PMID- 21149604
OWN - NLM
STAT- MEDLINE
DCOM- 20110214
LR  - 20220317
IS  - 1550-6606 (Electronic)
IS  - 0022-1767 (Print)
IS  - 0022-1767 (Linking)
VI  - 186
IP  - 2
DP  - 2011 Jan 15
TI  - 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.
PG  - 685-96
LID - 10.4049/jimmunol.1001775 [doi]
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 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.
FAU - Chinnasamy, Nachimuthu
AU  - Chinnasamy N
AD  - Surgery Branch, National Cancer Institute, National Institutes of Health, 
      Bethesda, MD 20892, USA.
FAU - Wargo, Jennifer A
AU  - Wargo JA
FAU - Yu, Zhiya
AU  - Yu Z
FAU - Rao, Mahadev
AU  - Rao M
FAU - Frankel, Timothy L
AU  - Frankel TL
FAU - Riley, John P
AU  - Riley JP
FAU - Hong, Jenny J
AU  - Hong JJ
FAU - Parkhurst, Maria R
AU  - Parkhurst MR
FAU - Feldman, Steven A
AU  - Feldman SA
FAU - Schrump, David S
AU  - Schrump DS
FAU - Restifo, Nicholas P
AU  - Restifo NP
FAU - Robbins, Paul F
AU  - Robbins PF
FAU - Rosenberg, Steven A
AU  - Rosenberg SA
FAU - Morgan, Richard A
AU  - Morgan RA
LA  - eng
GR  - Z01 BC010984-01/Intramural NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Intramural
DEP - 20101213
PL  - United States
TA  - J Immunol
JT  - Journal of immunology (Baltimore, Md. : 1950)
JID - 2985117R
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Epitopes, T-Lymphocyte)
RN  - 0 (HLA-A Antigens)
RN  - 0 (HLA-A*02:01 antigen)
RN  - 0 (HLA-A2 Antigen)
RN  - 0 (MAGEA3 protein, human)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Receptors, Antigen, T-Cell, alpha-beta)
RN  - 82115-62-6 (Interferon-gamma)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Antigens, Neoplasm/administration & dosage/biosynthesis/*immunology
MH  - Base Sequence
MH  - Breast Neoplasms/immunology/metabolism/therapy
MH  - Carcinoma, Non-Small-Cell Lung/immunology/metabolism/therapy
MH  - Cell Line, Transformed
MH  - Cell Line, Tumor
MH  - Coculture Techniques
MH  - *Cytotoxicity Tests, Immunologic/methods
MH  - Epitopes, T-Lymphocyte/administration & dosage/immunology/*metabolism
MH  - Female
MH  - HLA-A Antigens/biosynthesis/immunology/*metabolism
MH  - HLA-A2 Antigen
MH  - Humans
MH  - Immunotherapy, Adoptive/methods
MH  - Interferon-gamma/metabolism
MH  - Melanoma/immunology/metabolism/therapy
MH  - Mice
MH  - Mice, Transgenic
MH  - Molecular Sequence Data
MH  - Multigene Family/immunology
MH  - Neoplasm Proteins/administration & dosage/biosynthesis/*immunology
MH  - Receptors, Antigen, T-Cell, alpha-beta/genetics/immunology/*metabolism
MH  - T-Lymphocytes/immunology/metabolism/transplantation
PMC - PMC6292200
MID - NIHMS999389
COIS- Disclosures The authors have no financial conflicts of interest.
EDAT- 2010/12/15 06:00
MHDA- 2011/02/15 06:00
PMCR- 2018/12/13
CRDT- 2010/12/15 06:00
PHST- 2010/12/15 06:00 [entrez]
PHST- 2010/12/15 06:00 [pubmed]
PHST- 2011/02/15 06:00 [medline]
PHST- 2018/12/13 00:00 [pmc-release]
AID - jimmunol.1001775 [pii]
AID - 10.4049/jimmunol.1001775 [doi]
PST - ppublish
SO  - J Immunol. 2011 Jan 15;186(2):685-96. doi: 10.4049/jimmunol.1001775. Epub 2010 
      Dec 13.