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

Nachimuthu Chinnasamy, Jennifer A. Wargo, Zhiya Yu, Mahadev Rao, Timothy L. Frankel, John P. Riley, Jenny J. Hong, Maria R. Parkhurst, Steven A. Feldman, David S. Schrump, Nicholas P. Restifo, Paul F. Robbins, Steven A. Rosenberg, Richard A. Morgan

Research output: Contribution to journalArticle

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Abstract

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 α- and β-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 α-chain were generated. Substitution of alanine to threonine at position 118 of the α-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.

Original languageEnglish
Pages (from-to)685-696
Number of pages12
JournalJournal of Immunology
Volume186
Issue number2
DOIs
Publication statusPublished - 15-01-2011

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Epitopes
Antigens
Neoplasms
Peptides
Adoptive Immunotherapy
compound A 12
Melanocytes
Testicular Neoplasms
Threonine
varespladib methyl
Alanine
Transgenic Mice
Melanoma
Histology
Clone Cells
HLA-A*02:01 antigen
Clinical Trials
T-Lymphocytes
Amino Acids

All Science Journal Classification (ASJC) codes

  • Immunology

Cite this

Chinnasamy, Nachimuthu ; Wargo, Jennifer A. ; Yu, Zhiya ; Rao, Mahadev ; Frankel, Timothy L. ; Riley, John P. ; Hong, Jenny J. ; Parkhurst, Maria R. ; Feldman, Steven A. ; Schrump, David S. ; Restifo, Nicholas P. ; Robbins, Paul F. ; Rosenberg, Steven A. ; Morgan, Richard A. / 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. In: Journal of Immunology. 2011 ; Vol. 186, No. 2. pp. 685-696.
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title = "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",
abstract = "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 α- and β-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 α-chain were generated. Substitution of alanine to threonine at position 118 of the α-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.",
author = "Nachimuthu Chinnasamy and Wargo, {Jennifer A.} and Zhiya Yu and Mahadev Rao and Frankel, {Timothy L.} and Riley, {John P.} and Hong, {Jenny J.} and Parkhurst, {Maria R.} and Feldman, {Steven A.} and Schrump, {David S.} and Restifo, {Nicholas P.} and Robbins, {Paul F.} and Rosenberg, {Steven A.} and Morgan, {Richard A.}",
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Chinnasamy, N, Wargo, JA, Yu, Z, Rao, M, Frankel, TL, Riley, JP, Hong, JJ, Parkhurst, MR, Feldman, SA, Schrump, DS, Restifo, NP, Robbins, PF, Rosenberg, SA & Morgan, RA 2011, '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', Journal of Immunology, vol. 186, no. 2, pp. 685-696. https://doi.org/10.4049/jimmunol.1001775

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. / Chinnasamy, Nachimuthu; Wargo, Jennifer A.; Yu, Zhiya; Rao, Mahadev; Frankel, Timothy L.; Riley, John P.; Hong, Jenny J.; Parkhurst, Maria R.; Feldman, Steven A.; Schrump, David S.; Restifo, Nicholas P.; Robbins, Paul F.; Rosenberg, Steven A.; Morgan, Richard A.

In: Journal of Immunology, Vol. 186, No. 2, 15.01.2011, p. 685-696.

Research output: Contribution to journalArticle

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T1 - 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

AU - Chinnasamy, Nachimuthu

AU - Wargo, Jennifer A.

AU - Yu, Zhiya

AU - Rao, Mahadev

AU - Frankel, Timothy L.

AU - Riley, John P.

AU - Hong, Jenny J.

AU - Parkhurst, Maria R.

AU - Feldman, Steven A.

AU - Schrump, David S.

AU - Restifo, Nicholas P.

AU - Robbins, Paul F.

AU - Rosenberg, Steven A.

AU - Morgan, Richard A.

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N2 - 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 α- and β-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 α-chain were generated. Substitution of alanine to threonine at position 118 of the α-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.

AB - 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 α- and β-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 α-chain were generated. Substitution of alanine to threonine at position 118 of the α-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.

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