IL-12p70–producing patient DC vaccine elicits Tc1-polarized immunity
Beatriz M. Carreno, … , Kathryn M. Trinkaus, Gerald P. Linette
Beatriz M. Carreno, … , Kathryn M. Trinkaus, Gerald P. Linette
Published July 11, 2013
Citation Information: J Clin Invest. 2013;123(8):3383-3394. https://doi.org/10.1172/JCI68395.
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Clinical Medicine Oncology

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 dose-limiting 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.

Trial registration. Clinicaltrials.gov NCT00683670.

Funding. Barnes-Jewish Hospital Foundation, Siteman Cancer Frontier Fund, Washington University/JNJ Translational Medicine Award, and NCI (P30 CA91842).

Authors

Beatriz M. Carreno, Michelle Becker-Hapak, Alexander Huang, Megan Chan, Amer Alyasiry, Wen-Rong Lie, Rebecca L. Aft, Lynn A. Cornelius, Kathryn M. Trinkaus, Gerald P. Linette

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Figure 7

IL-12p70 production and ex vivo antigen-specific T cell responses stimulated by CD40L/IFN-γ + poly I:C + R848–activated DCs.

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IL-12p70 production and ex vivo antigen-specific T cell responses stimul...
(A) iDCs were stimulated for 24 hours with CD40L/IFN-γ (mDCs), alone or in combination with poly I:C (5 μg/ml; TLR3 agonist) and R848 (5 μg/ml; TLR8 agonist), and supernatants were assayed for IL-12p70. Results are those obtained in 2 experiments. P values (paired 2-tailed t test) are indicated. (B and C) DCs derived from P3 and P4 were activated for 24 hours with CD40L/IFN-γ, alone or in combination with poly I:C and R848, and supernatants were analyzed for IL-12p70. Additionally, activated DCs were pulsed with G280-9V peptide (40 μg/ml) and used for stimulation of purified CD8+ T cells (see Methods). G280-9V–specific T cell frequencies within the CD8+ T cell population was determined at day 12 using YLE/HLA-A*0201 tetramers and anti-CD8 mAb. Results are representative of 3 experiments.