Title

Concerted potent humoral immune responses to autoantigens are associated with tumor destruction and favorable clinical outcomes without autoimmunity

UMMS Affiliation

University of Massachusetts Medical School

Publication Date

6-19-2008

Document Type

Article

Subjects

Antibody Formation; Autoantigens; Autoimmunity; Cancer Vaccines; Cell Line, Tumor; Humans; Immunotherapy; Lymphocytes, Tumor-Infiltrating; Neoplasms; Prognosis; Treatment Outcome; Tumor Cells, Cultured

Disciplines

Life Sciences | Medicine and Health Sciences

Abstract

PURPOSE: The therapeutic importance of immune responses against single versus multiple antigens is poorly understood. There also remains insufficient understanding whether responses to one subset of antigens are more significant than another. Autoantibodies are frequent in cancer patients. They can pose no biological significance or lead to debilitating paraneoplastic syndromes. Autoreactivity has been associated with clinical benefits, but the magnitude necessary for meaningful results is unknown. Autologous tumor cells engineered to secrete granulocyte macrophage colony-stimulating factor generate immune infiltrates in preexisting metastases with associated tumor destruction. We sought to identify targets of responses from this vaccination strategy.

EXPERIMENTAL DESIGN: Postvaccination sera used in screening a cDNA expression library prepared from a densely infiltrated metastasis of a long-term surviving melanoma patient identified several autoantigens. Additional autoantigens were identified through similar screenings in non-small cell lung cancer and murine models, and proteins implicated in cancer propagation. ELISAs for several targets were established using recombinant proteins, whereas others were evaluated by petit serologies.

RESULTS: Eleven gene products were identified through serologic screening from two patients showing highly favorable clinical outcomes. A subset of antigens revealed significant changes in antibody titers compared with weak responses to other proteins. Time course analyses showed coordinated enhanced titers against several targets as a function of vaccination in responding patients.

CONCLUSIONS: This study shows the range of biologically significant antigens resulting from a whole-cell vaccine. Targets include autoantigens that are components of cell cycle regulation. Potent antibody responses against multiple autoantigens are associated with effective tumor destruction without clinical autoimmunity.

Rights and Permissions

Citation: Clin Cancer Res. 2008 Jun 15;14(12):3896-905. Link to article on publisher's site

DOI of Published Version

10.1158/1078-0432.CCR-07-4782

Related Resources

Link to Article in PubMed

Journal/Book/Conference Title

Clinical cancer research : an official journal of the American Association for Cancer Research

PubMed ID

18559611