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 Research and Public Health 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 3

Vaccine-induced T cells recognize native gp100 and display high affinity for antigen.

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Vaccine-induced T cells recognize native gp100 and display high affinity...
(A) PBMCs collected after D3 were cultured in the presence of G209-2M (white bars and symbols) or G280-9V (black bars and symbols) peptide for 12 days as described in Figure 2 and tested in a standard 4-hour 51Cr release assay for their ability to recognize native gp100 antigen on human melanoma cells lines DM6 (HLA-A2+gp100+) and A375 (HLA-A2+gp100–). Percent specific lysis at a 30:1 effector/target ratio is shown; spontaneous lysis was <10%. Results are representative of 2 experiments. (B) Avidity of G209-2M– and G280-9V–specific T cells was determined in a standard 4-hour 51Cr release assay using peptide titrations and T2 (HLA-A*0201+) cells as targets. Percent specific lysis is shown for each peptide concentration; spontaneous lysis was <5%. Results are representative of 2 experiments.