Langerhans-type dendritic cells electroporated with TRP-2 mRNA stimulate cellular immunity against melanoma: Results of a phase I vaccine trial

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. Experime...

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Vydané v:	Oncoimmunology Ročník 7; číslo 1; s. e1372081
Hlavní autori:	Chung, David J., Carvajal, Richard D., Postow, Michael A., Sharma, Sneh, Pronschinske, Katherine B., Shyer, Justin A., Singh-Kandah, Shahnaz, Dickson, Mark A., D'Angelo, Sandra P., Wolchok, Jedd D., Young, James W.
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	United States Taylor & Francis 02.01.2018 Taylor & Francis Group
Predmet:	cancer vaccines clinical immunology Langerhans-type dendritic cell melanoma phase I trial melanoma phase I trial cancer vaccines clinical immunology Langerhans-type dendritic cell
ISSN:	2162-402X, 2162-4011, 2162-402X
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Shrnutí:	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 × 10 6 mRNA-electroporated LCs, based on absolute number of CD83 + CD86 bright HLA-DR bright CD14 neg 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.
Bibliografia:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Supplemental data for this article can be accessed on the publisher's website.
ISSN:	2162-402X 2162-4011 2162-402X
DOI:	10.1080/2162402X.2017.1372081