Immunological analysis of hybrid neoantigen peptide encompassing class I/II neoepitope-pulsed dendritic cell vaccine.

Neoantigens/ are tumor-specific antigens that evade central immune tolerance mechanisms in the thymus. Long-term tumor-specific cytotoxic T lymphocyte activity maintenance requires class II antigen-reactive CD4+ T cells. We had previously shown that intranodal vaccination with class I neoantigen peptide-pulsed dendritic cells (DCs) induced a robust immune response in a subset of patients with metastatic cancer. The present study aimed to perform a detailed ex vivo analysis of immune responses in four patients receiving an intranodal hybrid human leukocyte antigen class II neoantigen peptide encompassing a class I neoantigen epitope (hybrid neoantigen)-pulsed DC vaccine. After vaccination, strong T-cell reactions against the hybrid class II peptide and the class I-binding neoantigen peptide were observed in all four patients. We found that hybrid class II neoantigen peptide-pulsed DCs stimulated CD4+ T cells via direct antigen presentation and CD8+ T cells via cross-presentation. Further, we demonstrated that hybrid class II peptides encompassing multiple class I neoantigen epitope-pulsed DCs could present multiple class I peptides to CD8+ T cells via cross-presentation. Our findings provide insight into the mechanisms underlying hybrid neoantigen-pulsed DC vaccine therapy and suggest future neoantigen vaccine design.

Efficacy of Intranodal Neoantigen Peptide-pulsed Dendritic Cell Vaccine Monotherapy in Patients With Advanced Solid Tumors: A Retrospective Analysis.

BACKGROUND/AIM: Neoantigens are tumor-specific antigens that emerge due to gene mutations in tumor cells, and are highly antigenic epitopes that escape central immune tolerance in the thymus, making cancer vaccine therapy a desirable option. PATIENTS AND METHODS: Tumor neoantigens were predicted in 17 patients with advanced cancer. They were resistant to the standard treatment regime, and their synthetic peptides were pulsed to the patient's monocyte-derived dendritic cells (DCs), and administered to the patient's lymph nodes via ultrasound. RESULTS: Some patients showed sustained tumor shrinkage after this treatment, while some did not respond, showing no ELISpot reaction. Although the number of mutations and the predicted neoantigen epitopes differed between patients, the clinical effect depended more on the presence or absence of an immune response after vaccination rather than the number of neoantigens. CONCLUSION: Intranodal neoantigen peptide-pulsed DC vaccine administration therapy has clinical and immunological efficacy and safety.

Theranostics with Hybrid Liposomes in an Orthotopic Graft Model Mice of Breast Cancer.

BACKGROUND/AIM: This study aimed to elucidate the therapeutic effects of hybrid liposomes (HL) composed of L-α-dimyristylphosphatidylcholine (DMPC) and polyoxyethylene [25] dodecyl ether (C12(EO)25) and the ability of HL-containing fluorescent probe to detect cancer in orthotopic graft model mice of breast cancer (MDA-MB-453). MATERIALS AND METHODS: HL composed of 90 mol% DMPC and 10 mol% C12(EO)25 were prepared by the sonication method. Anti-tumor activities of HL were investigated in vivo using orthotopic graft-bearing mice of MDA-MB-453 cells. RESULTS: With regard to the therapeutic effects of HL for breast cancer, HL inhibited the growth of MDA-MB-453 cells and induced apoptosis. Intravenous administration of HL resulted in a remarkable reduction of relative tumor weight in orthotopic graft model mice of breast cancer. The TUNEL assay revealed that this effect was due to induction of apoptosis. With regard to detection (diagnosis) of breast cancer, enhanced accumulation of HL carrying a fluorescence probe (Indocyanine green; ICG) was observed for MDA-MB-453 cells, although no accumulation of HL/ICG was obtained for normal breast cells. Enhanced accumulation of HL/ICG into the tumor of orthotopic graft model mice of breast cancer was observed. CONCLUSION: HL and HL/ICG could be theranostic targets since they showed therapeutic effects and ability to detect (diagnose) cancer in an orthotopic graft model mouse of breast cancer (MDA-MB-453).