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Immunotherapy of metastatic melanoma using genetically engineered GD2-specific T cells.

ABSTRACT: Genetic engineering of human T lymphocytes to express tumor-directed chimeric antigen receptors (CAR) can produce antitumor effector cells that bypass tumor immune escape mechanisms that are due to abnormalities in protein-antigen processing and presentation. Moreover, these transgenic receptors can be directed to tumor-associated antigens that are not protein-derived, such as the ganglioside GD2, which is expressed in a high proportion of melanoma cells.We generated chimeric T cells specific for the ganglioside GD2 by joining an extracellular antigen-binding domain derived from the GD2-specific antibody sc14.G2a to cytoplasmic signaling domains derived from the T-cell receptor zeta-chain, with the endodomains of the costimulatory molecules CD28 and OX40. We expressed this CAR in human T cells and assessed the targeting of GD2-positive melanoma tumors in vitro and in a murine xenograft.Upon coincubation with GD2-expressing melanoma cells, CAR-GD2 T lymphocytes incorporating the CD28 and OX40 endodomains secreted significant levels of cytokines in a pattern comparable with the cytokine response obtained by engagement of the native CD3 receptor. These CAR-T cells had antimelanoma activity in vitro and in our xenograft model, increasing the survival of tumor-bearing animals.Redirecting human T lymphocytes to the tumor-associated ganglioside GD2 generates effector cells with antimelanoma activity that should be testable in subjects with disease.

SUBMITTER: Yvon E

PROVIDER: S-EPMC2745508 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Immunotherapy of metastatic melanoma using genetically engineered GD2-specific T cells.

Yvon Eric E Del Vecchio Michele M Savoldo Barbara B Hoyos Valentina V Dutour Aurélie A Anichini Andrea A Dotti Gianpietro G Brenner Malcolm K MK

Clinical cancer research : an official journal of the American Association for Cancer Research 20090908 18

<h4>Purpose</h4>Genetic engineering of human T lymphocytes to express tumor-directed chimeric antigen receptors (CAR) can produce antitumor effector cells that bypass tumor immune escape mechanisms that are due to abnormalities in protein-antigen processing and presentation. Moreover, these transgenic receptors can be directed to tumor-associated antigens that are not protein-derived, such as the ganglioside GD2, which is expressed in a high proportion of melanoma cells.<h4>Experimental design</ ...[more]

PMID: 19737958

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Project description:Purpose:The combined use of anatomical magnetic resonance imaging (MRI), cellular MRI, and bioluminescence imaging (BLI) allows for sensitive and improved monitoring of brain metastasis in preclinical cancer models. By using these complementary technologies, we can acquire measurements of viable single cell arrest in the brain after systemic administration, the clearance and/or retention of these cells thereafter, the growth into overt tumours, and quantification of tumour volume and relative cancer cell viability over time. While BLI is very useful in measuring cell viability, some considerations have been reported using cells engineered with luciferase such as increased tumour volume variation, changes in pattern of metastatic disease, and inhibition of in vivo tumour growth. Procedures:Here, we apply cellular and anatomical MRI to evaluate in vivo growth differences between iron oxide labeled naïve (4T1BR5) and luciferase-expressing (4T1BR5-FLuc-GFP) murine brain-seeking breast cancer cells. Balb/C mice received an intracardiac injection of 20,000?cells and were imaged with MRI on days 0 and 14. Mice that received 4T1BR5-FLuc-GFP cells were also imaged with BLI on days 0 and 14. Results:The number of signal voids in the brain (representing iron-labeled cancer cells) on day 0 was significantly higher in mice receiving 4T1BR5 cells compared to mice receiving 4T1BR5-FLuc-GFP cells (p < 0.0001). Mice that received 4T1BR5 cells also had significantly higher total brain tumour burden and number of brain metastases than mice that received 4T1BR5-FLuc-GFP cells (p < 0.0001). Conclusions:By employing highly sensitive cellular MRI tools, we demonstrate that engineered cells did not form tumours as well as their naïve counterparts, which appear to primarily be due to a reduction in cell arrest. These results indicate that engineering cancer cells with reporter genes may alter their tropism towards particular organs and highlight another important consideration for research groups that use reporter gene imaging to track metastatic cancer cell fate in vivo.

Dataset Information

Immunotherapy of metastatic melanoma using genetically engineered GD2-specific T cells.

Publications

Immunotherapy of metastatic melanoma using genetically engineered GD2-specific T cells.

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