Originally published as JCO Early Release 10.1200/JCO.2005.03.158 on June 27 2005

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Immunization With Mutant p53- and K-ras–Derived Peptides in Cancer Patients: Immune Response and Clinical Outcome

From the Hamon Center for Therapeutic Oncology Research, Department of Internal Medicine, Division of Hematology/Oncology, and Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX; The Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN; Vaccine Branch, Navy Medicine Branch, Cancer Therapy Evaluation Program, and Monoclonal Antibody/Recombinant Protein Production Facility, National Cancer Institute; Division of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, MD; Department of Radiation Oncology, Zürich University Hospital; and Institute for Social and Preventive Medicine, University of Zürich, Zürich, Switzerland.

Address reprint requests to I.F. Ciernik, MD, Radiation Oncology, Zürich University Hospital, Rämistrasse 100, Zürich 8091, Switzerland; e-mail: ciernik{at}usz.ch; or D.P. Carbone, MD, PhD, Vanderbilt-Ingram Cancer Center, 691 Preston Research Bldg, Nashville, TN 37232-6838; e-mail: d.carbone{at}vanderbilt.edu

PURPOSE: To determine the ability to induce tumor-specific immunity with individual mutant K-ras–or p53-derived peptides and to monitor clinical outcome.

PATIENTS AND 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-) 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-, 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- responses occurred in 16 patients (42%) after vaccination, whereas four patients had positive IFN- 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- 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- response (P = .02), respectively, were detected.

CONCLUSION: 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.

Supported in part by National Institutes of Health grant Nos. RO1 CA57856 and RO1 CA61242 (D.P.C.) and SPORE P50 CA70907 (J.D.M.) and Swiss National Foundation grant No. 81ZH-36667 (I.F.C.).

Presented in part at the 36th Annual Meeting of the American Society of Clinical Onocology, New Orleans, LA, May 20-23, 2000 and at ECCO 12: The European Cancer Conference, Copenhagen, Denmark, September 21-25, 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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