A Multipeptide Vaccine is Safe and Elicits T-cell Responses in Participants With Advanced Stage Ovarian Cancer

Abstract

Nine participants with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, who were human leukocyte antigen (HLA)-A1, HLA-A2, or HLA-A3, were eligible to enroll in a phase 1 study designed to assess the safety and immunogenicity of a peptide-based vaccine. Participants received 5 class I major histocompatibility complex-restricted synthetic peptides derived from multiple ovarian cancer-associated proteins plus a class II major histocompatibility complex-restricted synthetic helper peptide derived from tetanus toxoid protein. The vaccines were administered with granulocyte macrophage-colony stimulating factor in Montanide ISA-51 adjuvant over a 7-week period. All vaccine-related toxicities were grade 1 to 2, the most common being injection site reaction (grade 2, 100%), fatigue (grade 1, 78%), and headache (grade 1, 67%). Lymphocytes from the peripheral blood and a node draining a secondary vaccine site (sentinel immunized node) were harvested during the course of vaccination and T-cell responses to the peptides were evaluated using an enzyme-linked immunosorbent spot assay. CD8 T-cell responses were detected in 1 participant ex vivo and in 8 of 9 participants (89%) after in vitro stimulation. All 4 HLA-A2 and HLA-A3-restricted peptides were immunogenic. This includes 2 peptides, folate binding protein (FBP191-199) and Her-2/neu754-762, which had not previously been evaluated in vaccines in humans. Responding T cells required over 200 nM for half-maximal reactivity. These data support continued investigation of these peptides as immunogens for patients with ovarian cancer but, owing to low potency, also suggest a need for additional immunomodulation in combination with vaccines to increase the magnitude and to improve the quality of the T-cell responses.

Human Plasmacytoid Dendritic Cells Phagocytose, Process, and Present Exogenous Particulate Antigen

“…We here show that pDCs produce high levels of IFN-a and IL-6 and induce proliferative CD4 + T cell responses against a universal Th epitope on phagocytosis of PLGA microparticles, containing peptide Ag and TLR-Ls. The TT peptide is frequently used in clinical trials as a Th cell epitope to increase immunogenicity of a vaccine (46). Altogether, this indicates that PLGA microparticles might be a promising tool to efficiently load pDCs with tumor Ags and helper epitopes and simultaneously activate them by coencapsulated TLR-Ls, resulting in fully functional pDCs capable of stimulating antitumor responses via both production of IFN-a and direct induction of Ag-specific T cell responses.…”

Use of booster inoculations to sustain the clinical effect of an adjuvant breast cancer vaccine

“…9,10 Directly stimulating CD8 þ lymphocytes with HLA class I peptides makes intuitive sense, because class I molecules are present on most nonhematopoietic tumor cells, allowing CD8…”

Immunotherapy in ovarian cancer

“…42 However, 50% of the ovarian cancer patients experienced recurrence over a median follow-up of 492 d. An additional phase I trial examined the safety and immunogenicity of a vaccination with five MHC-1 restricted peptides and one MHC-2 restricted peptide along with Montanide ISA-51 and GM-CSF in nine women with epithelial ovarian, fallopian or primary peritoneal cancer who were HLA-A1, HLA-A2 or HLA-A3 positive. 43 Following in vitro stimulation, CD8+ T-cell responses were reported to the peptides in this vaccine, including folate binding protein ) and Her-2/neu 754-762 . While vaccine-related toxicities were low-grade, the vaccine lacked potency, did not demonstrate ex vivo immune responses, and failed to produce a substantial clinical effect.…”