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


METHODS
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.
Sittler
Taylor
T
University of Massachusetts Medical School, Worcester, Massachusetts, USA.
Zhou
Jun
J
Park
Joosang
J
Yuen
Noah K
NK
Sarantopoulos
Stefanie
S
Mollick
Joseph
J
Salgia
Ravi
R
Giobbie-Hurder
Anita
A
Dranoff
Glenn
G
Hodi
F Stephen
FS
D000917:Antibody Formation / Q000187:drug effects* / Q000502:physiology; D001324:Autoantigens / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use*; D015551:Autoimmunity / Q000187:drug effects*; D019496:Cancer Vaccines / Q000627:therapeutic use; D045744:Cell Line, Tumor; D006801:Humans; D007167:Immunotherapy; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology*; D009369:Neoplasms / Q000175:diagnosis* / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011379:Prognosis; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D001324:Autoantigens; D019496:Cancer Vaccines