Clinical short-term and long-term efficacy of targeted cd19-cart in the treatment of relapsed and refractory childhood B-line acute lymphoblastic leukemia

Start Date20 Mar 2017

Sponsor / Collaborator-

100 Clinical Results associated with CD19-CART (Shanghai Children's Medical Center)

100 Translational Medicine associated with CD19-CART (Shanghai Children's Medical Center)

100 Patents (Medical) associated with CD19-CART (Shanghai Children's Medical Center)

Literatures (Medical) associated with CD19-CART (Shanghai Children's Medical Center)

15 Nov 2024·Clinical Cancer Research

Metabolic Tumor Volume Response after Bridging Therapy Determines Chimeric Antigen Receptor T-Cell Outcomes in Large B-Cell Lymphoma

Article

Author: Boardman, Alexander P. ; Alarcon Tomas, Ana ; Yahalom, Joachim ; Saldia, Amethyst ; Hajj, Carla ; Palomba, Maria L. ; Shah, Gunjan ; Giralt, Sergio ; Landego, Ivan ; Shouval, Roni ; Perales, Miguel-Angel ; Parascondola, Allison ; Ghosh, Arnab ; Lin, Richard J. ; Hubbeling, Harper ; Schöder, Heiko ; Dahi, Parastoo B. ; Bedmutha, Akshay ; Leithner, Doris ; Salles, Gilles ; Park, Jae ; Imber, Brandon S. ; Fregonese, Beatrice ; Devlin, Sean ; Flynn, Jessica ; Silverman, Emily A. ; Wills, Beatriz ; Scordo, Michael

AbstractPurpose:Greater disease burden is a well-established predictor of poorer outcomes following chimeric antigen receptor T-cell (CAR T) therapy. Although bridging therapy (BT) is widely used between leukapheresis and CAR T infusion, limited data have evaluated the impact of BT on CAR T outcomes. In this study, we hypothesized that the quantitative dynamics of radiomic cytoreduction during bridging are prognostic.Experimental Design:Patients with large B-cell lymphoma treated with CD19-CAR T from 2016 to 2022 were included in the study. Metabolic tumor volume (MTV) was determined for all patients on pre-leukapheresis PET and on post-BT/pre-infusion PET in those who received BT. Patients were stratified into “High” and “Low” disease burden using an MTV cutpoint of 65.4cc established by maximally selected log-rank statistic for progression-free survival (PFS).Results:Of 191 patients treated with CAR T, 144 (75%) received BT. In the BT cohort, 56% had a reduction in MTV post-BT. On multivariate analysis, the MTV trajectory across the bridging period remained significantly associated with PFS (P < 0.001); however, notably, patients with improved MTV (High->Low) had equivalent PFS compared with those with initially and persistently low MTV (Low->Low; HR for High->Low MTV: 2.74; 95% confidence interval, 0.82–9.18). There was a reduction in any grade immune effector cell–associated neurotoxicity syndrome in the High->Low MTV cohort as compared with the High->High MTV cohort (13% vs. 41%; P = 0.05).Conclusions:This is the first study to use radiomics to quantify disease burden pre- and post-BT in a large real-world large B-cell lymphoma cohort. We demonstrate that effective BT can enable initially high–disease burden patients to achieve post–CAR T outcomes comparable with low–disease burden patients.

01 Aug 2024·HemaSphere

PD‐L1⁺ macrophage and tumor cell abundance and proximity to T cells in the pretreatment large B‐cell lymphoma microenvironment impact CD19 CAR‐T cell immunotherapy efficacy

Article

Author: Smythe, Kimberly S. ; Maloney, David G. ; Gauthier, Jordan ; Hirayama, Alexandre V. ; Fiorenza, Salvatore ; Wright, Jocelyn H. ; Shaw, Akira N. ; Turtle, Cameron J. ; Naresh, Kikkeri N. ; Yeung, Cecilia C. S.

AbstractCD19‐targeted chimeric antigen receptor T‐cell (CAR‐T) immunotherapy has transformed the management of relapsed/refractory large B‐cell lymphoma (LBCL), yet durable remissions are observed in less than half of treated patients. The tumor microenvironment (TME) is a key and understudied factor impacting CD19 CAR‐T therapy outcomes. Using NanoString nCounter transcriptome profiling (n = 24) and multiplex immunohistochemistry (mIHC, n = 15), we studied the TME in pretreatment biopsies from patients with LBCL undergoing CD19 CAR‐T therapy. Patients who achieved complete response (CR) after CAR‐T therapy demonstrated higher expression of genes associated with T‐cell trafficking and function, whereas those who did not achieve CR had higher expression of genes associated with macrophages and T‐cell dysfunction. Distinct patterns of immune infiltration and fibrosis in the TME were associated with CAR‐T therapy outcomes, and these findings were corroborated using artificial intelligence‐assisted image analyses. Patients who achieved CR had a lower proportion of the biopsy occupied by an interspersed immune infiltrate and a higher proportion of hypocellular/fibrotic regions. Furthermore, mIHC revealed lower density of CD4+ T cells and higher densities of both macrophages and tumor cells expressing PD‐L1 in non‐CR patients. Spatial analysis revealed that PD‐1+ T cells were in close proximity to PD‐L1+ macrophages or PD‐L1+ tumor cells in patients who did not compared to those who did achieve CR after CAR‐T therapy. These findings suggest that morphologic patterns in the TME and engagement of the PD‐1/PD‐L1 axis in pretreatment biopsies may impact CD19 CAR‐T immunotherapy response in patients with LBCL.

01 Apr 2024·Apoptosis

A novel safer CD19CAR with shRNA interference of IFN-γ can reduce multiple cytokine levels without significantly compromising its killing efficacy

Article

Author: Tang, Yongmin ; Xu, Weiqun ; Liu, Rongrong ; Li, Hongzhe ; Tang, Yang ; Ying, Peiting ; Zhang, Ping ; Li, Sisi ; Zhao, Ning

Cytokine release syndrome (CRS) is a great challenge for the application of anti-CD19 CAR-T cell therapy. The aim of this study was to investigate the effect of knocking down interferon gamma (IFN-γ) by shRNA as a potential strategy to reduce the cytokine storms. A newly designed short hairpin interference RNA of IFN-γ (shIFN-γ) in CD19CAR gene was constructed. Several cellular model systems of approach using Nalm-6 cell lines including Nalm-6^CD19pos and Nalm-6^CD19neg with or without monocytes and endothelial cells were used to analyze the different levels of cytokines after shIFN-γ-anti-CD19CAR-T cell targeted therapy. The activity of this novel CD19CAR-T was evaluated both in vitro and in NSG mouse model. The killing efficacy of shIFN-γ-anti-CD19CAR-T at the E:T ratio of 2:1 was similar to that of regular anti-CD19CAR-T at the E:T ratio of 1:1. The IFN-γ level in the shIFN-γ-anti-CD19CAR-T cell group was (2673.1 ± 307.4) pg/ml at the E:T ratio of 2:1 which was significantly lower than that ((8261.5 ± 345.5) pg/ml) in the regular anti-CD19CAR-T group at the E:T ratio of 1:1. Cytotoxicity experiments in vitro showed significantly reduced concentrations of IFN-γ, IL-6 and TNFα in the shIFN-γ-anti-CD19CAR-T cell group compared to regular anti-CD19CAR-T cell group. Both regular anti-CD19CAR and shIFN-γ-CD19CAR-T exerted bystander killing effect in vitro. We conclude that shIFN-γ-anti-CD19CAR-T cells can reduce the generation of cytokine storms without significantly compromising their therapeutic efficacy in the preclinical setting. In mouse model, 3 × 10⁶ shIFN-γ-anti-CD19CAR-T cells/mouse generated the similar killing efficacy to that with 2 × 10⁶ regular anti-CD19CAR-T cells/mouse.

100 Deals associated with CD19-CART (Shanghai Children's Medical Center)

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Indication	Highest Phase	Country/Location	Organization	Date
Acute Lymphoblastic Leukemia	Phase 1	-	Shanghai Children's Medical Center	-

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