scholarly journals Sequential Infusion of Anti-CD22 and Anti-CD19 Chimeric Antigen Receptor T Cells for Adult Patients with Refractory/Relapsed B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 846-846
Author(s):  
Liang Huang ◽  
Na Wang ◽  
Chunrui Li ◽  
Yang Cao ◽  
Yi Xiao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Lymphoblastic Leukemia ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Antigen Loss

Abstract Clinical trials of second generation chimeric antigen receptor engineered T cells (CAR-T cells) have yielded unprecedented efficacy in refractory/relapsed B-cell acute lymphoblastic leukemia (B-ALL), especially in children and young adult. However, antigen loss relapse has been observed in approximately 14% of patients in anti-CD19 CAR-T cell therapy across institutions, which emerges as a challenge for the long-term disease control of this promising immunotherapy. Recently, CD19/CD20 and CD19/CD22 dual antigen targeting have been proposed to overcome antigen loss relapse after the administration of anti-CD19 CAR-T cells. This strategy may result in enhanced anti-tumor activity, while safety concern regarding the risk of cytokine release syndrome (CRS) due to significant CAR-T cell activation and cytokine release needs to be addressed. Here, we conducted an open-label, single-center and single-arm pilot study of sequential infusion of anti-CD22 and anti-CD19 CAR-T cells. We aimed to evaluate its safety and efficacy in adult patients with refractory or relapsed B-ALL. This trial is registered with ChiCTR, number ChiCTR-OPN-16008526. Between March 2016 and March 2017, 27 patients with refractory or relapsed B-ALL were enrolled in this clinical trial, with a median age of 30±12 years (range, 18-62 years). Thirteen patients (48.1%) had a history of at least two prior relapsed or primary refractory disease. Twenty-six patients received fludarabine and cyclophosphamide before the infusion of CAR-T cells. The median cell dosages of anti-CD22 and anti-CD19 CAR-T cells were 2.44 ± 1.02 × 106 /kg and 1.98 ± 1.05 × 106 /kg, respectively. 24/29 (88.9%) patients achieved CR or Cri, including 7 patients who received prior hematopoietic stem cell transplantation, and 13/27 (48.1%) patients achieved minimal residual disease negative (MRD-) CR accessed by flow cytometry. Sustained remission was achieved with a 6-month overall survival rate of 79% (95% CI, 66-97) and an event-free survival rate of 72% (95% CI, 55-95). 24/29 (88.9%) patients experienced CRS and 6/27 (22.2%) patients had reversible sever CRS (grade 3-4). And 3/27 (11.1%) patients developed neurotoxicity. Multi-color flow cytometry was used to screen and quantitate MRD in blood, bone marrow and cerebrospinal fluid. Antigen escape of CD19 and CD22 was not detected in any relapsed patient post-CAR-T cell therapy. Our results indicated that sequential infusion of third generation Anti-CD22 and Anti-CD19 CAR-T cell therapy is feasible and safe for patients with refractory/relapsed B-ALL. Dual antigen targeting should be a promising approach for overcoming antigen escape relapse, while needs to be further determined in our clinical trial. Disclosures No relevant conflicts of interest to declare.

scholarly journals Antitumor efficacy of BAFF-R targeting CAR T cells manufactured under clinic-ready conditions

2020 ◽  
Vol 69 (10) ◽  
pp. 2139-2145
Author(s):  
Zhenyuan Dong ◽  
Wesley A. Cheng ◽  
D. Lynne Smith ◽  
Brian Huang ◽  
Tiantian Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
B Cell ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Antigen Loss

Abstract B-cell malignancies can potentially be cured by CD19 chimeric antigen receptor (CAR) T-cell therapy. Although clinical response rates can be up to 93% in acute lymphoblastic leukemia, treatment-related antigen loss and lack of therapeutic persistence contribute to disease relapse. These shortcomings of current CAR T-cell therapy indicate the need for biologically relevant target selection and for improving the efficacy and persistence of the CAR T cells, which we have addressed by developing a novel B-cell activating factor receptor (BAFF-R) CAR T-cell therapy with improved therapeutic persistence. BAFF-R is a B-cell survival receptor and highly expressed in B-cell malignancies. We developed a prototype CAR T cell that efficiently and specifically eliminated BAFF-R expressing human B-cell tumors in several xenogeneic mouse models, including models of CD19 antigen loss. We proceeded with translational development and validation of BAFF-R CAR T cells produced under current good manufacturing practices (cGMP). cGMP-grade BAFF-R CAR T cells underwent in vitro and in vivo validation in established models to confirm that the potency and efficacy of our original research modeling was replicated. Food and Drug Administration required release testing was performed to ensure our BAFF-R CAR T cells meet specifications for new drug products. Completing and exceeding these requirements, the data fully support the initiation of a first-in-human Phase 1 trial for BAFF-R-positive relapsed/refractory (r/r) B-ALL.

Targeting CD19-negative relapsed B-acute lymphoblastic leukemia using trivalent CAR T cells.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 121-121 ◽  
Author(s):  
Kristen Fousek ◽  
Junji Watanabe ◽  
Ann George ◽  
Xingyue An ◽  
Heba Samir Samaha ◽  
...  
Keyword(s):  
T Cells ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Cell Therapy ◽  
Lymphoblastic Leukemia ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

121 Background: Chimeric antigen receptor (CAR) T cells targeting CD19 have shown remarkable efficacy in treating relapsed B cell acute lymphoblastic leukemia (B-ALL). However, recent reports show that up to 40% of patients who relapse after CD19 CAR T cell therapy have CD19-negative disease, justifying a need to expand CAR T cell therapy for B-ALL to include additional tumor-associated antigens. We hypothesize that targeting CD19, CD20, and CD22 will improve B-ALL therapy outcomes and control disease progression during CD19-negative relapse. Methods: We designed two trivalent CAR T cell products with exodomains derived from single chain variable fragments (ScFv) targeting CD19, CD20, and CD22. Each CAR contains the 4-1BB and T-cell receptor zeta chains. Donor T cells were engineered to express the CARs using a retroviral system. We used primary CD19-negative relapsed bone marrow samples and CRISPR CD19 knockouts of primary ALL to model CD19 escape and standard cytotoxicity and immune assays to evaluate anti-tumor efficacy. Results: Due to the use of viral 2A sequences we detected near equal expression of each CAR by flow cytometry. The first T cell product expresses three CARs individually (TriCAR), and the second expresses a single CAR targeting CD19 and a second bi-specific CAR targeting CD20 and CD22 via a tandem arrangement (SideCAR). Using primary B-ALL cells, we observed that TriCAR and SideCAR T cells killed ALL cells more robustly than CD19 CAR T cells at low E:T ratios. Further, in ImageStream analysis of single cell interactions between CAR T cells and primary B-ALL cells, TriCAR T cells exhibited increased actin polymerization compared to CD19 CAR T cells, suggesting remodeling and increased cell activation. Finally, in multiple models of CD19 escape in primary ALL, we showed that trivalent CAR T cells mitigated CD19 negative relapse, producing IFN-γ/TNF-α and killing CD19-negative primary ALL, while CD19 CAR T cells remained ineffective. Conclusions: Trivalent CAR T cells effectively target primary ALL cells with varying antigen profiles and mitigate CD19-negative relapse. This strategy has the potential for use as an initial CAR therapy in relapsed ALL or a salvage therapy for patients with CD19-negative disease.

scholarly journals Anti-Mesothelin CAR T cell therapy for malignant mesothelioma

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Laura Castelletti ◽  
Dannel Yeo ◽  
Nico van Zandwijk ◽  
John E. J. Rasko
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Malignant Mesothelioma ◽  
Oncolytic Viruses ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

AbstractMalignant mesothelioma (MM) is a treatment-resistant tumor originating in the mesothelial lining of the pleura or the abdominal cavity with very limited treatment options. More effective therapeutic approaches are urgently needed to improve the poor prognosis of MM patients. Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a novel potential treatment for this incurable solid tumor. The tumor-associated antigen mesothelin (MSLN) is an attractive target for cell therapy in MM, as this antigen is expressed at high levels in the diseased pleura or peritoneum in the majority of MM patients and not (or very modestly) present in healthy tissues. Clinical trials using anti-MSLN CAR T cells in MM have shown that this potential therapeutic is relatively safe. However, efficacy remains modest, likely due to the MM tumor microenvironment (TME), which creates strong immunosuppressive conditions and thus reduces anti-MSLN CAR T cell tumor infiltration, efficacy and persistence. Various approaches to overcome these challenges are reviewed here. They include local (intratumoral) delivery of anti-MSLN CAR T cells, improved CAR design and co-stimulation, and measures to avoid T cell exhaustion. Combination therapies with checkpoint inhibitors as well as oncolytic viruses are also discussed. Preclinical studies have confirmed that increased efficacy of anti-MSLN CAR T cells is within reach and offer hope that this form of cellular immunotherapy may soon improve the prognosis of MM patients.

scholarly journals Metabolic and Mitochondrial Functioning in Chimeric Antigen Receptor (CAR)—T Cells

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1229
Author(s):  
Ali Hosseini Rad S. M. ◽  
Joshua Colin Halpin ◽  
Mojtaba Mollaei ◽  
Samuel W. J. Smith Bell ◽  
Nattiya Hirankarn ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Chimeric Antigen Receptor ◽  
Metabolic State ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized adoptive cell therapy with impressive therapeutic outcomes of >80% complete remission (CR) rates in some haematological malignancies. Despite this, CAR T cell therapy for the treatment of solid tumours has invariably been unsuccessful in the clinic. Immunosuppressive factors and metabolic stresses in the tumour microenvironment (TME) result in the dysfunction and exhaustion of CAR T cells. A growing body of evidence demonstrates the importance of the mitochondrial and metabolic state of CAR T cells prior to infusion into patients. The different T cell subtypes utilise distinct metabolic pathways to fulfil their energy demands associated with their function. The reprogramming of CAR T cell metabolism is a viable approach to manufacture CAR T cells with superior antitumour functions and increased longevity, whilst also facilitating their adaptation to the nutrient restricted TME. This review discusses the mitochondrial and metabolic state of T cells, and describes the potential of the latest metabolic interventions to maximise CAR T cell efficacy for solid tumours.

IMMU-45. COMBINATION OF EGFRVIII CAR T-CELL THERAPY AND PARACRINE GAM MODULATION FOR THE TREATMENT OF GBM

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi102-vi103
Author(s):  
Tomás A Martins ◽  
Marie-Françoise Ritz ◽  
Tala Shekarian ◽  
Philip Schmassmann ◽  
Deniz Kaymak ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Differential Expression Analysis ◽  
Dependent Manner ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Abstract The GBM immune tumor microenvironment mainly consists of protumoral glioma-associated microglia and macrophages (GAMs). We have previously shown that blockade of CD47, a ‘don't eat me’-signal overexpressed by GBM cells, rescued GAMs' phagocytic function in mice. However, monotherapy with CD47 blockade has been ineffective in treating human solid tumors to date. Thus, we propose a combinatorial approach of local CAR T cell therapy with paracrine GAM modulation for a synergistic elimination of GBM. We generated humanized EGFRvIII CAR T-cells by lentiviral transduction of healthy donor human T-cells and engineered them to constitutively release a soluble SIRPγ-related protein (SGRP) with high affinity towards CD47. Tumor viability and CAR T-cell proliferation were assessed by timelapse imaging analysis in co-cultures with endogenous EGFRvIII-expressing BS153 cells. Tumor-induced CAR T-cell activation and degranulation were confirmed by flow cytometry. CAR T-cell secretomes were analyzed by liquid chromatography-mass spectrometry. Immunocompromised mice were orthotopically implanted with EGFRvIII+ BS153 cells and treated intratumorally with a single CAR T-cell injection. EGFRvIII and EGFRvIII-SGRP CAR T-cells killed tumor cells in a dose-dependent manner (72h-timepoint; complete cytotoxicity at effector-target ratio 1:1) compared to CD19 controls. CAR T-cells proliferated and specifically co-expressed CD25 and CD107a in the presence of tumor antigen (24h-timepoint; EGFRvIII: 59.3±3.00%, EGFRvIII-SGRP: 52.6±1.42%, CD19: 0.1±0.07%). Differential expression analysis of CAR T-cell secretomes identified SGRP from EGFRvIII-SGRP CAR T-cell supernatants (-Log10qValue/Log2fold-change= 3.84/6.15). Consistent with studies of systemic EGFRvIII CAR T-cell therapy, our data suggest that intratumoral EGFRvIII CAR T-cells were insufficient to eliminate BS153 tumors with homogeneous EGFRvIII expression in mice (Overall survival; EGFRvIII-treated: 20%, CD19-treated: 0%, n= 5 per group). Our current work focuses on the functional characterization of SGRP binding, SGRP-mediated phagocytosis, and on the development of a translational preclinical model of heterogeneous EGFRvIII expression to investigate an additive effect of CAR T-cell therapy and GAM modulation.

scholarly journals 124 Functionalizing CAR T cells for selective proliferation and dual-targeting using the meditope technology

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A133-A133
Author(s):  
Cheng-Fu Kuo ◽  
Yi-Chiu Kuo ◽  
Miso Park ◽  
Zhen Tong ◽  
Brenda Aguilar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

BackgroundMeditope is a small cyclic peptide that was identified to bind to cetuximab within the Fab region. The meditope binding site can be grafted onto any Fab framework, creating a platform to uniquely and specifically target monoclonal antibodies. Here we demonstrate that the meditope binding site can be grafted onto chimeric antigen receptors (CARs) and utilized to regulate and extend CAR T cell function. We demonstrate that the platform can be used to overcome key barriers to CAR T cell therapy, including T cell exhaustion and antigen escape.MethodsMeditope-enabled CARs (meCARs) were generated by amino acid substitutions to create binding sites for meditope peptide (meP) within the Fab tumor targeting domain of the CAR. meCAR expression was validated by anti-Fc FITC or meP-Alexa 647 probes. In vitro and in vivo assays were performed and compared to standard scFv CAR T cells. For meCAR T cell proliferation and dual-targeting assays, the meditope peptide (meP) was conjugated to recombinant human IL15 fused to the CD215 sushi domain (meP-IL15:sushi) and anti-CD20 monoclonal antibody rituximab (meP-rituximab).ResultsWe generated meCAR T cells targeting HER2, CD19 and HER1/3 and demonstrate the selective specific binding of the meditope peptide along with potent meCAR T cell effector function. We next demonstrated the utility of a meP-IL15:sushi for enhancing meCAR T cell proliferation in vitro and in vivo. Proliferation and persistence of meCAR T cells was dose dependent, establishing the ability to regulate CAR T cell expansion using the meditope platform. We also demonstrate the ability to redirect meCAR T cells tumor killing using meP-antibody adaptors. As proof-of-concept, meHER2-CAR T cells were redirected to target CD20+ Raji tumors, establishing the potential of the meditope platform to alter the CAR specificity and overcome tumor heterogeneity.ConclusionsOur studies show the utility of the meCAR platform for overcoming key challenges for CAR T cell therapy by specifically regulating CAR T cell functionality. Specifically, the meP-IL15:sushi enhanced meCAR T cell persistence and proliferation following adoptive transfer in vivo and protects against T cell exhaustion. Further, meP-ritiuximab can redirect meCAR T cells to target CD20-tumors, showing the versatility of this platform to address the tumor antigen escape variants. Future studies are focused on conferring additional ‘add-on’ functionalities to meCAR T cells to potentiate the therapeutic effectiveness of CAR T cell therapy.

scholarly journals Feasibility, and Efficacy of Donor-Derived cd19-Targeted Car t-Cell Therapy in Refractory/Relapsed(r/r)b-Cell Acute Lymphoblastic Leukemia (b-all) Patients

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 4-6
Author(s):  
Xian Zhang ◽  
Junfang Yang ◽  
Wenqian Li ◽  
Gailing Zhang ◽  
Yunchao Su ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T ◽  
Grade 3

Backgrounds As CAR T-cell therapy is a highly personalized therapy, process of generating autologous CAR-T cells for each patient is complex and can still be problematic, particularly for heavily pre-treated patients and patients with significant leukemia burden. Here, we analyzed the feasibility and efficacy in 37 patients with refractory/relapsed (R/R) B-ALL who received CAR T-cells derived from related donors. Patients and Methods From April 2017 to May 2020, 37 R/R B-ALL patients with a median age of 19 years (3-61 years), were treated with second-generation CD19 CAR-T cells derived from donors. The data was aggregated from three clinical trials (www.clinicaltrials.gov NCT03173417; NCT02546739; and www.chictr.org.cn ChiCTR-ONC-17012829). Of the 37 patients, 28 were relapsed following allogenic hematopoietic stem cell transplant (allo-HSCT) and whose lymphocytes were collected from their transplant donors (3 HLA matched sibling and 25 haploidentical). For the remaining 9 patients without prior transplant, the lymphocytes were collected from HLA identical sibling donors (n=5) or haploidentical donors (n=4) because CAR-T cells manufacture from patient samples either failed (n=5) or blasts in peripheral blood were too high (>40%) to collect quality T-cells. The median CAR-T cell dose infused was 3×105/kg (1-30×105/kg). Results For the 28 patients who relapsed after prior allo-HSCT, 27 (96.4%) achieved CR within 30 days post CAR T-cell infusion, of which 25 (89.3%) were minimal residual disease (MRD) negative. Within one month following CAR T-cell therapy, graft-versus-host disease (GVHD) occurred in 3 patients including 1 with rash and 2 with diarrhea. A total of 19 of the 28 (67.9%) patients had cytokine release syndrome (CRS), including two patients (7.1%) with Grade 3-4 CRS. Four patients had CAR T-cell related neurotoxicity including 3 with Grade 3-4 events. With a medium follow up of 103 days (1-669days), the median overall survival (OS) was 169 days (1-668 days), and the median leukemia-free survival (LFS) was 158 days (1-438 days). After CAR T-cell therapy, 15 patients bridged into a second allo-HSCT and one of 15 patients (6.7%) relapsed following transplant, and two died from infection. There were 11 patients that did not receive a second transplantation, of which three patients (27.3%) relapsed, and four parents died (one due to relapse, one from arrhythmia and two from GVHD/infection). Two patients were lost to follow-up. The remaining nine patients had no prior transplantation. At the time of T-cell collection, the median bone marrow blasts were 90% (range: 18.5%-98.5%), and the median peripheral blood blasts were 10% (range: 0-70%). CR rate within 30 days post CAR-T was 44.4% (4/9 cases). Six patients developed CRS, including four with Grade 3 CRS. Only one patient had Grade 3 neurotoxicity. No GVHD occurred following CAR T-cell therapy. Among the nine patients, five were treated with CAR T-cells derived from HLA-identical sibling donors and three of those five patients achieved CR. One patient who achieved a CR died from disseminated intravascular coagulation (DIC) on day 16. Two patients who achieved a CR bridged into allo-HSCT, including one patient who relapsed and died. One of two patients who did not response to CAR T-cell therapy died from leukemia. Four of the nine patients were treated with CAR T-cells derived from haploidentical related donors. One of the four cases achieved a CR but died from infection on day 90. The other three patients who had no response to CAR T-cell therapy died from disease progression within 3 months (7-90 days). Altogether, seven of the nine patients died with a median time of 19 days (7-505 days). Conclusions We find that manufacturing CD19+ CAR-T cells derived from donors is feasible. For patients who relapse following allo-HSCT, the transplant donor derived CAR-T cells are safe and effective with a CR rate as high as 96.4%. If a patient did not have GVHD prior to CAR T-cell therapy, the incidence of GVHD following CAR T-cell was low. Among patients without a history of transplantation, an inability to collect autologous lymphocytes signaled that the patient's condition had already reached a very advanced stage. However, CAR T-cells derived from HLA identical siblings can still be considered in our experience, no GVHD occurred in these patients. But the efficacy of CAR T-cells from haploidentical donors was very poor. Disclosures No relevant conflicts of interest to declare.

scholarly journals Successful 24-Hours Manufacture of Anti-CD19/CD22 Dual Chimeric Antigen Receptor (CAR) T Cell Therapy for B-Cell Acute Lymphoblastic Leukemia (B-ALL)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 2-3
Author(s):  
Junfang Yang ◽  
Pengfei Jiang ◽  
Xian Zhang ◽  
Jingjing Li ◽  
Yan Wu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Lymphoblastic Leukemia ◽  
Observation Time ◽  
High Dose ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Introduction Multiple issues arise for a wider application of chimeric antigen receptor (CAR) T cell therapy including manufacturing time and antigen escape. Here we report data on an anti-CD19/CD22 dual CAR-T (GC022F) therapy based on a novel manufacturing platform, from a phase I clinical study (NCT04129099) in treating patients with B-cell acute lymphoblastic leukemia (B-ALL). Methods Peripheral blood (PB) mononuclear cells were obtained by leukapheresis. T-cells were separated and transduced with lentivirus that encodes a CD19/CD22 directed 4-1BB: ζ CAR. GC022F cells were manufactured using a novel FasTCARTM platform which takes 24 hours, while the conventional CD19/CD22 dual CAR-T (GC022C) cells used as parallel control in the preclinical study were manufactured by conventional process which typically takes 9-14 days. The phase I dose escalation study was initiated to explore the safety and efficacy of GC022F in patients with B-ALL. All patients received a conditioning regimen of IV fludarabine (25mg/m2/d) and cyclophosphamide (250mg/m2/d) for 3 days prior to GC022F infusion. Results When compared with the GC022C, GC022F cells showed 1) less exhaustion as indicated by lower percentage of PD-1+LAG3+ cells following co-culturing with tumor cells, 2) younger phenotypes as demonstrated by more abundant T central memory cells (Tcm; CCR7+CD45RA+ or CD45RO+CD62L+), 3) higher expansion fold at in vitro culture, and 4) high anti-leukemia efficacy in mice model (Fig.1). Comparing in vivo efficacy of GC022F with GC022C cells at lower doses, GC022F treatment were more potent and could reduce tumor burden earlier and faster, and led to significantly prolonged overall survival of the experimental animals. From Nov. 2019 to Jun. 2020, 9 children and 1 adult with B-ALL were enrolled and infused with GC022F, 2 in low-dose (6.0×104/kg), 7 in medium dose (1.0-1.5×105/kg), 1 in high-dose (2.25×105/kg). Patients' median observation time was 99 (14-210) days on the day of cut-off. Characteristics of enrolled patients are shown in Table 1. The median age was 10 (3-48) years, and the median bone marrow (BM) blasts were 21.0 (0.1-63.5) % at enrollment. Three patients had prior CD19 CAR-T cell therapy history and one of whom had prior allogeneic hematopoietic stem cell transplantation (allo-HSCT). After infusion, the median peak of circulating CAR-T cell copy number was 2.29 ×105 copies/µg genomic DNA (0.0014-5.66), which occurred around day 14 (day10 - day 28). Importantly, GC022F persisted well in PB with a median of 2.40×105 copies/µg genomic DNA (0.75-3.98) on day 28 in 5 of 9 patients with available 4 weeks of cellular kinetics data. GC022F exerted a superior safety profile with no observed grade ≥ 3 cytokine release syndrome (CRS) and neurotoxicity in all patients. Among those 6 patients with CRS, only 1 at high dose level had grade 2 CRS; only 1 developed grade 1 neurotoxicity. After GC022F infusion, 6/6 patients with BM blasts > 5% at enrollment achieved complete remission (CR) by day 28, 5/6 with minimal residual disease (MRD)-negative CR. For those 4 patients with MRD positive disease at enrollment, 3 became MRD-negative CR by day 28, 1 had persist MRD positive disease and withdrew from the study by 2 weeks. Five of 8 MRD-negative CR patients subsequently made a choice to pursue consolidation allo-HSCT with a median time interval of 57 (48-71) days post GC022F infusion and all have remained in MRD-negative CR except 1 died from graft-versus-host disease (GVHD) and infection 143 days post GC022F infusion. Of the other 3 patients without allo-HSCT, 2 relapsed with CD19+/CD22+ disease at 12-16 weeks follow-up, including the patient with prior history of CD19 CAR-T treatment and transplant. Conclusion This study demonstrated that anti-CD19/CD22 dual CAR T-cells could be successfully manufactured by FasTCARTM technology in 24 hours, with younger and less exhausted phenotypes. Moreover, the Dual FasTCAR-T cells showed more potent efficacy in xenograft mouse model compared to the conventional dual CAR-T cells. Our clinical data demonstrate that GC022F is safe and efficacious in treating patients with CD19+CD22+ B-ALL. More data on additional patients and longer observation time are needed to further evaluate CD19/CD22 dual FasTCAR-T cell product. Disclosures Cai: Gracell Biotechnologies Ltd: Current Employment. Wang:Gracell Biotechnologies Ltd: Current Employment. Chen:Gracell Biotechnologies Ltd: Current Employment. Ye:Gracell Biotechnologies Co., Ltd.: Current Employment. He:Gracell Biotechnologies Co., Ltd.: Current Employment. Cao:Gracell Biotechnologies Ltd: Current Employment. Sersch:Gracell Biotechnologies Co., Ltd.: Current Employment.

scholarly journals Allogeneic Hematopoietic Cell Transplantation Is Critical to Maintain Remissions after CD19-CAR T-Cell Therapy for Pediatric ALL: A Single Center Experience

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 39-40
Author(s):  
Aimee C Talleur ◽  
Renee M. Madden ◽  
Amr Qudeimat ◽  
Ewelina Mamcarz ◽  
Akshay Sharma ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
T Cell Therapy ◽  
Allogeneic Hct ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

CD19-CAR T-cell therapy has shown remarkable efficacy in pediatric patients with relapsed and/or refractory B-cell acute lymphoblastic leukemia (r/r ALL). Despite high short-term remission rates, many responses are not durable and the best management of patients who achieve a complete response (CR) post-CAR T-cell therapy remains controversial. In particular, it is unclear if these patients should be observed or proceed to consolidative allogeneic hematopoietic cell transplantation (HCT). To address this question, we reviewed the clinical course of all patients (n=22) who received either an investigational CAR T-cell product (Phase I study: SJCAR19 [NCT03573700]; n=12) or tisagenlecleucel (n=10) at our institution. The investigational CD19-CAR T cells were generated by a standard cGMP-compliant procedure using a lentiviral vector encoding a 2nd generation CD19-CAR with a FMC63-based CD19 binding domain, CD8a stalk and transmembrane domain, and 41BB.ζ signaling domain. Patients received therapy between 8/2018 and 3/2020. All products met manufacturing release specifications. Within the entire cohort, median age at time of infusion was 12.3 years old (range: 1.8-23.5) and median pre-infusion marrow burden using flow-cytometry minimal residual disease (MRD) testing was 6.8% (range: 0.003-100%; 1 patient detectable by next-generation sequencing [NGS] only). All patients received lymphodepleting chemotherapy (fludarabine, 25mg/m2 daily x3, and cyclophosphamide, 900mg/m2 daily x1), followed by a single infusion of CAR T-cells. Phase I product dosing included 1x106 CAR+ T-cells/kg (n=6) or 3x106 CAR+ T-cells/kg (n=6). Therapy was well tolerated, with a low incidence of cytokine release syndrome (any grade: n=10; Grade 3-4: n=4) and neurotoxicity (any grade: n=8; Grade 3-4: n=3). At 4-weeks post-infusion, 15/22 (68.2%) patients achieved a CR in the marrow, of which 13 were MRDneg (MRDneg defined as no detectable leukemia by flow-cytometry, RT-PCR and/or NGS, when available). Among the 2 MRDpos patients, 1 (detectable by NGS only) relapsed 50 days after CAR T-cell infusion and 1 died secondary to invasive fungal infection 35 days after infusion. Within the MRDneg cohort, 6/13 patients proceeded to allogeneic HCT while in MRDneg/CR (time to HCT, range: 1.8-2.9 months post-CAR T-cell infusion). All 6 HCT recipients remain in remission with a median length of follow-up post-HCT of 238.5 days (range 19-441). In contrast, only 1 (14.3%) patient out of 7 MRDneg/CR patients who did not receive allogeneic HCT, remains in remission with a follow up of greater 1 year post-CAR T-cell infusion (HCT vs. no HCT: p<0.01). The remaining 6 patients developed recurrent detectable leukemia within 2 to 9 months post-CAR T-cell infusion (1 patient detectable by NGS only). Notably, recurring leukemia remained CD19+ in 4 of 5 evaluable patients. All 4 patients with CD19+ relapse received a 2nd CAR T-cell infusion (one in combination with pembrolizumab) and 2 achieved MRDneg/CR. There were no significant differences in outcome between SJCAR19 study participants and patients who received tisagenlecleucel. With a median follow up of one year, the 12 month event free survival (EFS) of all 22 patients is 25% (median EFS: 3.5 months) and the 12 month overall survival (OS) 70% (median OS not yet reached). In conclusion, infusion of investigational and FDA-approved autologous CD19-CAR T cells induced high CR rates in pediatric patients with r/r ALL. However, our current experience shows that sustained remission without consolidative allogeneic HCT is not seen in most patients. Our single center experience highlights not only the need to explore maintenance therapies other than HCT for MRDneg/CR patients, but also the need to improve the in vivo persistence of currently available CD19-CAR T-cell products. Disclosures Sharma: Spotlight Therapeutics: Consultancy; Magenta Therapeutics: Other: Research Collaboration; CRISPR Therapeutics, Vertex Pharmaceuticals, Novartis: Other: Clinical Trial PI. Velasquez:St. Jude: Patents & Royalties; Rally! Foundation: Membership on an entity's Board of Directors or advisory committees. Gottschalk:Patents and patent applications in the fields of T-cell & Gene therapy for cancer: Patents & Royalties; TESSA Therapeutics: Other: research collaboration; Inmatics and Tidal: Membership on an entity's Board of Directors or advisory committees; Merck and ViraCyte: Consultancy.

scholarly journals CAR T-cell therapy of solid tumors: promising approaches to modulating antitumor activity of CAR T cells

2019 ◽  
pp. 5-12 ◽  
Author(s):  
Ya.Yu. Kiseleva ◽  
A.M. Shishkin ◽  
A.V. Ivanov ◽  
T.M. Kulinich ◽  
V.K. Bozhenko
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Solid Tumors ◽  
Functional Activity ◽  
T Cell Therapy ◽  
Car T Cells ◽  
Car T Cell ◽  
Car T Cell Therapy ◽  
Car T

Adoptive immunotherapy that makes use of genetically modified autologous T cells carrying a chimeric antigen receptor (CAR) with desired specificity is a promising approach to the treatment of advanced or relapsed solid tumors. However, there are a number of challenges facing the CAR T-cell therapy, including the ability of the tumor to silence the expression of target antigens in response to the selective pressure exerted by therapy and the dampening of the functional activity of CAR T cells by the immunosuppressive tumor microenvironment. This review discusses the existing gene-engineering approaches to the modification of CAR T-cell design for 1) creating universal “switchable” synthetic receptors capable of attacking a variety of target antigens; 2) enhancing the functional activity of CAR T cells in the immunosuppressive microenvironment of the tumor by silencing the expression of inhibiting receptors or by stimulating production of cytokines.

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