Immunization with mutant p53- and K-ras-derived peptides in cancer patients: immune response and clinical outcome.
OBJECTIVE
To determine the ability to induce tumor-specific immunity with individual mutant K-ras-or p53-derived peptides and to monitor clinical outcome.


METHODS
Patients in varying stages of disease underwent genetic analysis for mutations in K-ras and p53. Thirty-nine patients were enrolled. Seventeen-mer peptides were custom synthesized to the corresponding mutation. Baseline immunity was assessed for cytotoxic T-lymphocyte (CTL) response and interferon gamma (IFN-gamma) release from mutant peptide-primed lymphocytes. Patients' peripheral-blood mononuclear cells were pulsed with the corresponding peptide, irradiated, and applied intravenously. Patients were observed for CTL, IFN-gamma, interleukin (IL) -2, IL-5, and granulocyte-macrophage colony-stimulating factor responses, for treatment-related toxicity, and for tumor response.


RESULTS
No toxicity was observed. Ten (26%) of 38 patients had detectable CTL against mutant p53 or K-ras, and two patients were positive for CTL at baseline. Positive IFN-gamma responses occurred in 16 patients (42%) after vaccination, whereas four patients had positive IFN-gamma reaction before vaccination. Of 29 patients with evident disease, five experienced a period of stable disease. Favorable prognostic markers were detectable CTL activity and a positive IFN-gamma reaction but not IL-5 release. Median survival times of 393 v 98 days for a positive versus negative CTL response (P = .04), respectively, and of 470 v 88 days for a positive versus negative IFN-gamma response (P = .02), respectively, were detected.


CONCLUSIONS
Custom-made peptide vaccination is feasible without any toxicity. CTL and cytokine responses specific to a given mutation can be induced or enhanced with peptide vaccines. Cellular immunity to mutant p53 and K-ras oncopeptides is associated with longer survival.
Carbone
David P
DP
Hamon Center for Therapeutic Concology Research, University of Texas Southwestern Medical Center, Dallas, TX, USA. d.carbone@vanderbilt.edu
Ciernik
I Frank
IF
Kelley
Michael J
MJ
Smith
M Charles
MC
Nadaf
Sorena
S
Kavanaugh
Denise
D
Maher
V Ellen
VE
Stipanov
Michael
M
Contois
David
D
Johnson
Bruce E
BE
Pendleton
C David
CD
Seifert
Burkhardt
B
Carter
Charley
C
Read
Elizabeth J
EJ
Greenblatt
Jay
J
Top
Lois E
LE
Kelsey
Morris I
MI
Minna
John D
JD
Berzofsky
Jay A
JA
D000328:Adult; D000368:Aged; D019496:Cancer Vaccines; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005260:Female; D016158:Genes, p53; D011905:Genes, ras; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D011379:Prognosis; D016019:Survival Analysis; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53
D019496:Cancer Vaccines; D016207:Cytokines; D016159:Tumor Suppressor Protein p53; D007371:Interferon-gamma