Phenotypic and Functional Maturation of Tumor Antigen-Reactive CD8 + T Lymphocytes in Patients Undergoing Multiple Course Peptide Vaccination

Daniel J. Powell, Steven A. Rosenberg

Research output: Contribution to journalArticle

Abstract

Successful immunotherapy with peptide vaccines depends on the in vivo generation of sufficient numbers of anti-tumor T cells with appropriate phenotypic and functional characteristics to mediate tumor destruction. Herein, we report the induction of high frequencies of circulating CD8+ T cells (4.8% to 38.1%) directed against the native gp100:209-217 peptide derived from the gp100 melanoma-melanocyte tumor antigen in five HLA-A*0201 patients at high risk of recurrence of melanoma after multiple courses of immunization with modified gp100:209-217(210M) peptide in IFA. Longitudinal peripheral blood mononuclear cell (PBMC) analysis revealed a phenotypic shift of native peptide-specific CD8+ T cells from an early effector to an effector memory (CD27- CD28- CD62L- CD45RO +) phenotype with repeated immunizations and functional maturation that correlated with gp100:209-217 peptide-specific T-cell precursor frequencies. Postimmunization PBMC exhibited direct ex vivo recognition of melanoma cell lines in ELISPOT analysis, showed lytic capability against peptide-pulsed target cells, and proliferated in response to native peptide stimulation. One year after final immunization, circulating vaccine-specific CD8+ T cells persisted in patients' PBMC with a maintained effector memory phenotype. The results herein demonstrate the efficacy of a multiple course peptide-immunization strategy for the generation of high frequencies of tumor antigen-specific T cells in vivo, and further show that continued peptide immunization results in the escalating generation of functionally mature, tumor-reactive effector memory CD8+ T lymphocytes.

Original languageEnglish (US)
Pages (from-to)36-47
Number of pages12
JournalJournal of Immunotherapy
Volume27
Issue number1
DOIs
StatePublished - Jan 2004
Externally publishedYes

Fingerprint

Neoplasm Antigens
Vaccination
T-Lymphocytes
Peptides
Immunization
Melanoma
Blood Cells
T-Lymphoid Precursor Cells
Peptide T
Phenotype
Enzyme-Linked Immunospot Assay
Neoplasms
Subunit Vaccines
Melanocytes
Immunotherapy
Vaccines
Recurrence
Cell Line

Keywords

  • Differentiation
  • Human antigen/peptide/epitope
  • T lymphocytes
  • Tumor immunity
  • Vaccination

ASJC Scopus subject areas

  • Cancer Research
  • Pharmacology
  • Immunology

Cite this

Phenotypic and Functional Maturation of Tumor Antigen-Reactive CD8 + T Lymphocytes in Patients Undergoing Multiple Course Peptide Vaccination. / Powell, Daniel J.; Rosenberg, Steven A.

In: Journal of Immunotherapy, Vol. 27, No. 1, 01.2004, p. 36-47.

Research output: Contribution to journalArticle

@article{4e6409810ca54aa69e9b7bb07e5b95b5,
title = "Phenotypic and Functional Maturation of Tumor Antigen-Reactive CD8 + T Lymphocytes in Patients Undergoing Multiple Course Peptide Vaccination",
abstract = "Successful immunotherapy with peptide vaccines depends on the in vivo generation of sufficient numbers of anti-tumor T cells with appropriate phenotypic and functional characteristics to mediate tumor destruction. Herein, we report the induction of high frequencies of circulating CD8+ T cells (4.8{\%} to 38.1{\%}) directed against the native gp100:209-217 peptide derived from the gp100 melanoma-melanocyte tumor antigen in five HLA-A*0201 patients at high risk of recurrence of melanoma after multiple courses of immunization with modified gp100:209-217(210M) peptide in IFA. Longitudinal peripheral blood mononuclear cell (PBMC) analysis revealed a phenotypic shift of native peptide-specific CD8+ T cells from an early effector to an effector memory (CD27- CD28- CD62L- CD45RO +) phenotype with repeated immunizations and functional maturation that correlated with gp100:209-217 peptide-specific T-cell precursor frequencies. Postimmunization PBMC exhibited direct ex vivo recognition of melanoma cell lines in ELISPOT analysis, showed lytic capability against peptide-pulsed target cells, and proliferated in response to native peptide stimulation. One year after final immunization, circulating vaccine-specific CD8+ T cells persisted in patients' PBMC with a maintained effector memory phenotype. The results herein demonstrate the efficacy of a multiple course peptide-immunization strategy for the generation of high frequencies of tumor antigen-specific T cells in vivo, and further show that continued peptide immunization results in the escalating generation of functionally mature, tumor-reactive effector memory CD8+ T lymphocytes.",
keywords = "Differentiation, Human antigen/peptide/epitope, T lymphocytes, Tumor immunity, Vaccination",
author = "Powell, {Daniel J.} and Rosenberg, {Steven A.}",
year = "2004",
month = "1",
doi = "10.1097/00002371-200401000-00004",
language = "English (US)",
volume = "27",
pages = "36--47",
journal = "Journal of Immunotherapy",
issn = "1524-9557",
publisher = "Lippincott Williams and Wilkins",
number = "1",

}

TY - JOUR

T1 - Phenotypic and Functional Maturation of Tumor Antigen-Reactive CD8 + T Lymphocytes in Patients Undergoing Multiple Course Peptide Vaccination

AU - Powell, Daniel J.

AU - Rosenberg, Steven A.

PY - 2004/1

Y1 - 2004/1

N2 - Successful immunotherapy with peptide vaccines depends on the in vivo generation of sufficient numbers of anti-tumor T cells with appropriate phenotypic and functional characteristics to mediate tumor destruction. Herein, we report the induction of high frequencies of circulating CD8+ T cells (4.8% to 38.1%) directed against the native gp100:209-217 peptide derived from the gp100 melanoma-melanocyte tumor antigen in five HLA-A*0201 patients at high risk of recurrence of melanoma after multiple courses of immunization with modified gp100:209-217(210M) peptide in IFA. Longitudinal peripheral blood mononuclear cell (PBMC) analysis revealed a phenotypic shift of native peptide-specific CD8+ T cells from an early effector to an effector memory (CD27- CD28- CD62L- CD45RO +) phenotype with repeated immunizations and functional maturation that correlated with gp100:209-217 peptide-specific T-cell precursor frequencies. Postimmunization PBMC exhibited direct ex vivo recognition of melanoma cell lines in ELISPOT analysis, showed lytic capability against peptide-pulsed target cells, and proliferated in response to native peptide stimulation. One year after final immunization, circulating vaccine-specific CD8+ T cells persisted in patients' PBMC with a maintained effector memory phenotype. The results herein demonstrate the efficacy of a multiple course peptide-immunization strategy for the generation of high frequencies of tumor antigen-specific T cells in vivo, and further show that continued peptide immunization results in the escalating generation of functionally mature, tumor-reactive effector memory CD8+ T lymphocytes.

AB - Successful immunotherapy with peptide vaccines depends on the in vivo generation of sufficient numbers of anti-tumor T cells with appropriate phenotypic and functional characteristics to mediate tumor destruction. Herein, we report the induction of high frequencies of circulating CD8+ T cells (4.8% to 38.1%) directed against the native gp100:209-217 peptide derived from the gp100 melanoma-melanocyte tumor antigen in five HLA-A*0201 patients at high risk of recurrence of melanoma after multiple courses of immunization with modified gp100:209-217(210M) peptide in IFA. Longitudinal peripheral blood mononuclear cell (PBMC) analysis revealed a phenotypic shift of native peptide-specific CD8+ T cells from an early effector to an effector memory (CD27- CD28- CD62L- CD45RO +) phenotype with repeated immunizations and functional maturation that correlated with gp100:209-217 peptide-specific T-cell precursor frequencies. Postimmunization PBMC exhibited direct ex vivo recognition of melanoma cell lines in ELISPOT analysis, showed lytic capability against peptide-pulsed target cells, and proliferated in response to native peptide stimulation. One year after final immunization, circulating vaccine-specific CD8+ T cells persisted in patients' PBMC with a maintained effector memory phenotype. The results herein demonstrate the efficacy of a multiple course peptide-immunization strategy for the generation of high frequencies of tumor antigen-specific T cells in vivo, and further show that continued peptide immunization results in the escalating generation of functionally mature, tumor-reactive effector memory CD8+ T lymphocytes.

KW - Differentiation

KW - Human antigen/peptide/epitope

KW - T lymphocytes

KW - Tumor immunity

KW - Vaccination

UR - http://www.scopus.com/inward/record.url?scp=0346024187&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0346024187&partnerID=8YFLogxK

U2 - 10.1097/00002371-200401000-00004

DO - 10.1097/00002371-200401000-00004

M3 - Article

C2 - 14676632

AN - SCOPUS:0346024187

VL - 27

SP - 36

EP - 47

JO - Journal of Immunotherapy

JF - Journal of Immunotherapy

SN - 1524-9557

IS - 1

ER -