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A multipeptide vaccine plus toll-like receptor agonists LPS or polyICLC in combination with incomplete Freund’s adjuvant in melanoma patients
- Source :
- Journal for ImmunoTherapy of Cancer, Vol 7, Iss 1, Pp 1-13 (2019), Journal for Immunotherapy of Cancer
- Publication Year :
- 2019
- Publisher :
- BMJ, 2019.
-
Abstract
- Background Cancer 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 methods Participants 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). Results Fifty-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. Conclusions LPS 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 registration The 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. Electronic supplementary material The online version of this article (10.1186/s40425-019-0625-x) contains supplementary material, which is available to authorized users.
- Subjects :
- CD4-Positive T-Lymphocytes
Lipopolysaccharides
Male
0301 basic medicine
Cancer Research
medicine.medical_treatment
Freund's Adjuvant
CD8-Positive T-Lymphocytes
ELIspot
0302 clinical medicine
Immunology and Allergy
Cytotoxic T cell
Polylysine
Melanoma
Peptide vaccine
ELISPOT
Toll-Like Receptors
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Lipids
3. Good health
Clinical trial
medicine.anatomical_structure
Oncology
030220 oncology & carcinogenesis
Vaccines, Subunit
Incomplete freund’s adjuvant
Cohort
Molecular Medicine
Female
Adjuvant
Research Article
T cell
Immunology
CD8 T cells
Lipopolysaccharide
Cancer Vaccines
lcsh:RC254-282
03 medical and health sciences
Immune system
Adjuvants, Immunologic
Toll-like receptor
medicine
Humans
Immune response
Pharmacology
business.industry
Poly I-C
030104 developmental biology
Carboxymethylcellulose Sodium
polyICLC
business
CD8
Subjects
Details
- ISSN :
- 20511426
- Volume :
- 7
- Database :
- OpenAIRE
- Journal :
- Journal for ImmunoTherapy of Cancer
- Accession number :
- edsair.doi.dedup.....87f92b4c74f6e58cb15e90ed2dbfd238