A TCR Targeting the HLA-A*0201-Restricted Epitope of MAGE-A3 Recognizes Multiple Epitopes of the MAGE-A Antigen Superfamily in Several Types of Cancer

被引：131

作者：

Chinnasamy, Nachimuthu ^{[1
]}

Wargo, Jennifer A. ^{[1
]}

Yu, Zhiya ^{[1
]}

Rao, Mahadev ^{[1
]}

Frankel, Timothy L. ^{[1
]}

Riley, John P. ^{[1
]}

Hong, Jenny J. ^{[1
]}

Parkhurst, Maria R. ^{[1
]}

Feldman, Steven A. ^{[1
]}

Schrump, David S. ^{[1
]}

Restifo, Nicholas P. ^{[1
]}

Robbins, Paul F. ^{[1
]}

Rosenberg, Steven A. ^{[1
]}

Morgan, Richard A. ^{[1
]}

机构：

[1] NCI, Surg Branch, NIH, Bethesda, MD 20892 USA

来源：

JOURNAL OF IMMUNOLOGY | 2011年 / 186卷 / 02期

基金：

美国国家卫生研究院;

关键词：

CYTOLYTIC T-LYMPHOCYTES; TISSUE MICROARRAY EVALUATION; TUMOR-CELL RECOGNITION; MELANOMA PATIENTS; METASTATIC MELANOMA; DENDRITIC CELLS; LUNG-CANCER; ENGINEERED LYMPHOCYTES; POTENTIAL INDICATIONS; PROGNOSTIC RELEVANCE;

D O I：

10.4049/jimmunol.1001775

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Adoptive immunotherapy using TCR-engineered PBLs against melanocyte differentiation Ags mediates objective tumor regression but is associated with on-target toxicity. To avoid toxicity to normal tissues, we targeted cancer testis Ag (CTA) MAGE-A3, which is widely expressed in a range of epithelial malignancies but is not expressed in most normal tissues. To generate high-avidity TCRs against MAGE-A3, we employed a transgenic mouse model that expresses the human HLA-A*0201 molecule. Mice were immunized with two HLA-A*0201-restricted peptides of MAGE-A3: 112-120 (KVAELVHFL) or MAGE-A3: 271-279 (FLWGPRALV), and T cell clones were generated. MAGE-A3-specific TCR alpha-and beta-chains were isolated and cloned into a retroviral vector. Expression of both TCRs in human PBLs demonstrated Ag-specific reactivity against a range of melanoma and nonmelanoma tumor cells. The TCR against MAGE-A3: 112-120 was selected for further development based on superior reactivity against tumor target cells. Interestingly, peptide epitopes from MAGE-A3 and MAGE-A12 (and to a lesser extent, peptides from MAGE-A2 and MAGE-A6) were recognized by PBLs engineered to express this TCR. To further improve TCR function, single amino acid variants of the CDR3 alpha-chain were generated. Substitution of alanine to threonine at position 118 of the alpha-chain in the CDR3 region of the TCR improved its functional avidity in CD4 and CD8 cells. On the basis of these results, a clinical trial is planned in which patients bearing a variety of tumor histologies will receive autologous PBLs that have been transduced with this optimized anti-MAGE-A3 TCR. The Journal of Immunology, 2011, 186: 685-696.

引用

页码：685 / 696

页数：12

共 65 条

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