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. 2015 Sep 1;21(17):3879-87.
doi: 10.1158/1078-0432.CCR-15-0233. Epub 2015 May 12.

Vaccination with Melanoma Helper Peptides Induces Antibody Responses Associated with Improved Overall Survival

Caroline M Reed  1 , Nicole D Cresce  1 , Ileana S Mauldin  1 , Craig L Slingluff Jr  1 , Walter C Olson  2
Affiliations

Vaccination with Melanoma Helper Peptides Induces Antibody Responses Associated with Improved Overall Survival

Caroline M Reed et al. Clin Cancer Res. .

Abstract

Purpose: A melanoma vaccine incorporating six peptides designed to induce helper T-cell responses to melanoma antigens has induced Th1-dominant CD4(+) T-cell responses in most patients, and induced durable clinical responses or stable disease in 24% of evaluable patients. The present study tested whether this vaccine also induced antibody (Ab) responses to each peptide, and whether Ab responses were associated with T-cell responses and with clinical outcome.

Experimental design: Serum samples were studied from 35 patients with stage III-IV melanomas vaccinated with 6 melanoma helper peptides (6MHP). IgG Ab responses were measured by ELISA. Associations with immune response and overall survival were assessed by log-rank test and χ(2) analysis of Kaplan-Meier data.

Results: Ab responses to 6MHP were detected by week 7 in 77% of patients, and increased to peak 6 weeks after the last vaccine and persisted to 6 months. Ab responses were induced most frequently to longer peptides. Of those with T-cell responses, 82% had early Ab responses. Survival was improved for patients with early Ab response (P = 0.0011) or with early T-cell response (P < 0.006), and was best for those with both Ab and T-cell responses (P = 0.0002).

Conclusions: Vaccination with helper peptides induced both Ab responses and T-cell responses, associated with favorable clinical outcome. Such immune responses may predict favorable clinical outcome to guide combination immunotherapy. Further studies are warranted to understand mechanisms of interaction of these Abs, T-cell responses, and tumor control.

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Conflict of interest statement

Disclosure of conflicts: Dr. Slingluff is an inventor for patents on peptides used in cancer vaccines, but not for the peptides studied in the present report, and he is a consultant for companies that develop and test cancer vaccines (Immatics, and Polynoma), but the peptides studied in this report are not owned or licensed by these companies but funds from those relationships go to the University of Virginia, not to him personally. The University of Virginia also receives funds from Glaxo Smith Kline (GSK) for an unrelated vaccine trial, but GSK has licensed some of the peptides used in this trial. C.M.R, N.D.C., I.S.M. and W.C.O. have no conflicts of interest to disclose.

Figures

Figure 1
Figure 1. Antibody response to the 6MHP vaccine mixture
A) The Ab response to 6MHP peptides, as the serum Ab titer prevaccine (week 0), early after vaccination (week 5–7), or at maximal titer time point (more than 10 weeks) plotted on a square root scale. B) Ab responses to 6MHP (plotted on a log to the base 4 scale) early vs late by study arm (Arm A p = 0.03, Arm B p = 0.01, Arm C p = 0.003). C) Ab responses were defined by titer and by serum concentration, and these measures were closely correlated (R2 = 0.92). D) Serum Ab concentrations measured through week 25, plotted on a square root scale, with box plots (each box 25th–75th percentiles; vertical lines define maximum and minimum; horizontal lines represent median values). E) % of patients with detectable Ab to each peptide (graphed by peptide amino acid length).
Figure 2
Figure 2. Associations of clinical factors with patient survival
Kaplan-Meier curves represent overall survival of patients with clinical features A) disease status: measurable disease vs no evidence of disease (NED, p = 0.003); B) AJCC stage (III vs IV, p = 0.21); C) Age (< 60 vs ≥ 60, p = 0.16); and D) study arm (p = 0.10).
Figure 3
Figure 3. Associations of immune response with patient survival
Kaplan-Meier curves represent overall survival of patients with immune response findings: A) Antibody response by week 7 (p = 0.0011); B) T cell response in PBMC or SIN by week 7 (p < 0.006); C,D) Combined Ab and/or T-cell responses (p = 0.001 and p = 0.0002, respectively); E) Combined Ab plus T cell response for patients with measurable disease (p = 0.033); F) Combined Ab plus T cell response for patients with no evidence of disease (NED, p = 0.015).
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