HLA-restricted NY-ESO-1 peptide immunotherapy for metastatic castration resistant prostate cancer

Abstract

Background: Given the immunogenicity of NY-ESO-1 peptides in prostate cancer, a phase I clinical trial was designed to evaluate HLA class-I and class-II restricted NY-ESO-1 peptides in metastatic castration-resistant prostate cancer (mCRPC).

Methods: Patients with progressive mCRPC, Zubrod Performance Status ≤2, PSA ≥10 ng/ml who had appropriate HLA class I (A2) and class II haplotypes (DR4, DP4) were eligible. Three groups with 3 patients each received the vaccine subcutaneously every 2 weeks for 6 doses. Group 1 received a peptide presented by an HLA class I haplotype (HLA-A2), Group 2 with a peptide presented by HLA class II haplotype (DR4, DP4), and Group 3 with peptides presented by both Class I and II haplotypes. Androgen-deprivation was continued. Owing to a myocardial infarction, the protocol was amended to omit the use of GM-CSF.

Results: Fourteen patients were evaluable for toxicities and 9 received all 6 doses and were evaluable for efficacy. One death from myocardial infarction following GM-CSF occurred in a patient with generalized myalgias. After omitting GM-CSF, no grade >2 toxicities were observed. Among 9 patients evaluable for efficacy, the median PSA doubling time pre-therapy and during therapy were 3.1 and 4.92 months, respectively. NY-ESO-1 specific T-cell response observed by ELISPOT appeared more frequent in docetaxel-naïve patients (4 of 4) than docetaxel-pretreated patients (2 of 5).

Conclusion: In men with mCRPC, individualized HLA class-I and/or class-II restricted NY-ESO-1 peptides were tolerable, appeared to slow PSA doubling time and yielded antigen-specific T-cell responses more often in chemonaïve patients.

Trial registration: ClinicalTrials.gov NCT00711334.

Fig. 1

Changes in the frequency of NY-ESO-1 peptide specific T cells in PBMCs from the prostate cancer patients. PBMCs were collected prior to and after vaccinations with peptides, and then were stimulated with the peptides in vitro for a week. Vaccination-induced T cell responses against the corresponding NY-ESO-1 peptides were measured by ELISPOT analysis and data show the mean number of peptide specific IFN-γ spot-forming cells (SFC) in response to a given peptide by 1×10⁶ in vitro stimulated PBMCs. Numbers of non-specific IFN-γ spot-forming cells are subtracted

Fig. 2

Presence of NY-ESO-1 antibody in the prostate cancer patients. Sera were collected prior to and after vaccinations with peptides, and were diluted in 2 % BSA/PBS at 1:100. ELISA assay was used for detection of the presence of NY-ESO-1 antibody in the diluted sera. Each symbol represents a patient at baseline (week 0), week 3, week 6 or 13 after initial peptide immunization. Positive reaction is defined as an OD value of diluted serum that exceeds the mean OD value of sera from normal donors by 2 SD values

Fig. 3

Waterfall plot of maximum percent change in PSA from baseline within 12 weeks