A viral vaccine encoding prostate-specific antigen induces antigen spreading to a common set of self-proteins in prostate cancer patients.
OBJECTIVE
We previously reported a randomized phase II clinical trial combining a poxvirus-based vaccine encoding prostate-specific antigen (PSA) with radiotherapy in patients with localized prostate cancer. Here, we investigate whether vaccination against PSA induced immune responses to additional tumor-associated antigens and how this influenced clinical outcome.


METHODS
Pretreatment and posttreatment serum samples from patients treated with vaccine + external beam radiation therapy (EBRT) versus EBRT alone were evaluated by Western blot and serologic screening of a prostate cancer cDNA expression library (SEREX) to assess the development of treatment-associated autoantibody responses.


RESULTS
Western blotting revealed treatment-associated autoantibody responses in 15 of 33 (45.5%) patients treated with vaccine + EBRT versus 1 of 8 (12.5%) treated with EBRT alone. SEREX screening identified 18 antigens, which were assembled on an antigen array with 16 previously identified antigens. Antigen array screening revealed that 7 of 33 patients (21.2%) treated with vaccine + EBRT showed a vaccine-associated autoantibody response to four ubiquitously expressed self-antigens: DIRC2, NDUFS1, MRFAP1, and MATN2. These responses were not seen in patients treated with EBRT alone, or other control groups. Patients with autoantibody responses to this panel of antigens had a trend toward decreased biochemical-free survival.


CONCLUSIONS
Vaccine + EBRT induced antigen spreading in a large proportion of patients. A subset of patients developed autoantibodies to a panel of four self-antigens and showed a trend toward inferior outcomes. Thus, cancer vaccines directed against tumor-specific antigens can trigger autoantibody responses to self-proteins, which may influence the efficacy of vaccination.
Nesslinger
Nancy J
NJ
Trev & Joyce Deeley Research Centre, BC Cancer Agency-Vancouver Island Centre, 2410 Lee Avenue, Victoria, British Columbia, Canada.
Ng
Alvin
A
Tsang
Kwong-Yok
KY
Ferrara
Theresa
T
Schlom
Jeffrey
J
Gulley
James L
JL
Nelson
Brad H
BH
D000368:Aged; D000369:Aged, 80 and over; D000941:Antigens / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology*; D001323:Autoantibodies / Q000097:blood / Q000276:immunology; D015153:Blotting, Western; D019496:Cancer Vaccines / Q000276:immunology* / Q000627:therapeutic use; D003131:Combined Modality Therapy; D015870:Gene Expression; D020869:Gene Expression Profiling; D005822:Genetic Vectors; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D011212:Poxviridae; D017430:Prostate-Specific Antigen / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000401:mortality / Q000628:therapy*; D011878:Radiotherapy
D000941:Antigens; D000951:Antigens, Neoplasm; D001323:Autoantibodies; D019496:Cancer Vaccines; D017430:Prostate-Specific Antigen