Common human cancers have been found to be associated with mutations in dominant and recessive oncogenes including the ras and p53 genes(1-4) and frequently produce mutant oncogene proteins that are uniquely present in the patient's cancer but not in normal cells. These tumor specific proteins could form the basis for highly tumor specific immunotherapy which targets an epitope that is present in each cancer cell and is fundamental to the maintenance of the malignant phenotype. The immune cells responsible for tumor cell killing appear to be major histocompatibility complex (MHC) restricted cytotoxic T lymphocytes (CTL). It is now known that such T cells detect target cells for killing by recognizing short peptide fragments of endogenous proteins that are presented to them by class I MHC molecules on the surface of the target cell. Such naturally presented peptides are found to be 8 or 9 residues long and are generated by endogenous antigen processing of both intracellular and membrane proteins (5-7). We have developed an effective method of peptide vaccination and have produced a CTL line specific for a lung cancer derived mutant human p53. We propose to 1) test a panel of mutant ras and p53 peptides for the ability to produce specific CTL, 2) to optimize positive peptides and vaccination procedures, 3) develop syngeneic animal tumor models expressing the effective mutant oncoproteins, and 4) evaluate anti-tumor efficacy of the optimized vaccination procedures.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA057856-03
Application #
2098594
Study Section
AIDS and Related Research Study Section 4 (ARRD)
Project Start
1992-08-07
Project End
1997-05-31
Budget Start
1994-08-01
Budget End
1995-05-31
Support Year
3
Fiscal Year
1994
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Carbone, David P; Ciernik, I Frank; Kelley, Michael J et al. (2005) Immunization with mutant p53- and K-ras-derived peptides in cancer patients: immune response and clinical outcome. J Clin Oncol 23:5099-107
Ciernik, I F; Berzofsky, J A; Carbone, D P (1996) Human lung cancer cells endogenously expressing mutant p53 process and present the mutant epitope and are lysed by mutant-specific cytotoxic T lymphocytes. Clin Cancer Res 2:877-82
Gabrilovich, D I; Ciernik, I F; Carbone, D P (1996) Dendritic cells in antitumor immune responses. I. Defective antigen presentation in tumor-bearing hosts. Cell Immunol 170:101-10
Lee, C T; Ciernik, I F; Wu, S et al. (1996) Increased immunogenicity of tumors bearing mutant p53 and P1A epitopes after transduction of B7-1 via recombinant adenovirus. Cancer Gene Ther 3:238-44
Ciernik, I F; Krayenbuhl, B H; Carbone, D P (1996) Puncture-mediated gene transfer to the skin. Hum Gene Ther 7:893-9
Ciernik, I F; Berzofsky, J; Carbone, D P (1995) Mutant oncopeptide immunization induces CTL specifically lysing tumor cells endogenously expressing the corresponding intact mutant p53. Hybridoma 14:139-42
Tang, D C; Johnston, S A; Carbone, D P (1994) Butyrate-inducible and tumor-restricted gene expression by adenovirus vectors. Cancer Gene Ther 1:15-20
Wiedenfeld, E A; Fernandez-Vina, M; Berzofsky, J A et al. (1994) Evidence for selection against human lung cancers bearing p53 missense mutations which occur within the HLA A*0201 peptide consensus motif. Cancer Res 54:1175-7
Tang, D C; Carbone, D P (1993) Potential application of gene therapy to lung cancer. Semin Oncol 20:368-73
Winter, S F; Sekido, Y; Minna, J D et al. (1993) Antibodies against autologous tumor cell proteins in patients with small-cell lung cancer: association with improved survival. J Natl Cancer Inst 85:2012-8

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