A multipeptide vaccine plus toll-like receptor agonists LPS or polyICLC in combination with incomplete Freund’s adjuvant in melanoma patients

Journal for ImmunoTherapy of Cancer

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[1] 0000 0000 9136 933X, grid.27755.32, Department of Medicine/Division of Hematology/Oncology, University of Virginia, Charlottesville, VA, USA;0000 0000 9136 933X, grid.27755.32, Department of Public Health Sciences/Division of Translational Research & Applied Statistics, University of Virginia, Charlottesville, VA, USA;0000 0000 9136 933X, grid.27755.32, Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, P.O. Box 801457, 1352 Pinn Hall, 22908, Charlottesville, VA, USA;0000 0000 9136 933X, grid.27755.32, Department of Surgery/Division of Surgical Oncology and the Human Immune Therapy Center, Cancer Center, University of Virginia, P.O. Box 801457, 1352 Pinn Hall, 22908, Charlottesville, VA, USA;0000 0000 9136 933X, grid.27755.32, Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA, USA;

关键词: Melanoma;    Peptide vaccine;    Incomplete freund’s adjuvant;    Toll-like receptor;    Lipopolysaccharide;    polyICLC;    Clinical trial;    CD8 T cells;    Immune response;    ELIspot;   

DOI  :  10.1186/s40425-019-0625-x

来源: publisher

【 摘 要 】

BackgroundCancer vaccines require adjuvants to induce effective immune responses; however, there is no consensus on optimal adjuvants. We hypothesized that toll-like receptor (TLR)3 agonist polyICLC or TLR4 agonist lipopolysaccharide (LPS), combined with CD4 T cell activation, would support strong and durable CD8+ T cell responses, whereas addition of an incomplete Freund’s adjuvant (IFA) would reduce magnitude and persistence of immune responses.Patients and methodsParticipants with resected stage IIB-IV melanoma received a vaccine comprised of 12 melanoma peptides restricted by Class I MHC (12MP), plus a tetanus helper peptide (Tet). Participants were randomly assigned 2:1 to cohort 1 (LPS dose-escalation) or cohort 2 (polyICLC). Each cohort included 3 subgroups (a-c), receiving 12MP + Tet + TLR agonist without IFA (0), or with IFA in vaccine one (V1), or all six vaccines (V6). Toxicities were recorded (CTCAE v4). T cell responses were measured with IFNγ ELIspot assay ex vivo or after one in vitro stimulation (IVS).ResultsFifty-three eligible patients were enrolled, of which fifty-one were treated. Treatment-related dose-limiting toxicities (DLTs) were observed in 0/33 patients in cohort 1 and in 2/18 patients in cohort 2 (11%). CD8 T cell responses to 12MP were detected ex vivo in cohort 1 (42%) and in cohort 2 (56%) and in 18, 50, and 72% for subgroups V0, V1, and V6, respectively. T cell responses to melanoma peptides were more durable and of highest magnitude for IFA V6.ConclusionsLPS and polyICLC are safe and effective vaccine adjuvants when combined with IFA. Contrary to the central hypothesis, IFA enhanced T cell responses to peptide vaccines when added to TLR agonists. Future studies will aim to understand mechanisms underlying the favorable effects with IFA.Trial registrationThe clinical trial Mel58 was performed with IRB (#15781) and FDA approval and is registered with Clinicaltrials.gov on April 25, 2012 (NCT01585350). Patients provided written informed consent to participate. Enrollment started on June 24, 2012.

【 授权许可】

CC BY