PMID- 16413390
OWN - NLM
STAT- MEDLINE
DCOM- 20060323
LR  - 20200804
IS  - 0301-472X (Print)
IS  - 0301-472X (Linking)
VI  - 34
IP  - 1
DP  - 2006 Jan
TI  - MDM2 is recognized as a tumor-associated antigen in chronic lymphocytic leukemia 
      by CD8+ autologous T lymphocytes.
PG  - 44-53
AB  - OBJECTIVE: Tumor-associated antigens (TAA) are the basis for antigen-specific 
      immunotherapy. The human homolog of the murine double-minute 2 oncoprotein (MDM2) 
      is a putative TAA because it is overexpressed in several malignancies, including 
      chronic lymphocytic leukemia (CLL) cells compared with normal B lymphocytes. 
      PATIENTS AND METHODS: Autologous, MDM2-specific human leukocyte antigen 
      (HLA)-A2-restricted T cells were identified using interferon (IFN)-gamma-ELISPOT 
      assays and HLA-A2/dimer-peptide staining after 4 weeks of in vitro culture. 
      RESULTS: Using native CLL cells as antigen-presenting cells (APCs), we 
      demonstrate the generation of MDM2-specific T cells in 7/12 CLL patients that 
      recognized specifically the MDM2-derived peptide MDM2(81-88) bound to 
      HLA-A2-dimers while they were inactive against an unrelated MAGE-3 peptide (p = 
      0.002). After 4 weeks, up to 32.3% of the expanded CD8(+) T cells specifically 
      recognized MDM2(81-88) by HLA-A2-dimer/peptide staining and up to 0.9% of all T 
      cells expanded reacted specifically against this MDM2-derived peptide in the 
      IFN-gamma-ELISPOT assay. If T cells were not expandable using native CLL cells as 
      APC, leukemic cells were stimulated with CD40-ligand to increase the 
      antigen-presenting capacity. This resulted in successful generation of 
      MDM2-specific T cells in three of five remaining cases tested. Additionally, the 
      factor that correlated best with successful generation of antigen-specific T 
      cells in CLL patients was the ability of APCs to secrete IFN-gamma upon 
      stimulation. CONCLUSION: In summary, MDM2(81-88) was shown for the first time in 
      humans to elicit a functional autologous immune response. MDM2 was demonstrated 
      to be naturally processed and presented as TAA in primary human CLL cells 
      enabling expansion of functional autologous tumor-specific T cells.
FAU - Mayr, Christine
AU  - Mayr C
AD  - KKG Gene Therapy, GSF-National Research Center for Environment and Health, 
      Munich, Germany.
FAU - Bund, Dagmar
AU  - Bund D
FAU - Schlee, Martin
AU  - Schlee M
FAU - Bamberger, Martina
AU  - Bamberger M
FAU - Kofler, David M
AU  - Kofler DM
FAU - Hallek, Michael
AU  - Hallek M
FAU - Wendtner, Clemens-Martin
AU  - Wendtner CM
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Netherlands
TA  - Exp Hematol
JT  - Experimental hematology
JID - 0402313
RN  - 0 (Antigens, Neoplasm)
RN  - 0 (Epitopes)
RN  - 0 (HLA-A Antigens)
RN  - 0 (HLA-A*02:01 antigen)
RN  - 0 (HLA-A2 Antigen)
RN  - 0 (RNA, Messenger)
RN  - EC 2.3.2.27 (Proto-Oncogene Proteins c-mdm2)
SB  - IM
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antigen Presentation/immunology
MH  - Antigens, Neoplasm/genetics/*immunology
MH  - B-Lymphocytes/immunology
MH  - CD8-Positive T-Lymphocytes/*immunology
MH  - Cells, Cultured
MH  - Epitopes/immunology
MH  - Female
MH  - Gene Expression Regulation, Leukemic/genetics/immunology
MH  - HLA-A Antigens/*immunology
MH  - HLA-A2 Antigen
MH  - Humans
MH  - In Vitro Techniques
MH  - Leukemia, Lymphocytic, Chronic, B-Cell/*immunology
MH  - Male
MH  - Middle Aged
MH  - Proto-Oncogene Proteins c-mdm2/genetics/*immunology
MH  - RNA, Messenger/genetics/immunology
MH  - Tumor Cells, Cultured
EDAT- 2006/01/18 09:00
MHDA- 2006/03/24 09:00
CRDT- 2006/01/18 09:00
PHST- 2005/08/19 00:00 [received]
PHST- 2005/09/26 00:00 [revised]
PHST- 2005/09/29 00:00 [accepted]
PHST- 2006/01/18 09:00 [pubmed]
PHST- 2006/03/24 09:00 [medline]
PHST- 2006/01/18 09:00 [entrez]
AID - S0301-472X(05)00467-4 [pii]
AID - 10.1016/j.exphem.2005.09.016 [doi]
PST - ppublish
SO  - Exp Hematol. 2006 Jan;34(1):44-53. doi: 10.1016/j.exphem.2005.09.016.