Amplification of virus-induced antimelanoma T-cell reactivity by high-dose interferon-alpha2b: implications for cancer vaccines.
OBJECTIVE
The therapeutic effectiveness of cancer vaccines, composed of tumor antigens that are also self-antigens, may be limited by the normal mechanisms that preserve immunological tolerance. Consistent with this notion, we found that vaccination of melanoma patients with recombinant viral vaccines expressing gp100 (a melanoma antigen also expressed by normal melanocytes) produced only transient increases in noncytotoxic T cells specific for immunodominant gp100 epitopes. To improve the therapeutic effects of these vaccines, IFN-alpha2b (IFN-alpha) was administered to some high-risk patients.


METHODS
7 HLA-A*0201(+) patients were injected with high doses of IFN-alpha (20 MU/m(2) x 20 doses) at various times after completing the vaccination protocol. Clinical toxicity and responses were documented, and the effects on gp100-reactive T cells were measured by IFN-gamma enzyme-linked immunospot assays, tetramers of HLA-A*0201 and gp100 epitopes, and cellular cytotoxicity assays.


RESULTS
In patients who had previously responded to vaccination, high doses of IFN-alpha recalled gp100-reactive T cells with the ability to kill gp100-expressing tumor targets in vitro. Concomitant with the reappearance of these cytotoxic T cells, tumor regression was observed in the two patients with clinically evident metastatic disease.


CONCLUSIONS
The finding that high-dose IFN recalls previously activated tumor-reactive T cells with potent killing ability suggests a strategy to maintain antitumor responses initiated by cancer vaccines.
Astsaturov
Igor
I
Division of Molecular and Cellular Biology, Research Institute, Sunnybrook and Women's College Health Sciences Center, Toronto, Ontario, Canada.
Petrella
Teresa
T
Bagriacik
E Umit
EU
de Benedette
Mark
M
Uger
Robert
R
Lumber
Gail
G
Berinstein
Neil
N
Elias
Ileana
I
Iscoe
Neill
N
Hammond
Caitlin
C
Hamilton
Paul
P
Spaner
David E
DE
D000328:Adult; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D028121:Canarypox virus / Q000502:physiology*; D019496:Cancer Vaccines / Q000008:administration & dosage*; D002455:Cell Division; D003602:Cytotoxicity, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D015234:HLA-A Antigens / Q000378:metabolism; D015789:HLA-A2 Antigen; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage*; D008207:Lymphatic Metastasis; D008297:Male; D008544:Melanocytes / Q000276:immunology / Q000473:pathology; D008545:Melanoma / Q000276:immunology* / Q000556:secondary / Q000628:therapy; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D011994:Recombinant Proteins; D013601:T-Lymphocytes / Q000276:immunology*; D014611:Vaccination; D058951:gp100 Melanoma Antigen
D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008562:Membrane Glycoproteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D011994:Recombinant Proteins; D058951:gp100 Melanoma Antigen