Induction of strong and persistent MelanA/MART‐1‐specific immune responses by adjuvant dendritic cell‐based vaccination of stage II melanoma patients

Abstract

A significant percentage of stage II melanoma patients (tumor thickness >1 mm) remain at risk of tumor recurrence after primary tumor excision. In this study, we used tumor antigen-pulsed dendritic cells as an adjuvant for immunization of these ''highrisk'' melanoma patients after resection of the primary tumor. A total of 13 patients were included and vaccinated 6 times every 14 days with autologous dendritic cells pulsed with a MelanA/ MART-1 peptide in combination with a recall antigen. Antigenspecific immune responses were monitored before, during and up to 1 year after the last vaccination. The majority of patients exhibited increased recall antigen-specific CD4 1 T cell responses upon vaccination. MelanA/MART-1-specific CD81 T cells were expanded in 9/13 patients resulting in increased frequencies of memory cells in these patients. CD81 T cells acquired the capacity to secrete IFN-c, to proliferate in culture in response to the tumor antigen used for vaccination and postvaccine samples contained MelanA/MART-1-specific T cells that recognized also the natural MelanA/MART-1-antigen expressed by tumor cells. Moreover, vaccination induced a long-lived tumor antigen-specific DTHreactivity in the majority of the patients, detectable even 12 months after the last immunization. These data demonstrate for the first time that vaccination with tumor antigen-pulsed dendritic cells in a clinically adjuvant setting induces strong and persistent antigen-specific T-cell responses in tumor-free stage II melanoma patients, suggesting that tumor protective T cell immunity can be achieved. ' 2005 Wiley-Liss, Inc.

Depletion of CD4+CD25+ human regulatory T cells in vivo: Kinetics of Treg depletion and alterations in immune functions in vivo and in vitro

“…[18][19][20][21] Similar frequencies of CD8 1 T cells could only be obtained before, after cellular immunization approaches, using peptide pulsed-or RNA-transduced dendritic cells. [22][23][24][25] However, because of ethical reasons as well as of limited numbers of patients we were not able to compare the vaccination success before and after ONTAK treatment individually in a comparative study, but collectively our data indicate that Treg depletion boosts efficacy of anti-tumor therapies and may support adjuvant strategies during peptide vaccinations.…”

Research in practice: Regulatory T cells – targets for therapeutic approaches?

“…Just a few months after the discontinuation of treatment, the induced melanomaspecific T-cell response is no longer detected [12]. In contrast to this dismal picture, our results show that adjuvant DC-based therapy in stage II (no increased number of Tregs) lead to longlasting immune responses and, thus, may protect these patients from renewed tumor growth [13]. Besides targeted manipulation of nTregs, the induction of antigen-specific iTregs in patients or the adoptive transfer of in vitro generated iTregs are potential therapy options in allergic and autoimmune disorders.…”

Dendritic cells as therapeutic agents against cancer

“…This measurement of cell-mediated immunological memory while extremely useful suffers from the same consequences as the RECIST criteria for it measures the immune response against the tumor after vaccination in a empirical way (56,133). Furthermore, these responses depend on the ability of the immune system to respond against the tumor and would not take into account the stage of the tumor or the tumor burden which might account for different results depending on the advancement of the tumor.…”