A Single Center, Open Label, Single Arm Exploratory Clinical Study of CD19-Directed Allogeneic Chimeric Antigen Receptor CART-cell Immunotherapy Cell Therapy in Pediatric Patients With Relapsed/Refractory B-Cell Acute Lymphoblastic Leukemia

The purpose of this study is to evaluate the safety and tolerability of CD19-Directed Allogeneic Chimeric Antigen Receptor T- cell (alloCART-19)therapy in pediatric patients with relapsed/refractory acute lymphoblastic leukemia（ALL）.

Start Date09 Jan 2020

Sponsor / Collaborator

Paediatrics Hospital Affiliated To Fudan University

100 Clinical Results associated with AlloCART-19(Children's Hospital of Fudan University)

100 Translational Medicine associated with AlloCART-19(Children's Hospital of Fudan University)

100 Patents (Medical) associated with AlloCART-19(Children's Hospital of Fudan University)

Literatures (Medical) associated with AlloCART-19(Children's Hospital of Fudan University)

01 Jan 2024·Cancer Immunology, Immunotherapy

Allogeneic CAR-T cells with of HLA-A/B and TRAC disruption exhibit promising antitumor capacity against B cell malignancies

Article

Author: Li, Ling ; Xing, Haizhou ; Li, Wei ; Cao, Weijie ; Huang, Jianmin ; Tan, Binghe ; Ping, Yu ; Lin, Boxu ; Chen, Xinfeng ; Liu, Mingyao ; Zhang, Yi ; Du, Bing ; Li, Xin ; Zhang, Mingzhi ; Zhang, Xudong ; Jiang, Zhongxing ; Zhang, Na ; Zhao, Xuan ; Zhang, Zhen ; Shi, Xiujuan

AbstractBackgroundAlthough chimeric antigen receptor T (CAR-T) cells have been proven to be an effective way of treating B cell malignancies, a lot of patients could not benefit from it because of failure in CAR-T cell manufacturing, disease progression, and unaffordable price. The study aimed to explore universal CAR-T cell products to extend the clinical accessibility.MethodsThe antitumor activity of CRISPR/Cas9-edited allogeneic anti-CD19 CAR-T (CAR-T19) cells was assessed in vitro, in animal models, and in patients with relapsed/refractory (R/R) acute B cell lymphoblastic leukemia (B-ALL) or diffuse large B cell lymphoma.ResultsB2M−/TRAC− universal CAR-T19 (U-CAR-T19) cells exhibited powerful anti-leukemia abilities both in vitro and in animal models, as did primary CD19+ leukemia cells from leukemia patients. However, expansion, antitumor efficacy, or graft-versus-host-disease (GvHD) was not observed in six patients with R/R B cell malignancies after U-CAR-T19 cell infusion. Accordingly, significant activation of natural killer (NK) cells by U-CAR-T19 cells was proven both clinically and in vitro. HLA-A−/B−/TRAC− novel CAR-T19 (nU-CAR-T19) cells were constructed with similar tumoricidal capacity but resistance to NK cells in vitro. Surprisingly, robust expansion of nU-CAR-T19 cells, along with rapid eradication of CD19+ abnormal B cells, was observed in the peripheral blood and bone marrow of another three patients with R/R B-ALL. The patients achieved complete remission with no detectable minimal residual disease 14 days after the infusion of nU-CAR-T19 cells. Two of the three patients had grade 2 cytokine release syndrome, which were managed using an IL-6 receptor blocker. Most importantly, GvHD was not observed in any patient, suggesting the safety of TRAC-disrupted CAR-T cells generated using the CRISPR/Cas9 method for clinical application.ConclusionsThe nU-CAR-T19 cells showed a strong response in R/R B-ALL. nU-CAR-T19 cells have the potential to be a promising new approach for treating R/R B cell malignancies.

23 Dec 2021·Zhonghua zhong liu za zhi [Chinese journal of oncology]

[Establishment of a cytokine release syndrome associated with chimeric antigen receptor T cell treatment in SCID/Beige mice model].

Article

Author: Nan, S F ; Shan, J Q ; Shen, C Y ; Zhang, Y ; Li, F

Objective: To establish a cytokine release syndrome (CRS) mouse model related to CAR-T cell therapy and provide a research model for the clinical phenomena. Methods: CAR-T cells targeting human CD19 molecule were constructed by molecular cloning and lentiviral transfection. Flow cytometry (FACS) was used to detect the transfection efficiency of CAR-T cells. The tumor-killing efficiency of CAR-T cells was detected by ELISA and flow cytometry. The CAR-T cells were injected into the tumor-bearing SCID/Beige mice through tail vein, and divided into phosphate buffered solution (PBS) group, low-burden group (1×10(5) Raji-Luc2 cells) and high-burden group (5×10(5) Raji-Luc2 cells). The tumor treatment effect was detected by animal in vivo imaging. Serum levels of cytokines including human IFN-γ, human IL-2, mouse IL-6, and mouse GM-CSF were measured by ELISA. The health status of the mice was evaluated by pathological examination. Results: The health scores of T cell group and T cell+ OKT-3 group were (1.15±0.08) and (2.90±0.15), respectively, after the injection of human T cell and T cell + OKT-3 antibody through tail vein, and the difference was statistically significant (P<0.001). The serum levels of human IL-2, human IFN-γ, human IL-15, mouse IL-6 and mouse GM-CSF in T cell+ OKT-3 group were (1 064.00±50.14), (1 285.00±193.90), (202.4±18.76), (1 478.00±289.20) and (350.70±42.27) pg/ml, respectively, higher than (22.67±6.36), (23.67±3.71), (44.33±14.45), (147.30±36.20), (138.00±22.74) pg/ml in T cell group (P<0.05). OKT-3 combined with human T cells caused a rapid increase in serum levels of human IL-2, human IFN-γ, mouse IL-6 and mouse GM-CSF, accompanied by an increase in body temperature and weight loss. CD19-targeting CAR-T cells were successfully constructed, and the positive rate of CAR-T cells was >30% detected by flow cytometry. ELISA results showed that in the presence of CD19 antigen, IL-2 and IFN-γ secreted by CAR-T19 cells co-incubated with Raji and Nalm were (561.00±37.07), (680.30±71.27), (369±25.71) and (523.00±26.31) pg/ml, respectively, higher than (55.00±20.53) and (64.00±7.55) pg/ml in the co-incubated with K562 group (P<0.001). Activated CAR-T19 cells were reinjected through the tail vein on the seventh day after tumor formation. Imaging experiments in mice showed that on the thirteenth day after tumor formation, the fluorescence intensities of tumors in the low-burden and high-burden groups were lower than on the seventh day of tumor inoculation, and the fluorescence intensity of tumors in the high-burden group decreased from 144.00±24.69 to 5.02±2.35 (P=0.005). The fluorescence intensity of low burden group decreased from 58.47±9.36 to 3.48±1.67 (P=0.004). The serum levels of T cell activation related cytokines IL-2, IL-15 and IFN-γ increased rapidly, and the secretion of monocyte related cytokines IL-16 and GM-CSF increased, accompanied by the typical characteristics of CRS such as increased body temperature and weight loss at 72 hours after injection of CAR-T19 cells. Conclusions: CAR-T cells targeting CD19 molecule are successfully constructed, and CRS phenomenon is verified in tumor-bearing mice by CAR-T cell re-infusion, providing an animal model for the mechanism of CAR-T treatment-related CRS and CRS prevention strategies.

01 Jul 2020·Anales de PediatríaQ4 · MEDICINE

Inmunoterapia con células CAR-T en hematooncología pediátrica

Q4 · MEDICINE

Article

Author: Antonio Pérez-Martínez ; Miguel Ángel Díaz ; Ana Patiño-García ; Pablo Menéndez ; Andrés Sánchez-Salinas ; Isabel Martínez ; Marta M. Alonso ; Marina García-Morín ; Pilar Guerra-García ; Hisse M. van Santen ; María Luisa Toribio ; Garbiñe Lizeaga ; José Luis Fuster ; Susana Rives ; Javier García-Castro ; Laura Alonso ; Isabel Mirones ; Pilar Palomo ; Javier Anguita ; Luisa Sisinni ; Lucas Moreno ; Jaime Verdú-Amorós ; José M. Moraleda ; Manuel Ramírez ; Marta González ; Miguel Blanquer

Despite being a rare disease, cancer is the first cause of mortality due to disease during the paediatric age in the developed countries. The current, great increase in new treatments, such as immunotherapy, constitutes a new clinical and regulatory paradigm. Cellular immunotherapy is one of these types of immunotherapy. In particular, the advanced therapy drugs with chimeric antigen receptors in the T-lymphocytes (CAR-T), and particularly the CAR-T19 cells, has opened up a new scenario in the approach to haematology tumours like acute lymphoblastic leukaemia and the B-Cell lymphomas. The approval of tisagenlecleucel and axicabtagene ciloleucel by the regulatory authorities has led to the setting up of the National Plan for Advanced Therapies-CAR-T drugs in Spain. There is evidence of, not only the advantage of identifying the centres most suitable for their administration, but also the need for these to undergo a profound change in order that their healthcare activity is extended, in some cases, to the ability for the in-house manufacture of these types of therapies. The hospitals specialised in paediatric haematology-oncology thus have the challenge of progressing towards a healthcare model that integrates cellular immunotherapy, having the appropriate capacity to manage all aspects relative to their use, manufacture, and administration of these new treatments.

100 Deals associated with AlloCART-19(Children's Hospital of Fudan University)

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Indication	Highest Phase	Country/Location	Organization	Date
Pre B-cell acute lymphoblastic leukemia	Phase 1	CN	Paediatrics Hospital Affiliated To Fudan University	09 Jan 2020

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