Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The . gov means it’s official VSports app下载. Federal government websites often end in . gov or . mil. Before sharing sensitive information, make sure you’re on a federal government site. .

Https

The site is secure V体育官网. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely. .

. 2008 Nov;14(11):1264-70.
doi: 10.1038/nm.1882. Epub 2008 Nov 2.

Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma

Martin A Pule  1 , Barbara Savoldo, G Doug Myers, Claudia Rossig, Heidi V Russell, Gianpietro Dotti, M Helen Huls, Enli Liu, Adrian P Gee, Zhuyong Mei, Eric Yvon, Heidi L Weiss, Hao Liu, Cliona M Rooney, Helen E Heslop, Malcolm K Brenner
Affiliations

"VSports手机版" Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma

Martin A Pule et al. Nat Med. 2008 Nov.

Abstract

Cytotoxic T lymphocytes (CTLs) directed to nonviral tumor-associated antigens do not survive long term and have limited antitumor activity in vivo, in part because such tumor cells typically lack the appropriate costimulatory molecules. We therefore engineered Epstein-Barr virus (EBV)-specific CTLs to express a chimeric antigen receptor directed to the diasialoganglioside GD2, a nonviral tumor-associated antigen expressed by human neuroblastoma cells. We reasoned that these genetically engineered lymphocytes would receive optimal costimulation after engagement of their native receptors, enhancing survival and antitumor activity mediated through their chimeric receptors VSports手机版. Here we show in individuals with neuroblastoma that EBV-specific CTLs expressing a chimeric GD2-specific receptor indeed survive longer than T cells activated by the CD3-specific antibody OKT3 and expressing the same chimeric receptor but lacking virus specificity. Infusion of these genetically modified cells seemed safe and was associated with tumor regression or necrosis in half of the subjects tested. Hence, virus-specific CTLs can be modified to function as tumor-directed effector cells. .

PubMed Disclaimer

Figures (VSports注册入口)

Figure 1
Figure 1
Transduction of CTLs and ATCs with GD2-specific CARs. (a) Transduction efficiency of subject-derived CTLs and ATCs by the GD2 vectors, as evaluated by quantitative PCR (qPCR, left) and FACS (right). Each symbol represents 1 of the 11 individual subjects, and the horizontal lines indicate the mean group value. Surface expression by FACS and qPCR amplification are described in Methods. (b) FACS analyses of receptor expression shown in more detail for subject 5. Percentages represent the proportion of transduced cells.
Figure 2
Figure 2
Immunophenotypes of CAR-transduced CTLs and ATCs. (a) Phenotypic composition of CTL and ATC population after transduction with the GD2-specific CARs. Percentages of CD4+ and CD8+ T cells, natural killer cells (CD3−CD56+) and T cells expressing TCR-γδ are shown. Each symbol represents a transduced cell line infused into a single subject. A significant difference between CTLs and ATCs was observed only for the percentage of CD8+ cells (P = 0.05). (b) Expression of naive, central memory and effector memory surface markers on GD2-specific CAR-CTLs and CAR-ATCs. The data are means ± s.d. (c) Expression of chemokine receptors and adhesion molecules on GD2-specific CAR-CTLs and CAR-ATCs. The data are means ± s.d. (d) Results of standard 51Cr release assay at an effector:tumor cell (E:T) ratio of 20:1. Data represent the mean ± s.d. percentage of specific chromium released from the CAR-CTLs and CAR-ATCs generated from each of the 11 subjects. Targets were autologous LCLs, allogeneic LCLs, autologous PHA blasts and LAN-1 cells.
Figure 3
Figure 3
In vivo persistence of infused CAR-CTLs versus CAR-ATCs in peripheral blood as determined by real-time quantitative PCR. A comparison of mean ± s.e.m. areas under the curve of the qPCR signal for ATCs and CTLs detected in PBMCs of treated subjects at the indicated times after infusion is shown. Five of the subjects (7 –11) received monoclonal antibodies to the common leukocyte antigen (CD45) at 2–3 d before ATC and CTL infusion and had 44–91% depletion of endogenous circulating lymphocytes. There were no measurable differences between the areas under the curve for either ATCs or CTLs between subjects 1–6 (no CD45) and 7–11 (CD45-treated).
Figure 4
Figure 4
Reactivation of CAR-CTLs ex vivo. (a,b) Fold change in the level of GD2-receptor-transgene positivity in the cultures before and after exposure to EBV antigen in ATCs (a) and CTLs (b). PBMCs were collected at increasing times after infusion (indicated on the x axis) and re-expanded ex vivo in the presence of EBV+ targets (total of three or four stimulations). Each symbol represents a single subject. (c) Change in percentage of cells expressing the GD2 chimeric receptor on ex vivo-reactivated CTLs. The y axis for the top panels indicates the isotype control, whereas for the bottom panels it indicates antibody 1A7. Percentages represent the proportions of cells expressing the CAR. (d) Cytotoxicity of ex vivo-reactivated CTLs against autologous LCLs, allogeneic LCLs or LAN-1 cells. The data are means ± s.d. of triplicate experiments.
Figure 5
Figure 5
Resolution of neuroblastoma in subjects 3 and 6 after infusion of genetically engineered T cells. (a) Sequential anatomic (MRI) and functional (MIBG) imaging of the head and neck of subject 3, a 4-year-old girl with relapsed metastatic neuroblastoma, with an extradural mass and overlying calvarial bone involvement. Progressive resolution of the extradural mass and loss of MIBG uptake in the lesion by 4 months after infusion are indicated by arrows. The signal in the salivary glands remains due to normal uptake. (b) H&E stain showing postinfusion normalization of bone marrow in subject 6 after extensive infiltration by neuroblasts.
See this image and copyright information in PMC

"V体育ios版" Comment in

References

    1. Morgan RA, et al. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science. 2006;314:126–129. - PMC - PubMed
    1. Heslop HE, et al. Long-term restoration of immunity against Epstein-Barr virus infection by adoptive transfer of gene-modified virus-specific T lymphocytes. Nat Med. 1996;2:551–555. - PubMed
    1. Bollard CM, et al. Cytotoxic T lymphocyte therapy for Epstein-Barr virus–positive Hodgkin’s disease. J Exp Med. 2004;200:1623–1633. - VSports最新版本 - PMC - PubMed
    1. Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer. 2004;4:757–768. - PubMed
    1. Khanna R, Moss D, Gandhi M. Technology insight: applications of emerging immunotherapeutic strategies for Epstein-Barr virus–associated malignancies. Nat Clin Pract Oncol. 2005;2:138–149. - PubMed

"V体育安卓版" Publication types

MeSH terms

"V体育安卓版" Substances

"VSports注册入口" LinkOut - more resources