Inflammatory adverse events are associated with disease-free survival after vaccine therapy among patients with melanoma.
BACKGROUND
Multipeptide vaccines for melanoma may cause inflammatory adverse events (IAE). We hypothesize that IAE are associated with a higher rate of immune response (IR) to vaccination and improved clinical outcomes.


METHODS
Adult patients with resected, high-risk (stage IIB to IV) melanoma were vaccinated with a combination of 12 class I major histocompatibility complex (MHC)-restricted melanoma epitopes, and IAE were recorded. A separate category for hypopigmentation (vitiligo) was also assessed. CD8(+) T cell IR was assessed by direct interferon gamma ELISpot analysis. Overall survival and disease-free survival were analyzed by Cox proportional hazard modeling.


RESULTS
Out of 332 patients, 57 developed IAE, the majority of which were dermatologic (minimum Common Terminology Criteria for Adverse Events [CTCAE] grade 3). Most nondermatologic IAE were CTCAE grade 1 and 2. Vitiligo developed in 23 patients (7 %). A total of 174 patients (53 %) developed a CD8(+) response. Presence of IAE was significantly associated with development of IR (70 vs. 49 %, p = 0.005) and with disease-free survival (hazard ratio 0.54, p = 0.043). There were no significant associations relating vitiligo or IR alone with clinical outcomes.


CONCLUSIONS
IAE are associated with a higher rate of CD8(+) T cell response after vaccination therapy for high-risk melanoma. Our findings suggest either that antitumor activity induced by class I MHC-restricted peptide vaccines may depend on immunologic effects beyond simple expansion of CD8(+) T cells or that the intrinsic inflammatory response of patients contributes to clinical outcome in melanoma.
Department of Surgery/Division of Surgical Oncology, University of Virginia Health System, Charlottesville, VA, USA, yh9b@virginia.edu.
Yinin
Y
Hu
Mark E
ME
Smolkin
Emily J
EJ
White
Gina R
GR
Petroni
Patrice Y
PY
Neese
Craig L
CL
Slingluff
D000328:Adult; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D005500:Follow-Up Studies; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D016233:Immunotherapy, Active / Q000009:adverse effects*; D007249:Inflammation / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality; D008171:Lung Diseases / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality; D008297:Male; D008545:Melanoma / Q000150:complications / Q000276:immunology* / Q000401:mortality* / Q000628:therapy; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D012871:Skin Diseases / Q000175:diagnosis / Q000209:etiology* / Q000401:mortality; D015996:Survival Rate
D000951:Antigens, Neoplasm; D015395:Histocompatibility Antigens Class I