Vaccination of stage III/IV melanoma patients with long NY-ESO-1 peptide and CpG-B elicits robust CD8⁺ and CD4⁺ T-cell responses with multiple specificities including a novel DR7-restricted epitope

Abstract

Long synthetic peptides and CpG-containing oligodeoxynucleotides are promising components for cancer vaccines. In this phase I trial, 19 patients received a mean of 8 (range 1-12) monthly vaccines s.c. composed of the long synthetic NY-ESO-1 79-108 peptide and CpG-B (PF-3512676), emulsified in Montanide ISA-51. In 18/18 evaluable patients, vaccination induced antigen-specific CD8C and CD4 C T-cell and antibody responses, starting early after initiation of immunotherapy and lasting at least one year. The Tcells responded antigen-specifically, with strong secretion of IFNg and TNFa, irrespective of patients' HLAs. The most immunogenic regions of the vaccine peptide were NY-ESO-1 89-102 for CD8C and NY-ESO-1 83-99 for CD4C T-cells. We discovered a novel and highly immunogenic epitope (HLA-DR7/NY-ESO-1 87-99 ); 7/7 HLA-DR7 C patients generated strong CD4 C T-cell responses, as detected directly ex vivo with fluorescent multimers. Thus, vaccination with the long synthetic NY-ESO-1 79-108 peptide combined with the strong immune adjuvant CpG-B induced integrated, robust and functional CD8C and CD4 C T-cell responses in melanoma patients, supporting the further development of this immunotherapeutic approach.

Harnessing neoantigen specific CD4 T cells for cancer immunotherapy

“…Several clinical trials have been conducted investigating vaccines and cellular therapies targeting these shared tumor antigens. In one such trial, melanoma patients immunized with NY‐ESO‐1 peptides and CpG adjuvant mounted CD8 + and CD4 + T cell responses 26 . Despite apparent antigen‐specific T cell responses, clinical efficacy has been limited in patients with established tumors receiving these and similar vaccines.…”

“…In one such trial, melanoma patients immunized with NY-ESO-1 peptides and CpG adjuvant mounted CD8 + and CD4 + T cell responses. 26 Despite apparent antigen-specific T cell responses, clinical efficacy has been limited in patients with established tumors receiving these and similar vaccines. This lack of efficacy may be due to either the immunosuppressive tumor microenvironment or an inherent defect in the T cell repertoire recognizing these antigens.…”

50-Gy Stereotactic Body Radiation Therapy to the Dominant Intraprostatic Nodule: Results From a Phase 1a/b Trial

“…Given the precursor frequencies of antigen-specific T cells in peripheral blood samples, a conventional highly sensitive assay was used to quantify antigen-specific T-cell responses. [32][33][34] Thawed PBMCs rested for 5 hours in RPMI (Invitrogen), and 8% human AB serum (HS; Biowest) supplemented with penicillin or streptomycin and betamercaptoethanol at 37 C (2.1) were plated in 96-well plates at 10E5 cells per well in RPMI-8% human serum. Peptide pools (see the following list) were added in replicates (2-6 wells per condition).…”

Unleashing the immune response to NY-ESO-1 cancer testis antigen as a potential target for cancer immunotherapy

“…Instead, these antibodies facilitate the formation of immune complexes, with NY-ESO-1 protein, for effective cross presentation by dendritic cells [44]. It is well understood that, in NY-ESO-1 expressing tumors, key anti-tumor responses involve integrated antibody, CD4 + and CD8 + T cell responses leading to robust immune response with significant clinical benefit [49][50][51][52]. Interestingly, clinical trials have shown that, therapeutic interventions against NY-ESO-1(for e.g.…”