Abstract
Abstract Ex-vivo generated dendritic cells (DC) have been used as therapeutic vaccines for the treatment of patients with metastatic cancer. However, these first-generation vaccines consist of DC activated to up-regulate costimulatory molecules with minimal to absent IL-12p70 production. Inflammatory cytokines, primarily IL-12p70 and interferons, provide a critical third signal along with antigen (signal 1) and costimulation (signal 2) for optimal effector CD8 T cell expansion/differentiation and memory formation. In order to generate IL-12p70-producing DC, a GMP-grade cell line expressing CD40L was developed and used in conjunction with IFN-γ to activate monocyte-derived DC. Stage IV melanoma patients (n=6) received an initial priming dose of CD40L/IFN-γ activated DC pulsed with 3 gp100 melanoma peptides (G154, G209-2M, G280-9V), followed by additional DC doses every 3 weeks for a total of 6 immunizations. Peripheral blood mononuclear cells isolated weekly during the course of immunizations were used to evaluate the kinetics and magnitude of vaccine-induced gp100-T cell responses. In all but one patient CD8+ T cell responses to all 3 gp100 peptides were detected, with strongest proliferative responses observed after 2 DC immunizations. Magnitude of responses was not heightened with further immunizations. Antigen-specific frequencies to the high affinity G154 peptide were consistently lower than those to low affinity G209 and G280 peptides. Notably, we observe a correlation between DC IL-12p70 production, immune responses to gp100, and clinical efficacy of vaccination. Patients (n=3) with highest DC IL-12p70 production levels exhibit high gp100 antigen-specific frequencies and are in remission (n=1) or have stable disease (n=2). A qualitative analysis of T cell responses generated among patients is currently underway. These results underscore the important role of DC activation status in vaccination and provide an immunological rationale for vaccine design whereby IL-12p70 contributes to effective immune-based therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5519. doi:10.1158/1538-7445.AM2011-5519
Published Version
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call