Review of clinical studies on dendritic cell-based vaccination of patients with malignant melanoma: assessment of correlation between clinical response and vaccine parameters

Abstract

During the past years numerous clinical trials have been carried out to assess the ability of dendritic cell (DC) based immunotherapy to induce clinically relevant immune responses in patients with malignant diseases. A broad range of cancer types have been targeted including malignant melanoma which in the disseminated stage have a very poor prognosis and only limited treatment options with moderate effectiveness. Herein we describe the results of a focused search of recently published clinical studies on dendritic cell vaccination in melanoma and review different vaccine parameters which are frequently claimed to have a possible influence on clinical response. These parameters include performance status, type of antigen, DC maturation status, route of vaccine administration, use of adjuvant, and vaccine induced immune response. In total, 38 articles found through Medline search, have been included for analysis covering a total of 626 patients with malignant melanoma treated with DC based therapy. Clinical response (CR, PR and SD) were found to be significantly correlated with the use of peptide antigens (p = 0.03), the use of any helper antigen/adjuvant (p = 0.002), and induction of antigen specific T cells (p = 0.0004). No significant correlations between objective response (CR and PR) and the tested parameters were found. However, a few non-significant trends were demonstrated; these included an association between objective response and use of immature DCs (p = 0.08), use of adjuvant (p = 0.09), and use of autologous antigen preparation (p = 0.12). The categorisation of SD in the response group is debatable. Nevertheless, when the SD group were analysed separately we found that SD was significantly associated with use of peptide antigens (p = 0.0004), use of adjuvant (p = 0.01), and induction of antigen specific T cells (p = 0.0003). No specific route of vaccine administration showed superiority. Important lessons can be learned from previous studies, interpretation of these findings should, however, be done with reservation for the many minor deviations in the different treatment schedules among the published studies, which were not considered in order to be able to process and group the data.

Therapeutic DC vaccination with IL-2 as a consolidation therapy for ovarian cancer patients: a phase I/II trial

“…Among the various cellular immune-monitoring methods, the ELISPOT assay is typically used to determine the frequency of effector cytokine (i.e., IFN-c)-secreting (CD8 1 ) T cells, and this assay has generated the most valuable results for evaluating the correlation between DC vaccine-induced immunological modulation and clinical response. 19 The value of the ELISPOT assay for measuring IFN-c-secreting T cells was also apparent in a previous study. 7 However, evidence for the importance of the tumor microenvironment and immune homeostasis in tumor development determined after measuring a single immunological parameter, such as cytotoxic T-cell activity, might not be sufficient to estimate the DC vaccine-induced anti-tumor response.…”

“…25 The data obtained herein support a complicated role for CD4 1 CD25 high T-cell alterations in anti-tumor immunity, demonstrating a treatment-associated, but not clinically relevant, reduction. Previous studies have suggested 7,9,19 the significance of ELISPOT analysis for determining the relevance of immunemodulation in DC vaccine-associated clinical responses. The induction of IFN-c-secreting T cells was observed in seven of the 10 patients after DC vaccination, but with no clinical relevance ( Figure 5).…”

Clinical Evaluation of Dendritic Cells Vaccination for Advanced Cancer Patients at Fukushima Medical University

“…In a review by Engell -Noerregaard et al 4) , 57 of 626 malignant melanoma patients (9%) showed objective response (20 CR and 37 PR) when treated with DC -based vaccinations, but no significant correlations were noted between those objective response and the tested parameters. Many initial vaccine studies used DCs charged with one or few tumor antigens, whereas the potential of DCs rests with their still untapped capacity to elicit a strong and broad immune attack to lessen the chance of tumor escape.…”

“…, MASASHI KANAZAWA 1) , YU SATO 1) , ATSUSHI IRISAWA 2) , TADAYUKI TAKAGI 2) , TAKASHI OGATA 2) , SHOGO KASHIMURA 3) , AKIRA KENJO 3) , HIROYUKI SUZUKI 3) , MASAHIKO SHIBATA 4) , TATSUO SHIMURA 4) , HIROMASA OHIRA 2) , MITSUKAZU GOTO 3) , SEIICHI TAKENOSHITA 1) and HITOSHI OHTO…”

Dendritic cells in cancer immunotherapy

“…By March 2010, almost 300 papers have been published reporting on 4422 patients treated (not all under Good Clinical Practice (GCP) conditions: primarily melanoma [32,33] and prostate cancer [34] patients -1301 and 510 patients, respectively). Most trials employed monocyte-derived DC (MoDC), which were most often generated from monocytes by culture in GM-CSF1IL-4 over approximately 6 days to obtain immature DC, followed by exposure to monocyte-conditioned medium or its mimic (cocktail composed of TNF-a1IL-1b1 IL-61PGE2) for 1-2 days, to yield ''cocktail''-matured DC.…”