Dynamic changes in cellular infiltrates with repeated cutaneous vaccination: a histologic and immunophenotypic analysis
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RESEARCH
Open Access
Dynamic changes in cellular infiltrates with repeated cutaneous vaccination: a histologic and immunophenotypic analysis Jochen T Schaefer 2,3,4, James W Patterson Emily M Jackson 2, Craig L Slingluff Jr1,2*
2,3,4
, Donna H Deacon
1,2
, Mark E Smolkin5, Gina R Petroni 5,
Abstract Background: Melanoma vaccines have not been optimized. Adjuvants are added to activate dendritic cells (DCs) and to induce a favourable immunologic milieu, however, little is known about their cellular and molecular effects in human skin. We hypothesized that a vaccine in incomplete Freund’s adjuvant (IFA) would increase dermal Th1 and Tc1-lymphocytes and mature DCs, but that repeated vaccination may increase regulatory cells. Methods: During and after 6 weekly immunizations with a multipeptide vaccine, immunization sites were biopsied at weeks 0, 1, 3, 7, or 12. In 36 participants, we enumerated DCs and lymphocyte subsets by immunohistochemistry and characterized their location within skin compartments. Results: Mature DCs aggregated with lymphocytes around superficial vessels, however, immature DCs were randomly distributed. Over time, there was no change in mature DCs. Increases in T and B-cells were noted. Th2 cells outnumbered Th1 lymphocytes after 1 vaccine 6.6:1. Eosinophils and FoxP3+ cells accumulated, especially after 3 vaccinations, the former cell population most abundantly in deeper layers. Conclusions: A multipeptide/IFA vaccine may induce a Th2-dominant microenvironment, which is reversed with repeat vaccination. However, repeat vaccination may increase FoxP3+T-cells and eosinophils. These data suggest multiple opportunities to optimize vaccine regimens and potential endpoints for monitoring the effects of new adjuvants. Trail Registration: ClinicalTrials.gov Identifier: NCT00705640
Background Existing therapies for advanced melanoma are rarely curative. Even recent exciting data with a novel specific B-raf kinase inhibitor are limited by the transience of the clinical responses [1]. On the other hand, a large percentage of complete responses to immune therapy with interleukin-2 have been durable for over a decade [2], and other new immune therapies have been associated with long-lasting complete responses [3,4]. There is a strong rationale for the development of immune therapies specifically targeting melanoma antigens. These vaccines may be employed in the adjuvant setting, * Correspondence: [email protected] 1 Division of Surgical Oncology, Department of Surgery, University of Virginia, Charlottesville, VA, USA Full list of author information is available at the end of the article
to treat patients who are at high risk of recurrence but are clinically free of disease. The failure of several cellbased melanoma vaccine Phase III trials has highlighted the need to optimize their efficacy [5-9]. Vaccination with purified defined antigens has the advantage of enabling the assessment of immune responses to the antigens, as well as avoiding possible toleragenic or immunosuppressive components of cel
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