Vaccine strategies against NY-ESO-1 in cancer patients

Abstract

Cancer-germline antigen NY-ESO-1, initially identified with the SEREX method by Yao Chen at the Ludwig Institute for Cancer Research, represents one of the most immunogenic antigens known to date. Spontaneous immune responses against NY-ESO-1 are found in approximately 50% of patients with advanced NY-ESO-1 expressing cancer. A close correlation between detectable NY-ESO-1 serum antibody and CD4+ and CD8+ T-cell responses was confirmed in a large series of patients. Spontaneous NY-ESO-1 antibody and T-cell reactivity was found to be associated with a more favorable prognosis in patients with advanced NY-ESO-1 expressing melanoma compared to patients without detectable NY-ESO-1 immunity.

Different strategies of vaccination against NY-ESO-1 have been explored in clinical phase I studies within the network of the Clinical Trials Center of the Ludwig Institute for Cancer Research. HLA-A2 restricted NY-ESO-1 peptides were used to immunize patients with NY-ESO-1 expressing cancer regardless of their spontaneous NY-ESO-1 antibody status. Intradermal peptide vaccinations administered at weekly intervals led to strong, primary NY-ESO-1 peptide-specific CD8+ T-cell responses after 2-3 months of immunization in the majority of NY-ESO-1 antibody negative patients. A subsequent protocol on intensive-course peptide vaccination over 5 consecutive days showed a rapid induction of high-magnitude CD8+ T-cell responses, which were detectable already after 1 cycle of immunization in the majority of patients. NY-ESO-1 peptide-specific responder T cells were cloned to study the specificity and function in more detail. NY-ESO-1 peptide-specific CD8+ T-cell clones induced during intensive-course peptide vaccination displayed strong tumor-reactivity against HLA-A2+, NY-ESO-1+ tumor cell lines detected in ELISPOT and cytotoxicity assays. Strong NY-ESO-1 specific CD8+ T-cell responses were maintained by prolonged immunization and were associated with extended progression-free intervals in a number of patients.

Recombinant NY-ESO-1 vaccinia and fowlpox constructs encoding the full-length NY-ESO-1 protein were used in a clinical phase I study to evaluate the effects on the induction of NY-ESO-1-specific CD4+ and CD8+ T-cell and antibody responses. Immunizations were administered at monthly intervals to patients with detectable or absent NY-ESO-1 immunity at baseline. NY-ESO-1 specific CD8+ T-cell responses were assessed in a cohort of HLA-A2+ patients using the known NY-ESO-1 epitopes p157-167 and p157-165 for monitoring. Strong NY-ESO-1 peptide-specific responses were detected in 9/12 evaluable HLA-A2 positive, NY-ESO-1 antibody negative, and in 2/2 evaluable NY-ESO-1 antibody positive patients after 4 immunizations. CD8+ T-cell responses against new NY-ESO-1 epitopes were identified in 1 patient, the analysis for the MHC class I restriction elements and functional reactivity is ongoing. NY-ESO-1 antibody was induced in 3/20 evaluable patients who were NY-ESO-1 antibody negative at baseline. CD4+ T-cell responses were monitored using a panel of overlapping 18- and 20-mer NY-ESO-1 peptides spanning the entire NY-ESO-1 protein. A primary induction of NY-ESO-1 specific CD4+ T-cell responses was observed in 8/14 NY-ESO-1 antibody negative patients evaluated so far. NY-ESO-1 specific CD4+ T-cell responses detected in NY-ESO-1 antibody positive patients at baseline were broadened against additional NY-ESO-1 epitopes during the course of vaccination in 1/3 cases. One patient with metastatic melanoma developed a partial remission of subcutaneous and peritoneal metastases, and another melanoma patient had a minor response of mediastinal lymph node metastases. Six of 21 evaluable patients experienced stabilization of disease with extended progression-free intervals during prolonged vaccination. These results show convincing efficacy of recombinant NY-ESO-1 viral constructs for the induction of potent CD4+ and CD8+ T-cell responses, which were associated with favorable clinical developments in patients with advanced cancer.

This abstract was published in Cancer Immunity, a Cancer Research Institute journal that ceased publication in 2013 and is now provided online in association with Cancer Immunology Research.