Langerhans-type dendritic cells electroporated with TRP-2 mRNA stimulate cellular immunity against melanoma: Results of a phase I vaccine trial Journal Article
| Authors: | Chung, D. J.; Carvajal, R. D.; Postow, M. A.; Sharma, S.; Pronschinske, K. B.; Shyer, J. A.; Singh-Kandah, S.; Dickson, M. A.; D'Angelo, S. P.; Wolchok, J. D.; Young, J. W. |
| Article Title: | Langerhans-type dendritic cells electroporated with TRP-2 mRNA stimulate cellular immunity against melanoma: Results of a phase I vaccine trial |
| Abstract: | Purpose: We conducted a phase I vaccine trial to determine safety, toxicity, and immunogenicity of autologous Langerhans-type dendritic cells (LCs), electroporated with murine tyrosinase-related peptide-2 (mTRP2) mRNA in patients with resected AJCC stage IIB, IIC, III, or IV (MIa) melanoma. Experimental Design: Nine patients received a priming immunization plus four boosters at three week intervals. Vaccines comprised 10 × 106 mRNA-electroporated LCs, based on absolute number of CD83+CD86brightHLA-DRbrightCD14neg LCs by flow cytometry. Initial vaccines used freshly generated LCs, whereas booster vaccines used viably thawed cells from the cryopreserved initial product. Post-vaccination assessments included evaluation of delayed-type hypersensitivity (DTH) reactions after booster vaccines and immune response assays at one and three months after the final vaccine. Results: All patients developed mild DTH reactions at injection sites after booster vaccines, but there were no toxicities exceeding grade 1 (CTCAE, v4.0). At one and three months post-vaccination, antigen-specific CD4 and CD8 T cells increased secretion of proinflammatory cytokines (IFN-γ, IL-2, and TNF-α), above pre-vaccine levels, and also upregulated the cytotoxicity marker CD107a. Next-generation deep sequencing of the TCR-V-β CDR3 documented fold-increases in clonality of 2.11 (range 0.85–3.22) for CD4 and 2.94 (range 0.98–9.57) for CD8 T cells at one month post-vaccines. Subset analyses showed overall lower fold-increases in clonality in three patients who relapsed (CD4: 1.83, CD8: 1.54) versus non-relapsed patients (CD4: 2.31, CD8: 3.99). Conclusions: TRP2 mRNA-electroporated LC vaccines are safe and immunogenic. Responses are antigen-specific in terms of cytokine secretion, cytolytic degranulation, and increased TCR clonality, which correlates with clinical outcomes. © 2018 Taylor & Francis Group, LLC. |
| Keywords: | melanoma; cancer vaccines; phase i trial; clinical immunology; langerhans-type dendritic cell |
| Journal Title: | OncoImmunology |
| Volume: | 7 |
| Issue: | 1 |
| ISSN: | 2162-4011 |
| Publisher: | Landes Bioscience |
| Date Published: | 2018-09-01 |
| Start Page: | e1372081 |
| Language: | English |
| DOI: | 10.1080/2162402x.2017.1372081 |
| PROVIDER: | scopus |
| PMCID: | PMC5739582 |
| PUBMED: | 29296525 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 September 2020 -- Source: Scopus |
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