scholarly journals CAR T cells vs allogeneic HSCT for poor-risk ALL

Hematology ◽  
2020 ◽  
Vol 2020 (1) ◽  
pp. 501-507
Author(s):  
Caroline Diorio ◽  
Shannon L. Maude
Keyword(s):  
T Cells ◽  
High Risk ◽  
Survival Benefit ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Poor Risk ◽  
Car T ◽  
First Remission ◽  
Very High

Abstract For subgroups of children with B-cell acute lymphoblastic leukemia (B-ALL) at very high risk of relapse, intensive multiagent chemotherapy has failed. Traditionally, the field has turned to allogeneic hematopoietic stem cell transplantation (HSCT) for patients with poor outcomes. While HSCT confers a survival benefit for several B-ALL populations, often HSCT becomes standard-of-care in subsets of de novo ALL with poor risk features despite limited or no data showing a survival benefit in these populations, yet the additive morbidity and mortality can be substantial. With the advent of targeted immunotherapies and the transformative impact of CD19-directed chimeric antigen receptor (CAR)–modified T cells on relapsed or refractory B-ALL, this approach is currently under investigation in frontline therapy for a subset of patients with poor-risk B-ALL: high-risk B-ALL with persistent minimal residual disease at the end of consolidation, which has been designated very high risk. Comparisons of these 2 approaches are fraught with issues, including single-arm trials, differing eligibility criteria, comparisons to historical control populations, and vastly different toxicity profiles. Nevertheless, much can be learned from available data and ongoing trials. We will review data for HSCT for pediatric B-ALL in first remission and the efficacy of CD19 CAR T-cell therapy in relapsed or refractory B-ALL, and we will discuss an ongoing international phase 2 clinical trial of CD19 CAR T cells for very-high-risk B-ALL in first remission.

Effect of chimeric antigen receptor-modified T (CAR-T) cells on responses in children with non-CNS extramedullary relapse of CD19+ acute lymphoblastic leukemia (ALL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10507-10507 ◽  
Author(s):  
Mala Kiran Talekar ◽  
Shannon L. Maude ◽  
George E Hucks ◽  
Laura S Motley ◽  
Colleen Callahan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lymphoblastic Leukemia ◽  
Phase 1 ◽  
Single Agent ◽  
Prior History ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T

10507 Background: Anti-CD19 CAR-T cell therapies have shown high efficacy in inducing durable marrow responses in patients with relapsed/refractory CD19+ ALL. We now report on outcome of 10 patients with extramedullary (EM) involvement of ALL treated with CAR-T, including 5 patients who had EM disease at time of infusion. Methods: We identified patients treated on pediatric phase 1/2a trials of murine (CTL019) or humanized (CTL119) anti-CD19 CAR-T cells for isolated EM or BM/EM relapse of ALL. EM relapse was defined as involvement of non-CNS site by imaging +/- pathology within 12 months (mos) of infusion. Post infusion, patients had diagnostic imaging done at 1, 3, 6, 9, and 12 mos. Results: Among 97 patients receiving CAR-T, ten (CTL019, n=6; CTL119, n=4) were identified who had EM involvement on average 2.3 mos (range 0-9 mos) prior to infusion; including 5/10 at time of infusion. Sites of EM relapses included testes, sinus, parotid, bone, uterus, kidney and skin, and 5 patients had multiple sites of EM involvement. Patients ranged from 2-4 relapses of their ALL pre-CAR-T. Two had isolated EM relapse (sites were parotid and multifocal bony lesions in one; testis and sinus in second). All 10 patients had undergone hematopoietic stem cell transplantation prior to EM relapse, 2 had received radiation directed to the EM site prior to CAR-T. Five patients evaluated by serial imaging had objective responses: 2 had resolution of EM disease by day 28; 2 had resolution by 3 mos; 1 had continued decrease in size of uterine mass at 3 and 6 mos and underwent hysterectomy at 8 mos with no evidence of disease on pathology. In the 4 patients with prior history of skin or testicular involvement, there was no evidence by exam at day 28. One patient had progressive EM disease within 2 weeks of CAR-T cell infusion and died at 6 weeks. Three relapsed with CD19+ disease [1 skin/medullary- died at 38 mos post CAR-T; 2 medullary (1 died at 17 mos, 1 alive at 28 mos)]. The remaining 6 are alive and well at median follow-up of 10 mos (range 3-16 mos) without recurrence of disease. Conclusions: Single agent CAR-T immunotherapy can induce potent and durable responses in patients with EM relapse of their ALL. Clinical trial information: NCT01626495, NCT02374333.

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.

Targeting Leukemias by CD123 Specific Chimeric Antigen Receptor

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1908-1908
Author(s):  
Radhika Thokala ◽  
Harjeet Singh ◽  
Simon Olivares ◽  
Richard Champlin ◽  
Laurence J N Cooper
Keyword(s):  
T Cells ◽  
Chimeric Antigen Receptor ◽  
Lymphoblastic Leukemia ◽  
Antigen Receptor ◽  
Leukemic Cell ◽  
Sleeping Beauty ◽  
Myelogenous Leukemia ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Car T

Abstract Abstract 1908 Chimeric antigen receptors (CARs) are employed to genetically modify T cells to redirect their specificity to target antigens on tumor cells. Typically a second generation CAR is derived by fusing an extracellular domain derived from the scFv of monoclonal antibody (CAR) specific to targeted antigen with CD3 zeta, and CD28 endodomains. CD123 (IL3RA) is expressed on 45% to 95%of acute myelogenous leukemia (AML) and B-cell lineage acute lymphoblastic leukemia (B-ALL). Expression of CD123 is high in the leukemic stem cell (LSC) population, but not in normal hematopoietic stem cells. Thus, CD123 appears to be potential target for immunotherapy in leukemias through chimeric antigen receptor (CAR). We hypothesized that the generation of CD123 specific CAR can redirect the specificity of T cells to CD123 and this was tested by cloning the scFv of CD123 mAb in our CAR construct. The sleeping beauty system was used to express the CAR and DNA plasmids were electroporated into peripheral blood mononuclear cells and cells were numerically expanded on artificial antigen presenting cells genetically modified to express co stimulatory molecules CD86, 4-1BBL, membrane-bound IL-15, and CD123 antigen in presence of IL-21 and 1L–2. CAR+ T numerically expanded to clinically relevant numbers and showed antigen specific cytotoxicity in leukemic celllines. CAR+ T cells expressed both effector and memory markers showing the potential for in vivo persistence after T cell infusion. The bonemarrow homing receptor CXCR4 was expressed by CAR T cells shows the potential to target LSC that reside in BM niches. The preliminary data suggests that mirroring an approach we are using to manufacture clinical grade CD19 specific CAR+ T cells.Figure 1:(A) CAR expression on day 35. (B) Cytotoxicity of CD123CAR in leukemic cell lines.Figure 1:. (A) CAR expression on day 35. (B) Cytotoxicity of CD123CAR in leukemic cell lines.CD3CD3 Disclosures: No relevant conflicts of interest to declare.

scholarly journals Haplo-Identical Non-Gene Editing CD7 CAR T-Cells Induced Bone Marrow and Extramedullary Remission in a Pediatric Patient with TP53 Mutated Relapsed and Refractory Early T-Cell Precursor Lymphoblastic Leukemia/Lymphoma after Haploidentical Hematopoietic Stem Cell Transplantation

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4817-4817
Author(s):  
Haiping Dai ◽  
Yang Lin ◽  
Huimin Meng ◽  
Qingya Cui ◽  
Wenjuan Zhu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Pediatric Patient ◽  
Gene Editing ◽  
Lymphoblastic Leukemia ◽  
Cell Precursor ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Car T

Abstract Patients with relapsed/refractory early T-cell precursor lymphoblastic leukemia/lymphoma (ETP-ALL/LBL) respond poorly to traditional therapy and have dismal prognosis. CD7 expresses in almost all blasts of T-cell lymphoma/leukemia and represents one of the most promising therapeutic targets for T-ALL/LBL by CD7 targeted chimeric antigen receptor modified T cell therapy (CD7-CART). Because of shared CD7 expression in the majority of normal T-cell surfaces, we utilized an non-gene editing strategy by co-transducing CAR-T cells with a CD7 protein expression blocker (PEBL), and successfully overcame the fratricide as well as maintain the proliferation and cytotoxicity of CD7-CART-cells. Here, we presented the efficacy and safety results of CD7-CART therapy in a pediatric patient with TP53 mutated ETP-ALL/LBL. The patient was diagnosed with ETP-ALL/LBL at 2016, achieved and maintained complete remission (CR) for 2 years with traditional chemotherapy. The disease relapsed at a month after discontinuation of chemotherapy. He underwent haploidentical HSCT at the second CR, but suffered relapse again 2 years post haplo-HSCT. TP53 mutation（VAF:96.5%） and extensive extramedullary infiltration was detected at relapse. The patient was resistant to venetoclax combined with decitabine, homoharringtonine, aclarubicin, cytarabine and granulocyte colony stimulating factor (G-CSF), high-dose cytarabine combined with cladribine, G-CSF, chidamide and CD38 CART therapy. Nanobody derived CD7-CART cells were manufactured from lymphocytes of the donor. The CART cells were negative for CD7, CD223 and CD279. 70.5% of blasts in the bone marrow aspirates were observed prior to CAR T-cells infusion. A total of 5×10 6/kg CD7-CART-cells were infused. CR was confirmed at day 30 bone marrow evaluation and maintained at the last followup at day 91. Partial remission was achieved as evaluated by PET-CT scan at day 93. Persistence of CD7-CART-cells can be detected with flowcytometry until day 96 post CAR T-cells infusion. Grade 3 cytokine release syndrome with high fever and hypotension were observed, which was relived by tocilizumab and dexamethosone. No organ dysfuction and immune effector cell-associated neurotoxicity syndrome were observed. In general, we showed for the first time that the nanobody derived CD7-CART with PEBL technology was a potent and safe salvage therapy in a relapsed/refractory ETP-ALL/LBL patient with high tumor burden. Disclosures No relevant conflicts of interest to declare.

scholarly journals Tandem CD19/CD22 Dual Targets CAR T-Cells Bridging Hematopoietic Stem Cells Transplantation Acquires Robust Remission for Relapsed and Refractory B Acute Lymphoblastic Leukemia Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1753-1753
Author(s):  
Wei Cui ◽  
Xinyue Zhang ◽  
Haiping Dai ◽  
Qingya Cui ◽  
Jia Yin ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
Cox Regression ◽  
Conflicts Of Interest ◽  
Lymphoblastic Leukemia ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Car T

Abstract Background: CD19 chimeric antigen receptor T (CAR-T) cells have demonstrated impressive early response rates in relapse and refractory B acute lymphoblastic leukemia (r/r B-ALL). However, a high rate of patients suffered a relapse, which occurred in a large subset of other trials and confers dismal outcomes. Dual targets approaches are proved to optimize the response rate and prevent CD19 - relapse. Alternatively, limited patients accepted the tandem CD19/CD22 CAR-T therapy, but the clinical trials in a large scale to investigate the tandem CAR-T were rare. Methods: We conducted an open label, single center clinical trial at the First Affiliated Hospital of Soochow University to investigate the efficacy and safety of tandem CD19/CD22 dual targets CAR T-cells for r/r B-ALL. All patients received FC (fludarabine, 30 mg/m2, days 1-3 and cyclophosphamide, 300 mg/m2, days 1-3) based chemotherapy as the lymphodepleting regimen. Median infusion dose of CAR-T cells was 1(0.5-2.5) *10 7 cells/kg. Results: From October 2017 to June 2021, a total of 47 patients were treated with CD19/CD22 CAR T-cells and included in our analysis. Among the 47 patients, primary refractory B-ALL patients account for 44.68%. 27 patients (57.4%) had a high disease burden, with 20% or more blasts in BM. Consequently, at day 28 assessment, 47 patients (100%) got hematological CR and the 40 out of 47 patients (85.1%) achieved minimal residual disease complete remission (MRD -CR). The toxicities of CD19/CD22 CAR T-cells therapy were reversible and clinically manageable. Cytokine reverse syndrome of any grades occurred in 41 of 47 patients (87.23%) and was severe (grade>2) in 8 (17.02%). Immune effector cell-associated neurotoxicity happened in one patient. The most common severe hematological abnormalities were grade 3/4 leukopenia (74.47%). Serious thrombocytopenia and anemia occurred in 48.93% and 57.44% patients. The non-hematological toxicity were reversible with tight monitoring and support care. Within a median follow-up of 21.83 months (range, 2.57 to 42.53), the median overall survival (OS) and leukemia free survival (LFS) for the entire cohort have not reached. The OS rate of all the patients was 93.569% (95%CI, 80.97% to 97.832%) at 6 months, 78.721% (95%CI, 60.719% to 87.625%) at 1 year and 74.578% (95%CI, 55.263% to 84.969%) at 2 years in all patients. The LFS rate was 87.031% (95%CI, 73.375% to 93.958%) and 68.297% (95%CI, 51.419% to 80.365%) at 6 month and 1 year, respectively. The 6-months cumulative incidence of relapse (CIR) was 8.96%, while 1-year CIR was 23.254%. Thirty-four of 47 patients (72.34%) proceeded to a bridging allogeneic hematopoietic stem cell transplantation (allo-HSCT). The OS of HSCT group was 94.118% at 6 months and 80.420% at 1 year. The 6-months OS of no-HSCT group was 83.916%, while 1-year OS was 74.592%. The HSCT group had significantly better LFS and lower CIR than the no-HSCT group (LFS, p=0.0459; CIR, p=0.0267). We initially performed multivariable Cox regression analyses, which shows that better long-term survival in patients with MRD -CR status, as well as bridging allo-HSCT. Conclusions: Tandem CD19/CD22 CAR-T cells are safety and highly effective in inducing CR for r/r B-ALL patients. The consolidative allo-HSCT can provide long-term durable disease control in these patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Posttransplant chimeric antigen receptor therapy

Blood ◽  
2018 ◽  
Vol 131 (10) ◽  
pp. 1045-1052 ◽  
Author(s):  
Melody Smith ◽  
Johannes Zakrzewski ◽  
Scott James ◽  
Michel Sadelain
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Cell Surface Molecule ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Car T

Abstract Therapeutic T-cell engineering is emerging as a powerful approach to treat refractory hematological malignancies. Its most successful embodiment to date is based on the use of second-generation chimeric antigen receptors (CARs) targeting CD19, a cell surface molecule found in most B-cell leukemias and lymphomas. Remarkable complete remissions have been obtained with autologous T cells expressing CD19 CARs in patients with relapsed, chemo-refractory B-cell acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. Allogeneic CAR T cells may also be harnessed to treat relapse after allogeneic hematopoietic stem cell transplantation. However, the use of donor T cells poses unique challenges owing to potential alloreactivity. We review different approaches to mitigate the risk of causing or aggravating graft-versus-host disease (GVHD), including CAR therapies based on donor leukocyte infusion, virus-specific T cells, T-cell receptor–deficient T cells, lymphoid progenitor cells, and regulatory T cells. Advances in CAR design, T-cell selection and gene editing are poised to enable the safe use of allogeneic CAR T cells without incurring GVHD.

scholarly journals Tandem CD19/CD22 Dual Targets CAR-T Cells Therapy Obtains Superior CR Rate Than Single CD19 CAR-T Cells Infusion As Well As Sequential CD19 and CD22 CAR-T Cells Infusion for Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1755-1755
Author(s):  
Sining Liu ◽  
Xinyue Zhang ◽  
Haiping Dai ◽  
Qingya Cui ◽  
Wei Cui ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Significant Difference ◽  
Car T ◽  
Cell Acute Lymphoblastic Leukemia

Abstract Background: CD19 chimeric antigen receptor T (CAR-T) cells therapy has shown great success in B-cell acute lymphoblastic leukemia (B-ALL). To reduce the possibility of relapse due to CD19 antigen loss, sequential CD19/CD22 and tandem CD19/CD22 dual targets CAR-T cells have been developed. However, the optimal combination strategy of target antigens for CAR-T cells is still uncertain. This study was designed to compare the efficacy and safety of single CD19, tandem CD19/CD22 and sequential CD19/CD22 CAR-T cells therapies in relapsed/refractory(R/R) B-ALL patients. Methods: Between March 2016 and August 2020, a total of 200 patients with R/R B-ALL successfully received 230 CAR-T treatments (30 patients received the second CAR-T therapy and 8 patients received the third CAR-T therapy) were screened in this study. Among them, 168 patients received single CD19 CAR-T therapy, 49 patients received tandem CD19/CD22 CAR-T therapy, and 13 patients received sequential CD19/CD22 CAR-T therapy. ALL patients enrolled in the CD19 CAR-T clinical trials (NCT03919240) or CD19/CD22 CAR-T clinical trials (NCT03614858). Results: The baseline characteristics of patients were similar among the three groups. The complete remission (CR) rates were 82.7% (139/168) in patients who received CD19 CAR-T therapy, 95.9% (47/49) in patients who received tandem CD19/CD22 CAR-T therapy, and 69.2% (9/13) in patients who received sequential CD19/CD22 CAR-T therapy (P=0.012). Tandem CD19/CD22 CAR-T therapy remained one of the significant favorable factors in multivariate logistic regression analysis of CR rate in all patients (hazard ratio, 0.081; 95% CI, 0.010-0.671). Furthermore, minimal residual disease (MRD)-negative CR rates were 66.7%, 81.6% and 61.5%, respectively (P=0.092). There was no significant difference in the incidence of adverse events among the three groups. Severe cytokine release syndrome (CRS, Grade ≥ 3) occurred in 25.0% of patients in CD19 group, 18.4% of patients in tandem CD19/CD22 group, and 23.1% in sequential CD19/CD22 group (P=0.641). There was no significant difference in overall survival (OS) and leukemia-free survival (LFS) among three groups (6-month OS: 83.1%, 90.0% and 88.9%, respectively, P=0.1620; 6-month LFS: 76.2%, 76.2% and 88.9%, respectively, P=0.8179). Univariate and multivariate Cox regression analyses showed that a better LFS related to less frequencies of relapse, lower tumor burden, MRD-negative CR and bridging allogeneic hematopoietic stem cell transplantation (allo-HSCT). Conclusions: Tandem CD19/CD22 dual targets CAR-T cells therapy obtains superior CR rate than single CD19 and sequential CD19/CD22 CAR-T cells therapy. This provides an effective treatment option for R/R B-ALL patients with chemotherapy resistance. Disclosures No relevant conflicts of interest to declare.

scholarly journals Haploidentical Donor-Derived CAR-T Cells Are Safely and Effectively Co-Infused with the Haploidentical Graft, Depleted of Ab T Cells: Report of Case Series

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1736-1736
Author(s):  
Larisa Shelikhova ◽  
Olga Molostova ◽  
Arina Rakhteenko ◽  
Rimma Khismatullina ◽  
Julia Abugova ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Median Time ◽  
Lymphoblastic Leukemia ◽  
Hematopoietic Stem ◽  
Platelet Recovery ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T ◽  
Grade 3

Abstract Introduction Autologous chimeric antigen receptor (CAR) T cells induce high rate of deep remissions among children with relapsed/refractory B-precursor acute lymphoblastic leukemia (R/R B-ALL). In a significant proportion of patients true cure is achieved only with HSCT as post-CAR-T consolidation. Seeking to combine the cytoreductive and curative power of HSCT with the antigen-specific activity of CAR-T we devised an approach with simultaneous infusion of haploidentical ab T cell-depleted graft and CAR-T cells, derived from the same donor. The approach was offered to patients with R/R B-ALL on a compassionate use basis and here the first experience is summarized. Patients and methods A total of 11 patients with relapsed/refractory BCP-ALL (n-10) and Burkitt leukemia(n-1), (5 female, 6 male, median age 8,3 y) were treated. Three patients had relapsed BCP-ALL after both haploidentical HSCT and autologous CD19 CAR-T cell, 3 after haploidentical HSCT, 2 after autologous CD19 CAR-T cell, 3 after intensive chemotherapy +/- blinatumomab (n=2). Seven patients had CD19 and CD22 positive leukemic cells in bone marrow (MRD+ n=1, >20% blasts n=6), 2 pts had MRD-level disease with CD22 positive blast cells and 2 pts were in CR2. Peripheral blood mononuclear cells used to produce CAR T cells were provided by the patient's transplant donor. The CliniMACS Prodigy T cell transduction (TCT) process was used to produce CD19 and СD19/22CAR-T cells. Five (45%) pts received treosulfan-based myeloablative preparative regimen, while TBI-based regimen was used in 6 (55%) pts. GvHD prophylaxis included tocilizumab at 8 mg/kg on day -1 and abatacept at 10 mg/kg on day -1, +7, +14, +28. Final product was administered without cryopreservation to the patients: 10 pts received allogeneic CAR T cell with haploidentical (n=10) and match related (n=1) TCRαβ-depleted graft (CD19 CAR- T cell n=1 and CD19/22 CAR- T cell n=10). The CAR-T cell product was administered at a dose of 0,1*10 6/kg of CAR-T cells in all pts. The median dose of CD34+ cells was 8.5 x10 6/kg (range 5-15), αβ T cells - 56x10 3/kg (range 9-172). Results Primary engraftment was achieved in 10 of 11 pts (non-engraftment patient relapsed early), the median time to neutrophil and platelet recovery was 13 and 14 days, respectively. Cytokine release syndrome occurred in 7 patients (63%) and all were grade ≤3. Six patients (54%) had neurologic events (ICANS grade 3, n=1). No aGVHD 3-4 were observed, 4 pts developed grade 2 aGVHD (skin and gut). The median time to CAR-T cell peak expansion was 14 days (7-28). The median time to CAR-T cell persisted was 6 months (2-12) and B cell aplasia was 7 months. All engrafted patients achieved CR (MRD negative) at day +28 after CAR-T cell therapy, one patient died due to Mucormycosis at day +31. One patient relapsed after 2 months after HST. Eight patients are alive in CR with a median follow up 291 days (85-388). Conclusion Our early experience suggests that haploidentical CAR-T cells can be safely infused simultaneously with the hematopoietic stem cell graft on the platform of ab T cell depletion. The infusions did not compromise engraftment and GVHD control, while specific CAR-T toxicity was mild and manageable. We have documented allogeneic haploidentical CAR-T expansion and persistence. Prospective testing of the approach is warranted. Disclosures Maschan: Miltenyi Biotec: Speakers Bureau.

scholarly journals Treatment Outcome of Pediatric B-ALL with Bone Marrow and Extramedullary Relapse by Anti-CD19 CAR-T

2021 ◽  
Author(s):  
Xinyu Wan ◽  
Fan Yang ◽  
Xiaomin Yang ◽  
tianyi Wang ◽  
Lixia Ding ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Lentiviral Vector ◽  
Lymphoblastic Leukemia ◽  
Single Chain ◽  
Single Chain Antibody ◽  
Hematopoietic Stem ◽  
Car T Cells ◽  
Car T ◽  
Extramedullary Relapse

Background: Anti-CD19 Chimeric Antigen Receptor T-Cell Immunotherapy (19CAR-T) has achieved impressive clinical achievements in both adult and pediatric relapsed/refractory (r/r) B-lineage acute lymphoblastic leukemia (B-ALL). However, the application and effect of CAR-T therapy in B-ALL patients with extramedullary relapse are rarely issued even disqualified in some clinical trials. Here, we examined the efficacy of 19CAR-T in patients with both bone marrow and extramedullary involvement. Methods: CAR-T cells were generated by a lentiviral vector transfection into primary human T lymphocytes to express anti-CD19 and anti-CD22 single chain antibody fragments (scFvs) with the cytoplasmic domains of 4-1BB and CD3ζ. Patients diagnosed as r/r B-ALL with extramedullary origination were infused with anti-CD19 CAR-T cells. The clinical responses were evaluated by bone marrow aspiration, imaging, and flow cytometry examination. Results: A total of 8 patients received 19CAR-T infusion and all of them acquired complete remission (CR), in which only 1 patient was bridged to hematopoietic stem cell transplantation (HSCT). Even though there were 3 patients relapsed after infusion, they received 19/22CAR-T infusion sequentially and acquired the second remission. To date, 5 patients are continuous CR, and all patients are still alive. The mean follow-up time was 21.9 months while the 24-month estimated event-free survival (EFS) is 51.4%. Conclusions: Anti-CD19 CAR-T therapy can lead to clinical remission for extramedullary relapsed pediatric B-ALL patients. However, the problem of CD19+ relapses after CAR-T remained to be solved. For patients relapsing after CAR-T, the second CAR-T therapy suggests creating another opportunity of remission for subsequent HSCT.

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