scholarly journals Humanized CD19-Specific Chimeric Antigen Receptor T Cells for Acute Lymphoblastic Leukemia

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3872-3872 ◽  
Author(s):  
Jiang Cao ◽  
Hai Cheng ◽  
Kunming Qi ◽  
Wei Chen ◽  
Ming Shi ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Chimeric Antigen Receptor ◽  
Therapeutic Efficacy ◽  
Lymphoblastic Leukemia ◽  
Car T Cells ◽  
Car T ◽  
Leukemia Relapse ◽  
Grade 3

Introduction: Adoptive infusion of CD19-targeted chimeric antigen receptor T (CAR-T) cells has showed promising treatment effects for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL). While immune response induced by murine single-chain variable fragment (scFv) of the CAR leads to its premature elimination, and thus increases the risk of leukemia relapse. Humanized scFv is expected to reduce the immunogenicity of CAR, thereby promoting the survival time as well as improving the therapeutic efficacy of CAR-T treatment. We developed a humanized anti-CD19 scFv domain and now report on treatment with humanized CD19 CAR-T cells (hCART19s). Methods: A pilot phase 1 study of CAR-modified T cells containing a humanized anti-CD19 scFv domain (hCART19s) was performed with recruitment of children and adults with R/R B-ALL with or without prior exposure to a murine CD19 CAR-T cell product. Patient-derived T cells were transduced ex vivo with a lentiviral vector encoding a CAR composed of humanized anti-CD19 scFv, the human CD8 transmembrane, CD8 hinge, 4-1BB costimulatory domain, CD3ζ intracellular regions and T2A-EGFRt sequence. After lymphodepletion chemotherapy with cyclophosphamide (750 mg/m2, day -5) and fludarabine (30 mg/m2/day, days -5 to -2), patients received a single dose of autologous hCART19s infusion at a dose of 1×106 cells/kg (body weight) on day 0. The post-infusion responses, toxicities, expansion and persistence of hCART19s in patients were observed and monitored. Results: 51 R/R B-ALL patients aged 3-69 yr were treated with hCART19s. 5 patients was diagnosed as Ph+ B-ALL. 2 patients had received prior allogeneic stem cell transplant (SCT). A total of 8 patients had central nervous system leukemia (CNSL), and 1 had testicular leukemia (TL). Among 46 patients without previous CAR-T therapy, 38 (82.6%) achieved complete remission (CR) or CR with incomplete count recovery (CRi) on day 30, while 2 of 5 patients, who relapsed after murine CAR-T infusion, achieved CR after hCART19s infusion. The rates of event-free survival and overall survival were 63% (95% confidence interval [CI], 46 to 75) and 79% (95% CI, 64 to 88), respectively, at 6 months and 44% (95% CI, 27 to 59) and 67% (95% CI, 51 to 79) at 12 months. Among the 40 patients with CR or CRi, 17 had a relapse before receiving additional anticancer therapy. 12 patients underwent allogeneic hematopoietic stem-cell transplantation (HSCT) while in remission, 10 were alive without relapse and 2 had a relapse after HSCT. During treatment, 37 (72.5%) patients developed grade 1-2 cytokine release syndrome (CRS), and 11 (21.6%) patients developed grade 3-5 CRS. Neurologic events occurred in 4 (7.8%) patients within 8 weeks after infusion. 2 (3.9%) patients had grade 3 neurologic events; no grade 4 events or cerebral edema were reported. Conclusions: This study demonstrated that hCART19s have high therapeutic efficacy and safety in children and adults with R/R B-ALL. More importantly, hCART19s was confirmed to exert anti-leukemic activities in patients who relapsed after murine CAR-T infusion. HSCT is a potential approach to reduce leukemia relapse in patients who achieved CR after CAR-T therapy. Disclosures No relevant conflicts of interest to declare.

Donor-Derived CD7 Chimeric Antigen Receptor T Cells for T-Cell Acute Lymphoblastic Leukemia: First-in-Human, Phase I Trial

2021 ◽  
pp. JCO.21.00389
Author(s):  
Jing Pan ◽  
Yue Tan ◽  
Guoling Wang ◽  
Biping Deng ◽  
Zhuojun Ling ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Phase I Trial ◽  
Lymphoblastic Leukemia ◽  
Car T Cells ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Grade 3

PURPOSE Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (r/r T-ALL) have few options and poor prognosis. The aim was to assess donor-derived anti-CD7 chimeric antigen receptor (CAR) T-cell safety and efficacy in patients with r/r T-ALL. METHODS In this single-center, phase I trial, we administered anti-CD7 CAR T cells, manufactured from either previous stem-cell transplantation donors or new donors, to patients with r/r T-ALL, in single infusions at doses of 5 × 105 or 1 × 106 (±30%) cells per kilogram of body weight. The primary end point was safety with efficacy secondary. RESULTS Twenty participants received infusions. Adverse events including cytokine release syndrome grade 1-2 occurred in 90% (n = 18) and grade 3-4 in 10% (n = 2), cytopenia grade 3-4 in 100% (n = 20), neurotoxicity grade 1-2 in 15% (n = 3), graft-versus-host disease grade 1-2 in 60% (n = 12), and viral activation grade 1-2 in 20% (n = 4). All adverse events were reversible, except in one patient who died through pulmonary hemorrhage related to fungal pneumonia, which occurred at 5.5 months, postinfusion. Ninety percent (n = 18) achieved complete remission with seven patients proceeding to stem-cell transplantation. At a median follow-up of 6.3 months (range 4.0-9.2), 15 remained in remission. CAR T cells were still detectable in five of five patients assessed in month 6, postinfusion. Although patients' CD7-positive normal T cells were depleted, CD7-negative T cells expanded and likely alleviated treatment-related T-cell immunodeficiency. CONCLUSION Among 20 patients with r/r T-ALL enrolled in this trial, donor-derived CD7 CAR T cells exhibited efficient expansion and achieved a high complete remission rate with manageable safety profile. A multicenter, phase II trial of donor-derived CD7 CAR T cells is in progress ( NCT04689659 ).

scholarly journals A Phase I Study of CD19 Chimeric Antigen Receptor-T Cells Generated By the PiggyBac Transposon Vector for Acute Lymphoblastic Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3831-3831
Author(s):  
Nobuhiro Nishio ◽  
Ryo Hanajiri ◽  
Yuichi Ishikawa ◽  
Makoto Murata ◽  
Rieko Taniguchi ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Phase I ◽  
Chimeric Antigen Receptor ◽  
Lymphoblastic Leukemia ◽  
Piggybac Transposon ◽  
Car T Cells ◽  
Car T ◽  
Grade 3

Abstract Introduction: Chimeric antigen receptor-modified T cells targeting CD19 (CD19.CAR-T cells) have shown clinical success in patients with hematological malignancies. Despite the encouraging results obtained with this novel therapy, a major concern to its global spread, particularly in developing countries, is its high cost. We developed a method of non-viral gene transfer using piggyBac transposon to reduce the cost of CAR-T therapy. In preclinical study, the median number and transduction efficiency of CAR-T cells obtained from 2x10 7 PBMC in 9 donors were 1.0x10 8 (range, 0.58-1.8x10 8) and 51% (range, 29-73%), respectively. The major subset of CAR-T cells was phenotypically CD8+CD45RA+CCR7+, closely related T-memory stem cells. Ex vivo, CD19.CAR-T cells showed cytotoxic effect on CD19 positive tumor cell lines. In NSG mice model, CD19.CAR-T cells successfully inhibit tumor growth. CAR gene integration sites were determined by inverse polymerase chain reaction and subsequent next-generation sequencing using MiSeq and equally distributed throughout the genome without preference for specific sites. The pre-clinical testing in mouse demonstrated safe toxicity profile at the 50 times dose of CD19.CAR-T cells. We started a human clinical trial to define feasibility, toxicity, maximum tolerated dose and clinical response of CD19.CAR-T cells (jRCTa040190099). Methods: We report the results of cohort 1 of the study in which the safety and efficacy of autologous CD19.CAR-T in patients with relapsed or refractory B-precursor acute lymphoblastic leukemia were evaluated. We engineered autologous T cells via the piggyBac transposon system with CD19.CAR-expression transposon vector and piggyBac transposase-expression vector to express CD19.CAR incorporating CD28 costimulatory domain. We designed this phase I trial using a modified 3 + 3 design to enroll 3-12 patients with relapsed or refractory acute lymphoblastic leukemia in both children and adults. In this study, patients in cohorts 1 (16-60 years old) and 2 (1-15 years old) receive 1 × 10 5 CAR-transduced T cells per kg. Patients in cohorts 3 and 4 (both 1-60 years old) receive 3 × 10 5 and 1 × 10 6 CAR-transduced T cells per kg, respectively. All patients receive 25mg/m 2/d of fludarabine and 250mg/m 2/d of cyclophosphamide for 3 days followed by a single infusion of CAR-T cells. Results: Three patients were enrolled in cohort 1 and infused with 1 × 10 5 CAR-transduced T cells per kg. All patients had previously undergone allogeneic hematopoietic stem cell transplantation. All patients had achieved a hematological complete response with salvage treatment before CAR-T therapy. None of the patients had dose-limiting toxicities (DLT) defined as nonhematological toxicities above grade 4 or cytokine release syndrome (CRS) above grade 4 or graft versus host disease (GVHD) above 4, or grade 3 nonhematological toxicities and GVHD not improved to grade 2 within 4 weeks after CAR-T infusion. There was no occurrence of non-hematological adverse events above grade 3. CRS was observed in one patient (grade 1) who also developed headache due to infiltration of CAR-T cells into the spinal fluid. In two patients, B cell aplasia lasted 2 and 9 months, respectively. Elevation of serum cytokine levels was observed in all patients and the peak time point was 7-21 days after CAR-T cell infusion. Conclusions: CD19.CAR-T cell infusion produced by the piggyBac transposon gene engineering system was safe in cohort 1 of our study. As no patients had DLT in cohort 1, we are enrolling the patients in further cohorts. Disclosures Murata: MSD: Honoraria; Kyowa Kirin: Honoraria; Sumitomo Dainippon Pharma: Honoraria; FUJIFILM: Honoraria; Toyama Chemical: Honoraria; Novartis: Honoraria; JCR Pharmaceutical: Honoraria; Astellas: Honoraria; Miyarisan Pharmaceutical: Honoraria; Asahi Kasei: Honoraria; GlaxoSmithKline: Honoraria; Celgene: Honoraria; Otsuka Pharmaceutical: Honoraria.

scholarly journals Sequential CD19- and CD22-CART Cell Therapies for Relapsed B-Cell Acute Lymphoblastic Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2126-2126 ◽  
Author(s):  
Shuangyou Liu ◽  
Biping Deng ◽  
Yuehui Lin ◽  
Zhichao Yin ◽  
Jing Pan ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Free Survival ◽  
Car T Cells ◽  
Car T

Abstract With traditional therapies, the prognosis of relapsed acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is extremely poor. Chimeric antigen receptor (CAR) T cell therapy targeting at CD19 has demonstrated a significant efficacy on refractory/relapsed (r/r) B-ALL, but single-target CART could not maintain a long-term remission. Recently, CD22-CART has also shown an exciting result in r/r B-ALL. Here we sequentially applied CD19- and CD22-specific CART cells to treat relapsed B-ALL post-HSCT and observed the therapeutic effect. From June 30,2017 through May 31,2018, twenty-four B-ALL patients (pts) relapsing after allo-HSCT with both antigens CD19 and CD22 expression on blasts were enrolled, the median age was 24 (2.3-55) years. Seventeen pts had hematologic relapse, 6 with both bone marrow and extramedullary (EM) involvements and 1 with EM disease (EMD) only. Fourteen pts had failed to previous therapies including chemotherapy, donor lymphocyte infusion, interferon and even murinized CD19-CART in other hospitals. Recipient-derived donor T cells were collected for producing CAR-T cells, which were transfected by a lentiviral vector encoding the CAR composed of CD3ζ and 4-1BB. Eighteen pts were initially infused with murinized CD19-CART, then humanized CD22-CART; while 6 pts (5 failed to prior murinized CD19-CART and 1 had bright CD22-expression) were initially infused with humanized CD22-CART, then humanized CD19-CART. The time interval between two infusions was 1.5-6 months based on patients' clinical conditions. The average dose of infused CAR T cells was 1.4×105/kg (0.4-9.2×105/kg) for CD19 and 1.9×105/kg (0.55-6.6×105/kg) for CD22. All patients received fludarabine with or without cyclophosphamide prior to each infusion, some pts accepted additional chemo drugs to reduce the disease burden. Treatment effects were evaluated on day 30 and then monthly after each CART, minimal residual disease (MRD) was detected by flow cytometry (FCM) and quantitative PCR for fusion genes, EMD was examined by PET-CT, CT or MRI. Sixteen patients finished sequential CD19- and CD22-CART therapies. Three cases could not undergo the second round of CART infusion (1 died, 1 gave up and 1 developed extensive chronic graft-versus-host disease (GVHD)). The rest of 5 pts are waiting for the second CART. After first T-cell infusion, 20/24 (83.3%) pts achieved complete remission (CR) or CR with incomplete count recovery (CRi), MRD-negative was 100% in CR or CRi pts, 3 (12.5%) cases with multiple EMD obtained partial remission (PR), and 1 (4.2%) died of severe cytokine release syndrome (CRS) and severe acute hepatic GVHD. Sixteen patients (15 CR and 1 PR) underwent the second CART therapy. Before second infusion, 3/15 pts in CR became MRD+ and others remained MRD-. On day 30 post-infusion, 1 of 3 MRD+ pts turned to MRD-, 1 maintained MRD+ ( BCR/ABL+) and 1 had no response then hematologic relapse later. The PR patient still had not obtained CR and then disease progressed. As of 31 May 2018, at a median follow-up of 6.5 (4-10) months, among 16 pts who received sequential CD-19 and CD-22 CART therapies, 1 had disease progression, 2 presented with hematological relapse and 2 with BCR/ABL+ only, the overall survival (OS) rate was 100% (16/16), disease-free survival (DFS) was 81.3% (13/16) and MRD-free survival was 68.8% (11/16). CRS occurred in 91.7% (22/24) pts in the first round of T-cell infusion, most of them were mild-moderate (grade I-II), merely 2 pts experienced severe CRS (grade III-IV). The second CART only caused grade I or no CRS since the leukemia burden was very low. GVHD induced by CART therapy was a major adverse event in these post-HSCT patients. After the first CART, 7/24 (29.2%) pts experienced GVHD, of them, 4 presented with mild skin GVHD, 2 with severe hepatic GVHD (1 recovered and 1 died), and 1 developed extensive chronic GVHD. No severe GVHD occurred in the second infusion. Our preliminary clinical study showed that for B-ALL patients who relapsed after allo-HSCT, single CD19- or CD22- CART infusion resulted in a high CR rate of 83.3%, sequentially combined CD19- and CD22-CART therapies significantly improved treatment outcome with the rate of OS, DFS and MRD-free survival being 100%, 81.3% and 68.8%, respectively, at a median follow-up of 6.5 months. The effect of CART on multiple EMD was not good and CART induced GVHD needs to be cautious. Disclosures No relevant conflicts of interest to declare.

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