Autologous Activated T-Cells Transduced With A 3rd Generation GD-2 Chimeric Antigen Receptor And iCaspase9 Safety Switch Administered To Patients With Relapsed Or Refractory Neuroblastoma (GRAIN)

Subjects that have relapsed or refractory neuroblastoma are invited to take part in this gene transfer research study.
We have found from previous research that we can put a new gene called a chimeric antigen receptor (CAR) into T cells that will make them recognize neuroblastoma cells and kill them. In a previous clinical trial, we used a CAR that recognizes GD2, a protein found on almost all neuroblastoma cells (GD2-CAR). We put this gene into T cells and gave them back to patients that had neuroblastoma. The infusions were safe and in patients with disease at the time of their infusion, the time to progression was longer if we could find GD2 T cells in their blood for more than 6 weeks. Because of this, we think that if T cells are able to last longer, they may have a better chance of killing neuroblastoma tumor cells.
Therefore, in this study we will add new genes to the GD2 T cells that can cause the cells to live longer. These new genes are called CD28 and OX40. The purpose of this study will be to determine the highest dose of iC9-GD2-CD28-OX40 (iC9-GD2) T cells that can safely be given to patients with relapsed/refractory neuroblastoma.
In other clinical studies using T cells, some investigators found that giving chemotherapy before the T cell infusion can improve the amount of time the T cells stay in the body and therefore the effect the T cells can have. This is called lymphodepletion and we think that it will allow the T cells we infuse to expand and stay longer in the body, and potentially kill cancer cells more effectively.
The chemotherapy we will use for lymphodepletion is a combination of cyclophosphamide and fludarabine.
Additionally, to effectively kill the tumor cells, it is important that the T cells are able to survive and expand in the tumor. Recent studies have shown that solid tumors release a substance (PD1) that can inhibit T cells after they arrive into the tumor tissue. In an attempt to overcome the effect of PD1 in neuroblastoma we will also give a medication called pembrolizumab.

开始日期2013-08-01

申办/合作机构

Baylor College of Medicine

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100 项与 VZV-specific-GD2-CAR(Baylor College of Medicine) 相关的临床结果

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项与 VZV-specific-GD2-CAR(Baylor College of Medicine) 相关的文献（医药）

2023-12-01·Cellular Oncology

Therapeutic effects against high-grade glioblastoma mediated by engineered induced neural stem cells combined with GD2-specific CAR-NK

Article

作者: Wu, Huantong ; Zheng, Xin ; Chen, Zhiguo ; Liu, Zhongfeng ; Zhang, Guangji ; Zhao, Yu ; Liu, Weihua ; Tang, Xihe

PURPOSEHigh-grade glioblastoma is extremely challenging to treat because of its aggressiveness and resistance to conventional chemo- and radio-therapies. On the contrary, genetic and cellular immunotherapeutic strategies based on the stem and immune cells are emerging as promising treatments against glioblastoma (GBM). We aimed to developed a novel combined immunotherapeutic strategy to improve the treatment efficacy using genetically engineered PBMC-derived induced neural stem cells (iNSCs) expressing HSV-TK and second-generation CAR-NK cells against GBM.METHODSiNSCs cells expressing HSV-TK (iNSCs^TK) and GD2-specific CAR-NK92 (GD2NK92) were generated from PBMC-derived iNSCs and NK92 cell lines, respectively. The anti-tumor effect of iNSCs^TK and the combinational therapeutics of iNSCs^TK and GD2NK92 were evaluated by GBM cell line using in vitro and in vivo experiments.RESULTSPBMC-derived iNSCs^TK possessed tumor-tropism migration ability in vitro and in vivo, which exhibited considerable anti-tumor activity via bystander effect in the presence of ganciclovir (GCV). iNSCs^TK/GCV could slow GBM progression and prolong median survival in tumor-bearing mice. However, the anti-tumor effect was limited to single therapy. Therefore, the combinational therapeutic effect of iNSCs^TK/GCV and GD2NK92 against GBM was investigated. This approach displayed a more significant anti-tumor effect in vitro and in xenograft tumor mice.CONCLUSIONSPBMC-derived iNSCs^TK showed a significant tumor-tropic migration and an effective anti-tumor activity with GCV in vitro and in vivo. In addition, combined with GD2NK92, iNSCs^TK therapeutic efficacy improved dramatically to prolong the tumor-bearing animal model's median survival.

Frontiers in Medicine3区 · 医学

Chimeric Antigen Receptor Signaling Domains Differentially Regulate Proliferation and Native T Cell Receptor Function in Virus-Specific T Cells

3区 · 医学

ArticleOA

作者: Sauer, Tim ; Cardenas, Mara ; Tanaka, Miyuki ; Lapteva, Natalia ; Tashiro, Haruko ; Castillo, Paul A ; Schmueck-Henneresse, Michael ; Shum, Thomas ; Huynh, Mai T A ; Mukherjee, Malini ; Rooney, Cliona M ; Parihar, Robin ; Gottschalk, Stephen ; Lewis, Andrew ; Omer, Bilal

The efficacy of T cells expressing chimeric antigen receptors (CARs) for solid tumors has been limited by insufficient CAR T cell expansion and persistence. The use of virus-specific T cells (VSTs) as carriers for CARs may overcome this limitation since CAR-VSTs can be boosted by viral vaccines or oncolytic viruses. However, there is limited understanding of the optimal combination of endodomains and their influence on the native T cell receptor (TCR) in VSTs. We therefore compared the function of GD2.CARs expressing the TCR zeta chain (ζ) alone or combined with endodomains from CD28 and 4-1BB in varicella zoster virus-specific (VZV) T cells. VZVSTs expressing GD2-CARs recognized VZV-derived peptides and killed GD2-expressing tumor cells. However, after repeated stimulation through their native TCR, the expansion of GD2-CAR.CD28ζ-VZVSTs was 3.3-fold greater (p < 0.001) than non-transduced VZVSTs, whereas GD2-CARζ- and GD2-CAR.41BBζ inhibited VZVST expansion (p < 0.01). Compared to control VZVSTs, GD2-CAR.ζ VZVSTs showed a greater frequency of apoptotic (p < 0.01) T cells, whereas prolonged downregulation of the native αβ TCR was observed in GD2-CAR.41BBζ VZVSTs (p < 0.001). We confirmed that CD28ζ can best maintain TCR function by expressing GD2.CARs in Epstein-Barr virus-specific T cells and CD19-CARs in VZVSTs. In response to CAR stimulation VSTs with CD28ζ endodomains also showed the greatest expansion (6 fold > GD2-CAR.41BBζ VZVSTs (p < 0.001), however anti-tumor efficacy was superior in GD2-CAR.41BBζ-VZVSTs. These findings demonstrate that CAR signaling domains can enhance or diminish the function of the native TCR and indicate that only CD28ζ may preserve the function of the native TCR in tonically signaling CAR-VSTs.

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
肉瘤	临床1期	-	Texas Children's Hospital	-
肉瘤	临床1期	-	Baylor College of Medicine	-
肉瘤	临床1期	-	National Cancer Institute	-
肉瘤	临床1期	-	The Methodist Hospitals, Inc.	-