Efficient In vivo Priming by Vaccination with Recombinant NY-ESO-1 Protein and CpG in Antigen Naïve Prostate Cancer Patients

Abstract

Purpose: NY-ESO-1, one of the most immunogenic tumor antigens, is expressed in 15% to 25% of metastatic prostate cancers. The immunological and clinical effects of vaccination with recombinant NY-ESO-1 protein combined with CpG as adjuvant were evaluated.Experimental Design: In a phase I clinical study, patients with advanced prostate cancer were vaccinated with recombinant NY-ESO-1 protein (100 mg) mixed with CpG 7909 (2.5 mg) every 3 weeks intradermally for 4 doses. Objectives of the study were the safety of the vaccine and changes of specific humoral and cellular immunological responses to NY-ESO-1 in relation to detectable NY-ESO-1 expression in the individual tumor.Results: All 12 baseline sero-negative patients developed high-titer NY-ESO-1 antibody responses. B-cell epitope mapping identified NY-ESO-1 p91-110 to be recognized most frequently by vaccine-induced antibodies. Two patients developed significant antibody titers against the adjuvant CpG. NY-ESO-1-specific CD4þ and/or CD8þ T-cell responses were induced in 9 patients (69%). Five of these 9 patients did not express NY-ESO-1 in the autologous tumor. Postvaccine CD8þ T-cell clones recognized and lyzed HLAmatched tumor cell lines in an antigen-specific manner.Conclusion: Our data provide clear evidence for the capacity of NY-ESO-1 protein/CpG vaccine to induce integrated antigen-specific immune responses in vivo and to efficiently prime CD8þ T-cell responses in NY-ESO-1 antigen-negative patients. Our results may also support further clinical vaccination protocols with NY-ESO-1 protein not only focused on the treatment of existing cancer, but also to prevent further development of NY-ESO-1 positive cancers in vivo. Clin Cancer Res; 17(4); 861-70. Ó2010 AACR.

Therapeutic Administration of a Synthetic CpG Oligodeoxynucleotide Triggers Formation of Anti-CpG Antibodies

“…We and other groups have shown that CpG 7909 when coadministered with Melan-A-or NY-ESO-1-specific peptide-or protein-based cancer vaccines can enhance both, antigen-specific humoral and cellular immune responses against the vaccine (9)(10)(11)(12). However, as CpG-ODNs can also activate suppressive pathways of the immune system, for example, interleukin-10 production and induction of Treg cells (15,16), chemical modifications of CpG-ODNs are currently being investigated to identify the most effective CpG-ODN for the modulation of different properties of the immune response.…”

“…CpG-specific antibodies were measured in the serum by standard ELISA assays as previously described (12). Briefly, sera were added to 96-well plates (Nunc Maxisorb) coated with 5 mg/mL (50 mL/well) of oligodeoxynucleotides overnight at 4 C and blocked with 2% bovine serum albumin/PBS.…”

“…Thirty-two of them received CpG 7909 as an adjuvant in combination with NY-ESO-1 peptide and/or NY-ESO-1 protein vaccination. Of these 32 patients, 25 were treated within clinical trials LUD02-007 and LUD03-024 (11,12) Fig. S1).…”

“…The most widely used CpG 7909, a class B oligodeoxynucleotide with the sequence 5 0 -TCG TCG TTT TGT CGT TTT GTC GTT-3 and a full phosphorothioate backbone, contains four CpG dinucleotides and three times the hexanucleotide sequence 5 0 -GTCGTT-3 0 , motifs that are known to be optimal to stimulate human immune cells. Our group and others have shown that CpG 7909, when used as an adjuvant for NY-ESO-1-specific cancer vaccines, has the potency to increase the immunogenicity of peptide-and protein-based vaccines by the induction of antigen-specific T cells and antibodies (8)(9)(10)(11)(12). CpG 7909 seems to be generally well tolerated with adverse events including flu-like symptoms and local injection site reactions.…”

Long-term Complete Remission Following Radiosurgery and Immunotherapy in a Melanoma Patient with Brain Metastasis: Immunologic Correlates

“…Longitudinal measurement of serum antibodies was performed by standard ELISA as described previously (10). Ex vivo or in vitro analysis of T cells was performed by IFN-g enzymelinked immunospot (ELISPOT) assay and by fluorescenceactivated cell sorting (FACS) analysis using peptide-MHC class I tetramer complexes as described previously (11).…”