A Phase I Study of CD19 Specific Chimeric Antigen Receptor T-cells for Therapy of Persistent and Relapsed B-cell Leukaemia and Lymphoma Post Allogeneic Stem Cell Transplantation

Start Date04 Dec 2017

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100 Clinical Results associated with Donor derived CAR19 T-cells (National Health & Medical Research Council)

100 Translational Medicine associated with Donor derived CAR19 T-cells (National Health & Medical Research Council)

100 Patents (Medical) associated with Donor derived CAR19 T-cells (National Health & Medical Research Council)

Literatures (Medical) associated with Donor derived CAR19 T-cells (National Health & Medical Research Council)

01 Mar 2024·Advanced Science

CAR‐Aptamers Enable Traceless Enrichment and Monitoring of CAR‐Positive Cells and Overcome Tumor Immune Escape

Article

Author: Zheng, Wei‐Wei ; Chen, Kaiming ; Zhou, Hang ; Duan, Cai‐Wen ; Abudureheman, Tuersunayi ; Liang, Ai‐Bin ; Yang, Li‐Ting ; Zhu, Jian‐Min

AbstractChimeric antigen receptor (CAR)‐positive cell therapy, specifically with anti‐CD19 CAR‐T (CAR19‐T) cells, achieves a high complete response during tumor treatment for hematological malignancies. Large‐scale production and application of CAR‐T therapy can be achieved by developing efficient and low‐cost enrichment methods for CAR‐T cells, expansion monitoring in vivo, and overcoming tumor escape. Here, novel CAR‐specific binding aptamers (CAR‐ap) to traceless sort CAR‐positive cells and obtain a high positive rate of CAR19‐T cells is identified. Additionally, CAR‐ap‐enriched CAR19‐T cells exhibit similar antitumor capacity as CAR‐ab (anti‐CAR antibody)‐enriched CAR‐T cells. Moreover, CAR‐ap accurately monitors the expansion of CAR19‐T cells in vivo and predicts the prognosis of CAR‐T treatment. Essentially, a novel class of stable CAR‐ap‐based bispecific circular aptamers (CAR‐bc‐ap) is constructed by linking CAR‐ap with a tumor surface antigen (TSA): protein tyrosine kinase 7 (PTK7) binding aptamer Sgc8. These CAR‐bc‐aps significantly enhance antitumor cytotoxicity with a loss of target antigens by retargeting CAR‐T cells to the tumor in vitro and in vivo. Overall, novel CAR‐aptamers are screened for traceless enrichment, monitoring of CAR‐positive cells, and overcoming tumor cell immune escape. This provides a low‐cost and high‐throughput approach for CAR‐positive cell‐based immunotherapy.

01 Mar 2024·Journal for ImmunoTherapy of Cancer

Dynamic monitoring of circulating tumor DNA reveals outcomes and genomic alterations in patients with relapsed or refractory large B-cell lymphoma undergoing CAR T-cell therapy

Article

Author: Ma, Tonghui ; Sui, Weiwei ; Zou, Hesong ; Liu, Wei ; Qiu, Chen ; Wang, Xiaojuan ; Qiu, Lugui ; Liu, Huimin ; An, Gang ; Zou, Dehui ; Shan, Dandan ; Wang, Yi ; Huang, Wenyang ; Yi, Shuhua ; Wang, Jianxiang ; Xie, Ting ; Xu, Yan ; Wang, Chunyang

BackgroundOver 50% of patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) receiving CD19-targeted chimeric antigen receptor (CAR19) T-cell therapy fail to achieve durable remission. Early identification of relapse or progression remains a significant challenge. In this study, we prospectively investigate the prognostic value of dynamic circulating tumor DNA (ctDNA) and track genetic evolution non-invasively, for the first time in an Asian population of r/r patients undergoing CAR19 T-cell therapy.MethodsLongitudinal plasma samples were prospectively collected both before lymphodepletion and at multiple timepoints after CAR19 T-cell infusion. ctDNA was detected using a capture-based next-generation sequencing which has been validated in untreated LBCL.ResultsThe study enrolled 23 patients with r/r LBCL and collected a total of 101 ctDNA samples. Higher pretreatment ctDNA levels were associated with inferior progression-free survival (PFS) (p=0.031) and overall survival (OS) (p=0.023). Patients with undetectable ctDNA negative (ctDNA–) at day 14 (D14) achieved an impressive 3-month complete response rate of 77.8% vs 22.2% (p=0.015) in patients with detectable ctDNA positive (ctDNA+), similar results observed for D28. CtDNA– at D28 predicted significantly longer 1-year PFS (90.9% vs 27.3%; p=0.004) and OS (90.9% vs 49.1%; p=0.003) compared with patients who remained ctDNA+. Notably, it is the first time to report that shorter ctDNA fragments (<170 base pairs) were significantly associated with poorer PFS (p=0.031 for D14; p=0.002 for D28) and OS (p=0.013 for D14; p=0.008 for D28) in patients with LBCL receiving CAR T-cell therapy. Multiple mutated genes exhibited an elevated prevalence among patients with progressive disease, includingTP53,IGLL5,PIM1,BTG1,CD79B,GNA13, andP2RY8. Notably, we observed a significant correlation betweenIGLL5mutation and inferior PFS (p=0.008) and OS (p=0.014).ConclusionsOur study highlights that dynamic ctDNA monitoring during CAR T-cell therapy can be a promising non-invasive method for early predicting treatment response and survival outcomes. Additionally, the ctDNA mutational profile provides novel insights into the mechanisms of tumor-intrinsic resistance to CAR19 T-cell therapy.

01 Nov 2023·Cancer Immunology, Immunotherapy

Anti-CD79b/CD3 bispecific antibody combined with CAR19-T cells for B-cell lymphoma treatment

Article

Author: Yang, Li-Ting ; Abudureheman, Tuersunayi ; Chen, Kai-Ming ; Qing, Kai ; Li, Ping ; Liang, Ai-Bin ; Duan, Cai-Wen ; Ye, Shi-Guang ; Zhou, Hang ; Zheng, Wei-Wei

CD19 CAR-T (chimeric antigen receptor-T) cell immunotherapy achieves a remission rate of approximately 70% in recurrent and refractory lymphoma treatment. However, the loss or reduction of CD19 antigen on the surface of lymphoma cells results in the escape of tumor cells from the immune killing of CD19 CAR-T cells (CAR19-T). Therefore, novel therapeutic strategies are urgently required. In this study, an anti-CD79b/CD3 bispecific antibody (BV28-OKT3) was constructed and combined with CAR19-T cells for B-cell lymphoma treatment. When the CD19 antigen was lost or reduced, BV28-OKT3 redirected CAR19-T cells to CD79b⁺ CD19^- lymphoma cells; therefore, BV28-OKT3 overcomes the escape of CD79b⁺ CD19^- lymphoma cells by the killing action of CAR19-T cells in vitro and in vivo. Furthermore, BV28-OKT3 triggered the antitumor function of CAR^- T cells in the infusion product and boosted the antitumor immune response of bystander T cells, markedly improving the cytotoxicity of CAR19-T cells to lymphoma cells in vitro and in vivo. In addition, BV28-OKT3 elicited the cytotoxicity of donor-derived T cells toward lymphoma cells in vitro, which depended on the presence of tumor cells. Therefore, our findings provide a new clinical treatment strategy for recurrent and refractory B-cell lymphoma by combining CD79b/CD3 BsAb with CAR19-T cells.

100 Deals associated with Donor derived CAR19 T-cells (National Health & Medical Research Council)

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Indication	Highest Phase	Country/Location	Organization	Date
B-Cell Lymphoma	Phase 1	-	National Health & Medical Research Council	-

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