IL-12p70–producing patient DC vaccine elicits Tc1-polarized immunity

Abstract

Background. Systemic administration of IL-12p70 has demonstrated clinical activity in cancer patients, but doselimiting toxicities have hindered its incorporation in vaccine formulations. Here, we report on the immunological and clinical outcomes upon vaccination with CD40L/IFN-γ-matured, IL-12p70-producing DCs.Methods. 7 HLA-A*0201 + newly diagnosed stage IV melanoma patients were immunized against the gp100 melanoma antigen using autologous peptide-pulsed, CD40L/IFN-γ-matured DCs. PBMCs were taken weekly for immune monitoring by tetramer analysis and functional assays. CT imaging was performed at baseline, week 9, and week 18 for clinical assessment using RECIST.Results. 6 of 7 treated patients developed sustained T cell immunity to all 3 melanoma gp100 antigen-derived peptides. 3 of the 6 immunological responders developed confirmed clinical responses (1 complete remission >4 years, 2 partial response). Importantly, DC vaccine-derived IL-12p70 levels positively correlated with time to progression (P = 0.019, log-rank), as did T-cytotoxic 1 (Tc1) immunity, as assessed by IFN-γ/IL-13 and IFN-γ/IL-5 ratios (P = 0.035 and P = 0.030, respectively, log-rank). In contrast, a pathway-specific defect in IL-12p35 transcription was identified upon CD40L/IFN-γ activation in clinical nonresponder patient DCs, and gp100-specific T cells from these patients displayed a Tc2 phenotype. Incorporation of TLR3 and TLR8 agonists into the CD40L/IFN-γ activation protocol corrected the IL-12p70 production defect in DCs derived from clinical nonresponder patients.Conclusion. These findings underscore the essential role of IL-12p70 in the development of therapeutic type 1 antigen-specific CD8 + T cell immunity in humans with cancer.

Intratumoral delivery of mTORC2-deficient dendritic cells inhibits B16 melanoma growth by promoting CD8+ effector T cell responses

“…37,38 Furthermore, the clinical efficacy of DC-based vaccines in patients with glioma or melanoma has been strongly associated with the level of IL-12p70 produced by patientderived DC at the time of their injection. 23,39 It has also been reported previously that i.t. DC expression of IL-12 is necessary for the priming of CD8 C T cell responses in patients with breast cancer.…”

“…[19][20][21] We have shown recently that DC deficiency in mTORC2 results in increased production of pro-inflammatory cytokines (mainly IL-12p70 and IL-23) after TLR4 ligation, leading to enhanced T-helper 1 (Th1) and Th17 responses when compared to control DC. 22 Given that IL-12p70-producing DC vaccines have been shown to elicit type-1 antigen-specific CD8 C T cell immunity in patients with melanoma, and to correlate positively with time to progression, 23 we hypothesized that mTORC2-deficient DC might facilitate more robust therapeutic CD8 C T cell responses capable of inhibiting melanoma growth in vivo.…”

Trial watch: Dendritic cell-based anticancer immunotherapy

“…Thus, the combinatorial administration of IL-12 or CD40 and TLR ligands (which stimulate IL-12 secretion) is generally encouraged. 173,174 It is important to mention that only one cellular therapy involving DCs (but not restricted to them) is presently licensed for use in humans, namely, sipuleucel-T (branded as Provenge Ò ). Since 2010, sipuleucel-T has been approved for the treatment of asymptomatic or minimally-symptomatic metastatic castration-resistant prostate cancer.…”

Dietary Consumption of Black Raspberries or Their Anthocyanin Constituents Alters Innate Immune Cell Trafficking in Esophageal Cancer

“…The proinflammatory IL1b was measured at 35 weeks because of its association with poor prognosis of esophageal SCC (21). IL12 was measured due to its stimulation of CD8 þ T cells and NK cells for tumor eradication (38). Finally, we compared expression of these two cytokines with the anti-inflammatory cytokine IL10 at week 35 (39).…”