Multiple therapeutic peptide vaccines consisting of combined novel cancer testis antigens and anti-angiogenic peptides for patients with non-small cell lung cancer

Abstract

BackgroundVaccine treatment using multiple peptides derived from multiple proteins is considered to be a promising option for cancer immune therapy, but scientific evidence supporting the therapeutic efficacy of multiple peptides is limited.MethodsWe conducted phase I trials using a mixture of multiple therapeutic peptide vaccines to evaluate their safety, immunogenicity and clinical response in patients with advanced/recurrent NSCLC. We administered two different combinations of four HLA-A24-restricted peptides. Two were peptides derived from vascular endothelial growth factor receptor 1 (VEGFR1) and 2 (VEGFR2), and the third was a peptide derived from up-regulated lung cancer 10 (URLC10, which is also called lymphocyte antigen 6 complex locus K [LY6K]). The fourth peptide used was derived from TTK protein kinase (TTK) or cell division associated 1 (CDCA1). Vaccines were administered weekly by subcutaneous injection into the axillary region of patients with montanide ISA-51 incomplete Freund’s adjuvant, until the disease was judged to have progressed or patients requested to be withdrawn from the trial. Immunological responses were primarily evaluated using an IFN-gamma ELiSPOT assay.ResultsVaccinations were well tolerated with no severe treatment-associated adverse events except for the reactions that occurred at the injection sites. Peptide-specific T cell responses against at least one peptide were observed in 13 of the 15 patients enrolled. Although no patient exhibited complete or partial responses, seven patients (47%) had stable disease for at least 2 months. The median overall survival time was 398 days, and the 1- and 2-year survival rates were 58.3% and 32.8%, respectively.ConclusionPeptide vaccine therapy using a mixture of four novel peptides was found to be safe, and is expected to induce strong specific T cell responses.Trial registrationThese studies were registered with ClinicalTrials.gov NCT00633724 and NCT00874588.

Recent advances in immunotherapy for non-small-cell lung cancer

“…Several recent studies including our own have shown that good PS is a significant prognostic factor. 29,43,44 Regarding multiple peptide therapy, as we mentioned previously, recent data showed the effectiveness of vaccines containing multiple epitopes. More recently, dendritic cell immunotherapy using multiple epitopes has also been reported in the treatment of brain tumors.…”

“…29 In this phase I study, we administered five kinds of peptides that originated from novel cancer-testis antigens and were developed from vascular endothelial growth factor receptors using a microarray-based technique. If the patients responded against multiple peptides, survival rate was significantly better than that in patients who responded to a single peptide or no peptides (P = 0.00176).…”

Revisiting of cancer vaccine?—Specific immunotherapy comes to field with the biomarker

“…This report highlights two important issues for cancer vaccination, which are biomarker analysis and combination therapy. In our past study of multiple peptide vaccines for patients with NSCLC, we observed that the specific CTL responses against one or more epitopes could be a prognostic biomarker (9). Like this study, most immunotherapy studies were focused on CTL responses as a prognostic biomarker, however, there has not been a predictive biomarker for cancer vaccination before treatment.…”

Engineering opportunities in cancer immunotherapy

“…Antigen-specific immunotherapy places selective pressure on the tumor, which in turn can down-regulate expression of those antigens (or even of MHC I) during immunotherapy. To avoid antigen selection, vaccines can contain multiple defined epitopes that induce broader T-cell immunity; several multipeptide vaccines have already shown promising clinical results (20,21). Furthermore, because central tolerance mechanisms often destroy those T cells with the highest avidity to such selfantigens, vaccine-induced effector CD8 + T-cell responses against self tumor antigens are often weak at best (22).…”