIN lentiviral vector that directs the co-expression of the FMC63scFv:IgG4hinge: CD28tm:4-1BB:ζ CAR and the selection/tracking/suicide construct EGFRt. Transduced cells are propagated using recombinant human cytokines to numbers suitable for clinical use over 10-20 days during which time they are subjected to EGFRt immunomagnetic positive selection. Shortly following lymphodepleting chemotherapy, cryopreserved CD4/EGFRt+ and CD8/EGFRt+T cell products are thawed and infused at the bedside such that patients receive a 1:1 ratio of EGFRt+CD4 and CD8 T cells at the protocol prescribed dose level. Results. Six subjects (4m – 3 yr s/p HSCT) have been treated at dose level 1 (5 X 105 CAR T cells/kg); four were treated with active disease, and two were treated while MRD negative. All patients received lymphodepleting chemotherapy prior to T cell infusion. The infusions were well tolerated with only 1 AE > grade 2 (grade 3 anaphylaxis related to the DMSO). All five responding subjects exhibited in vivo expansion of CAR T cells (peak engraftment 13.4 - 93.6 % CAR+ T cells/circulating T cells occurring 8-14 days post infusion) that were predominantly CD8+. Subjects with higher disease burden had higher peak PB CAR T cell levels compared to those with MRD negative marrows (62.7% v 19.6%). Accumulation of CAR T cells in bone marrow and CSF was observed. Five of the six subjects obtained or maintained an MRD negative CR following CAR T cell therapy, while the subject who did not have a therapeutic response failed to have detectable cell product engraftment. Four of the five subjects who had engraftment of CAR T cells have ongoing persistence with accompanying B cell aplasia and leukemia control (35 days-5 months as of August 1, 2014). Only one subject required immunomodulatory treatment for sCRS (tocilizumab and dexamethasone), and that subject lost persistence at day +42. Of the 2 subjects with identified malignant IgH rearrangement, deep sequencing of bone marrow (BM) showed no evidence of the clone by day +21 and day +63, respectively. Each of the five responding subjects developed some degree of CRS with fever and hypotension as the hallmark symptoms (2/6 admitted to ICU). Three of these patients developed encephalopathy (2 grade 1 and 1 grade 4) that was fully reversible. One subject developed de novo grade 2 acute skin GVHD shortly following CAR T cell engraftment and CRS. Skin biopsy revealed that only 9% of skin localized T cells marked EGFRt+ while 79% of circulating T cells marked EGFRt+. This subject was treated with a 2 week course of 1 mg/kg of prednisone, followed by a rapid taper over a six week period and resolution of the GVHD, and has ongoing persistent CAR+T cells. Conclusions. Infusions of 5x105 defined composition CD4:CD8 CD19CAR/EGFRt+ T cells/kg have produced encouraging rates of MRD negative CRs in pediatric and young adults ALL patients who have suffered a postHSCT relapse. Based on intent to treat, we have found it is feasible to generate donor-derived products from each of the six enrolled patients. Expected toxicities include CRS with ~30% ICU admission rate and encephalopathy with severity ranging from mild to severe, but fully reversible. Although one patient developed acute GVHD post T cell therapy, our preliminary assessment suggests that CAR T cells were not mediators of this response. This study continues to accrue at increasing dose levels and updated results will be reported at the meeting. Disclosures Off Label Use: tociluzimab for treatment of cytokine release syndrome cetuximab for the ablation of T cells CAR T cells for the treatment of leukemia. Jensen:Juno: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

scholarly journals Toxicity and response after CD19-specific CAR T-cell therapy in pediatric/young adult relapsed/refractory B-ALL

Blood ◽  
2019 ◽  
Vol 134 (26) ◽  
pp. 2361-2368 ◽  
Author(s):  
Kevin J. Curran ◽  
Steven P. Margossian ◽  
Nancy A. Kernan ◽  
Lewis B. Silverman ◽  
David A. Williams ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Young Adult ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract Chimeric antigen receptor (CAR) T cells have demonstrated clinical benefit in patients with relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We undertook a multicenter clinical trial to determine toxicity, feasibility, and response for this therapy. A total of 25 pediatric/young adult patients (age, 1-22.5 years) with R/R B-ALL were treated with 19-28z CAR T cells. Conditioning chemotherapy included high-dose (3 g/m2) cyclophosphamide (HD-Cy) for 17 patients and low-dose (≤1.5 g/m2) cyclophosphamide (LD-Cy) for 8 patients. Fifteen patients had pretreatment minimal residual disease (MRD; <5% blasts in bone marrow), and 10 patients had pretreatment morphologic evidence of disease (≥5% blasts in bone marrow). All toxicities were reversible, including severe cytokine release syndrome in 16% (4 of 25) and severe neurotoxicity in 28% (7 of 25) of patients. Treated patients were assessed for response, and, among the evaluable patients (n = 24), response and peak CAR T-cell expansion were superior in the HD-Cy/MRD cohorts, as compared with the LD-Cy/morphologic cohorts without an increase in toxicity. Our data support the safety of CD19-specific CAR T-cell therapy for R/R B-ALL. Our data also suggest that dose intensity of conditioning chemotherapy and minimal pretreatment disease burden have a positive impact on response without a negative effect on toxicity. This trial was registered at www.clinicaltrials.gov as #NCT01860937.

scholarly journals Title Point-of-Care Production of CD19 CAR-T Cells in an Automated Closed-System: Report of First Clinical Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5202-5202
Author(s):  
Olga Molostova ◽  
Larisa Shelikhova ◽  
Yakov Muzalevsky ◽  
Alexey Kazachenok ◽  
Dmitriy Pershin ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Point Of Care ◽  
Cell Lineage ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Mass Lesions

Abstract Introduction CD19 CAR-T cell products were recently approved as therapy for advanced B-cell lineage malignancies. The predominant manufacturing model for this type of therapy is a centralized industrial-type production process. An attractive model of CAR-T cell production and delivery to the patient is via a point-of care-manufacturing process. We report on first cases of implementation of this approach in a setting of compassionate use program. Patients and methods Four patients with relapsed/refractory B-cell lineage malignancies were eligible for compassionate use of CD19 CAR-T cell therapy. Three patients, median age 15 years, had relapsed B-cell lineage acute lymphoblastic leukemia (B-ALL) after haploidentical hematopoietic stem cell transplantation (HSCT). Bone marrow disease burden at therapy start was 12%, 74% and 0,159. The patient with low minimal residual disease (MRD) in the bone marrow had skeletal involvement with multiple lymphomatous mass lesions. One patient had refractory primary mediastinal B-cell lymphoma (PMBCL). The CliniMACS Prodigy T cell transduction (TCT) process was used to produce CD19 CAR-T cells from patient-derived leukapheresis product. Automatic production included CD4/CD8 selection, CD3/CD28 stimulation with MACS GMP T Cell TransAct, transduction with lentiviral (second generation CD19.4-1BB zeta) vector (Lentigen, Miltenyi Biotec company) and expansion over 12 days in the presence of TexMACS GMP Medium supplemented with MACS GMP IL-7/IL-15 combination. Final product was administered without cryopreservation to the patients after fludarabine/cyclophosphamide preconditioning. All patients received prophylactic tocilizumab 1 hour before CAR-T cell infusion at 8mg/kg. Results All production cycles were successful. Median transduction efficacy achieved was 57%(52-63). Median expansion of T cells was x26(24-43). CD4/CD8 ratio in the final product was 0,750,22-6). All final products passed the in-process and quality controls. The cell products were administered at a dose of 1*106/kg of CAR-T cells. No immediate infusion reactions were reported. In 2 cases mild cytokine release syndrome (CRS) was diagnosed. In one case mild CAR-T cell related encephalopathy developed. In one case additional dose of tocilizumab and one dose of dexamethasone were administered to control CRS and encephalopathy. All patients survived to the point of response evaluation. In 3 cases CAR-T cell expansion was detected to a maximum 25%. MRD-negative responses detected by flow cytometry and PCR were achieved in 2 cases with bone marrow involvement. In two cases with prominent mass lesions an objective response was documented. In the patient with 74% blast in bone marrow at start of therapy, neither CAR-T cell expansion nor leukemia response were documented. Details of therapy and response are summarized in table 1. Conclusion Production of CAR-T cells with the CliniMACS Prodigy TCT process is a feasible and an attractive option that provides a point-of-care manufacturing approach to enable rapid delivery of CAR-T cells to patients in need. Robustness and consistency of this approach provides a solid basis for multi-center academic trials in the field of adoptive cell therapy. Table 1. Table 1. Disclosures Dropulic: Lentigen, A Miltenyi Biotec company: Employment. Shneider:Lentigen, A Miltenyi Biotec company: Employment. Orentas:Lentigen, A Miltenyi Biotec company: Employment. Alex:Miltenyi Biotec: Employment. Essl:Miltenyi Biotec: Employment.

scholarly journals CAR T Cell Therapy Targeting G Protein-Coupled Receptor Class C Group 5 Member D (GPRC5D), a Novel Target for the Immunotherapy of Multiple Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 589-589 ◽  
Author(s):  
Eric L. Smith ◽  
Kimberly Harrington ◽  
Mette Staehr ◽  
Reed Masakayan ◽  
Jon Jones ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Employment Equity ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Equity Ownership ◽  
G Protein Coupled

Abstract Early clinical results using BCMA targeted CAR T cell therapies for advanced multiple myeloma (MM) have shown promise. However, BCMA expression can be variable, and BCMA downregulation has been correlated with relapse (Brudno J. JCO. 2018; Cohen A. ASH. 2017). Targeting multiple antigens may enhance response durability. We report that the orphan seven transmembrane G protein coupled receptor, GPRC5D, is an attractive additional target for CAR T cell therapy of MM. GPRC5D mRNA expression was previously identified in bone marrow cells from patients with MM; however its protein expression could not be detected with available FACS reagents (Frigyesi I. Blood. 2014). We evaluated 83 primary marrow samples by quantitative immunofluorescence (Q-IF) for CD138, BCMA, and GPRC5D. In 98% of the samples, CD138+ cells expressed surface GPRC5D. In most samples, the majority of CD138+ cells expressed both BCMA and GPRC5D, however, in several cases the dominant CD138+ population expressed only BCMA or GPRC5D, with GPRC5D expression independent of BCMA across samples (R2=0.156; Figure 1). The potential for "on target/off tumor" binding by targeting GPRC5D was evaluated by screening 30 essential normal tissue types by IHC (n=3 donors/type) followed by validation of any positive findings by RNA in situ hybridization and quantitative PCR. Results in non-plasma cell normal tissue were consistent with prior reports of GPRC5D off target expression restricted to cells from the hair follicle, a potentially immune privileged site. We developed GPRC5D-targeted CARs considering immunogenicity, spacer length, and tonic signaling. To minimize potential anti-CAR immunity, a human B cell-derived phage display library was screened. Seven diverse and highly specific human single chain variable fragments (scFvs) were identified. 42 CARs were derived from the 7 scFvs by modifying scFv orientation (VH/VL; VL/VH) and incorporating a short, medium, or long IgG4 based spacer. To monitor CAR-mediated signaling, we transduced each CAR into a Jurkat reporter line with RFP inserted in-frame, downstream of endogenous NR4A1 (Nur77). Nur77 expression is an immediate-early, specific marker of CD3z signaling (Ashouri J. J Immunol. 2017). Using this reporter, we observed that (1) a long spacer provided enhanced antigen-dependent activation across all anti-GPRC5D CARs; and (2) the use of different scFvs resulted in vastly different levels of tonic signaling. We selected potential lead and backup constructs and evaluated CAR activity on primary human T cells. When co-cultured specifically with MM cell lines, anti-GPRC5D CAR T cells secreted a polyfunctional cytokine profile, proliferated, and effectively lysed target cells. CD138+/CD38hi primary MM bone marrow aspirate cells were also specifically lysed. In vivo efficacy of GPRC5D-targeted CAR T cells was evaluated in NSG mice engrafted with a human MM cell line (ffLuc+) bone marrow xenograft. Donor T cells were gene-modified to express anti-GPRC5D CARs with either a 4-1BB or a CD28 co-stimulatory domain and membrane-anchored Gaussia luciferase (GLuc). Compared to control CAR T cells specific for an irrelevant target, anti-GPRC5D CAR T cells with either co-stimulatory domain proliferated and homed to the site of MM (Gluc imaging), eradicated MM xenograft (ffLuc imaging), and increased survival (Figure 2). One scFv that was highly functional in our GPRC5D CAR screen was evaluated for off-target binding against either >200 G protein-coupled receptors (cell based), or >4000 human transmembrane proteins (scFv-Fc based), and demonstrated binding only to GPRC5D. Studies with murine and cynomolgus cross-reactive GPRC5D targeting CARs did not show signs of alopecia or other unexpected toxicity in either species. In a murine model of post-BCMA CAR T cell treated antigen escape (CRISPR BCMA KO of a subpopulation of MM cells), anti-GPRC5D CAR T cells rescue BCMA- relapse. These results indicate that GPRC5D will be an important target for the immunotherapy of MM. We are translating this 4-1BB-containing, human-derived, GPRC5D-targeted CAR construct to the clinic. Disclosures Smith: Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Harrington:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Masakayan:Agentus Inc: Employment. Jones:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Long:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Ghoddusi:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Do:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Pham:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Wang:Eureka Therapeutics: Employment, Equity Ownership. Liu:Eureka Therapeutics, Inc.: Employment, Equity Ownership. Xu:Eureka Therapeutics: Employment, Equity Ownership. Riviere:Juno Therapeutics, a Celgene Company: Membership on an entity's Board of Directors or advisory committees, Research Funding; Fate Therapeutics Inc.: Research Funding. Liu:Eureka Therapeutics, Inc.: Employment, Equity Ownership. Sather:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Brentjens:Juno Therapeutics, a Celgene Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding.

scholarly journals CD19-CAR Therapy Using Naive/Memory or Central Memory T Cells Integrated into the Autologous Stem Cell Transplant Regimen for Patients with B-NHL

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 610-610 ◽  
Author(s):  
Leslie Popplewell ◽  
Xiuli Wang ◽  
Suzette Blanchard ◽  
Jamie Wagner ◽  
Araceli Naranjo ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Research Funding ◽  
Memory T Cells ◽  
Central Memory ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

Abstract Autologous stem cell transplantation (ASCT) remains an important consolidative therapy for patients with recurrent non-Hodgkin lymphoma (NHL), but is limited by the high incidence of NHL relapse. We report a Phase I clinical trial of ASCT followed by CD19-specific CD28-costimulatory chimeric antigen receptor (CD19:28z-CAR) T cells, with the goal of reducing NHL relapse rates. Safety and feasibility were the primary objectives, with CAR T cell persistence and expansion in the myeloablative ASCT setting as secondary objectives. This study examines safety and feasibility for two manufacturing platforms that differed in the T cell subset composition used for CAR engineering. Initially, the T cell population for CAR transduction was central memory (Tcm)-enriched: participants' peripheral blood mononuclear cells (PBMC) were depleted for CD14+ monocytes, CD25+ Tregs, and CD45RA+ naïve and stem-memory T cells, after which they were selected for CD62L+ Tcm (Wang et al. Blood;127:2980). Based on comparative preclinical data, a second arm was added to the trial to evaluate a Tn/mem-derived manufacturing platform that enriched central memory, naïve, and stem memory T cells (no CD45RA+ depletion). Either Tcm- or Tn/mem-enriched T cells were activated with CD3/CD28 beads, transduced with lentiviral vector encoding the CD19:28z-CAR, and expanded ex vivo. This phase I trial used the toxicity equivalence range design (Blanchard and Longmate. Contemp Clin Trials; 32;114) with an equivalence range for DLTs of 0.20-0.35 and a target toxicity rate of 0.25. The first 3 participants on each arm were followed one at a time, with later accrual in cohorts of 3. Twenty-three participants underwent ASCT and received CD19:28z-CAR T cells 2 days post stem cell infusion at the assigned dose level (DL): 17 on the Tcm arm (DL 50 million [M] CAR+ T cells [n=3], 200 M [n=5], 600 M [n=9]); 6 on the Tn/mem arm (DL 200 M). Participants were followed for dose limiting toxicity (DLT) for 28 days. Table 1 shows results by arm and DL. Both arms demonstrated safety and feasibility. There was no delayed hematopoietic reconstitution on either arm. On the Tcm arm, the only DLT was at DL 600 M (1 of 9 at 600 M). The Tn/mem arm was opened at 200 M and 6 participants were treated with no DLTs. The dose was not escalated as the protocol management team had seen activity at the 200M level in 2 other trials using the Tn/mem product. Tcm Arm: Fourteen of 17 participants (82%) had a diagnosis of diffuse large B-cell lymphoma (DLBCL) and 3 had mantle cell lymphoma. The mean age of the participants on the Tcm arm was 57 (35-75). The median number of prior chemotherapy regimens was 2 (1-5). The median progression-free survival (PFS) was 34.6 months 95% CI [21.8, undefined]. Seven of 17 participants (41%) have progressed, 1 died in remission of unrelated intracranial hemorrhage (6%), 7 (41%) remain in CR and are still in follow-up, and 2 are lost to follow-up (12%). All 17 participants achieved a CR or a continuing CR after ASCT and T cells. Tn/mem arm: Five of 6 participants (83%) had a DLBCL diagnosis, and 1 was NHL not otherwise specified. The mean age of the participants was 50 (40-72). The median number of prior chemotherapy regimens was 2.5 (1-3). The median follow-up time for the Tn/mem arm was 12 months, with median PFS not yet reached. One of 6 (17%) has progressed, 4 (66%) remain in CR and are still in follow-up, and 1 is lost to follow-up (17%). Five of 6 (83%) participants achieved a best response of CR or continuing CR after therapy. Several differences were observed between the manufacturing platforms. Since the Tn/mem production platform has fewer depletion steps, it resulted in a higher product yield, which shortened the ex vivo expansion period by 4.1 days (95% CI [1.5%, 6.6%]) from 18.9 days (15-24) for Tcm to 14.8 days (12-18) for Tn/mem (P<0.005). Notably in the ASCT minimal disease burden setting, the Tn/mem-derived CD19:28z-CAR T cell products exhibited significantly higher in vivo CAR T cell expansion compared to Tcm products at the 200M DL (Figure 1). We conclude that although both Tcm- and Tn/mem-enriched CD19CAR T cell therapies are safe, the Tn/mem product is more promising due to its 1) shorter production time, 2) higher cell yield, and 3) better in vivo expansion, despite the low antigen drive in these patients post-salvage and ASCT therapy. Longer follow-up for the 2-year PFS secondary objective will indicate if improved Tn/mem expansion impacts tumor control. Disclosures Wang: Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding. Budde:Mustang Therapeutics: Consultancy, Other: Licensing Agreement, Patents & Royalties, Research Funding. Brown:Mustang Therapeutics: Consultancy, Other: Licensing Agreement, Patents & Royalties, Research Funding. Forman:Mustang Therapeutics: Other: Licensing Agreement, Patents & Royalties, Research Funding.

scholarly journals Tandem CD19/CD22 Dual Targets CAR-T Cells Therapy Acquires Superior CR Rate Than CD19 CAR-T Cells: A Case Controlled Study

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-44
Author(s):  
Wei Cui ◽  
Xinyue Zhang ◽  
Haiping Dai ◽  
Qingya Cui ◽  
Baoquan Song ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Controlled Study ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Background: CD19 chimeric antigen receptor (CAR) T-cells therapy has shown unprecedented success in relapsed/refractory (r/r) ALL. Now it is recommended for the treatment of patients up to 25 years with r/r precursor B-ALL. Despite its high response rate, approximately 50% of r/r ALL patients relapsed after CD19 CAR T-cell therapy, which was mainly due to CD19 antigen loss or short persistence of CAR T-cells in vivo. CD19 and CD22 dual target CAR T-cells have demonstrated to reduce relapse post CD19 CAR T-cell therapy in limited cases. This study was designed to investigate the efficacy and safety of CD19/CD22 dual targets CAR-T cells and the correlation between that and CD19 CAR-T cells. Methods: A novel tandem CD19/CD22 CAR-T construct with CD28 and OX40 co-stimulatory domains were administered. All patients received FC (fludarabine, 30 mg/m2, days 1-3 and cyclophosphamide, 300 mg/m2, days 1-3) based regimen chemotherapy pre-infusion. Median infusion dose of CAR-T cells was 1(0.5-2.5) *107 cells/kg. All the patients accepted the bone marrow examination 28 days post CAR-T infusion. We conducted a retrospective, case controlled study analysis at the First Hospital of Soochow University. Every patient with active disease treated with CD19/CD22 CAR-T cells therapy was paired with one control subject who received CD19 CAR-T cells from January 2017 to September 2019. We matched the control group to prevent bias according to: (1) bone marrow blast before CAR-T infusion; (2) extramedullary involvement; (3) cytogenetic risk groups according to NCCN guideline; (4) transplantation status pre-infusion. Results: From 2017 Oct to 2020 Jul, 36 patients were enrolled into the clinical trial (NCT: 03614858). Patients who accepted more than 4 previous treatments account for 58.3% and 8 patients received stem cell transplantation pre-infusion. Bone marrow blasts 40.75 (0~94.5)%. After tandem CD19/CD22 CAR-T infusion, all patients achieved completely remission (CR) and minimal residual disease negative (MRD-) CR rate is 77.8%. The 6-month OS rate is 88.36% and 12-month OS rate is 70.6%. The 6-month LFS rate is 88.072% and the 12-month LFS rate is 69.216%. CAR-T bridging HSCT (25/36) obviously improves the 1-year LFS rate compared with non-transplantation group (11/36) (82.309% vs 31.169%, p=0.0135). All the side effects were mild and can be relieved through support treatments. 8 out of 36 patients developed with grade 3~4 CRS. 2 patients had HLH but soon relieved through low dose steroids. 28 out of 36 patients who accepted dual targets CAR-T cells didn't get complete remission before infusion. Therefore, 28 patients were enrolled in the CD19 CAR-T group. There are no significant differences between two groups at baseline. The CR rate was higher in CD19/CD22 group than that in CD19 group(100% vs 53.57%, p=0.000), so was MRD-CR rate(71.43% vs 42.86%,p=0.000). In survival analysis, 6 month overall survival rate of CD19/CD22 group was 69.276% while CD19 group was 53.571%. Of 28 patients who received dual target treatment, 7 patents relapsed while 4 relapsed out of 15 CR patients in CD19 group. Conclusions:The tandem CD19/22 dual CAR-T cell therapy is a safe and high efficacy treatment for R/R ALL patients. Our study demonstrated that dual targets CAR-T cells acquires higher CR rate than CD19 CAR-T cells. It is possible that multi-targeted CAR-T cell therapy may overcome this resistance mechanism and improve clinical outcomes. Disclosures No relevant conflicts of interest to declare.

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