Immunomodulatory effects of the Agaricus blazei Murrill-based mushroom extract AndoSan in patients with multiple myeloma undergoing high dose chemotherapy and autologous stem cell transplantation: a randomized, double blinded clinical study

Jon-Magnus Tangen, Anne Tierens, Jo Caers, Marilene Binsfeld, Ole Kristoffer Olstad, Anne-Marie Siebke Trøseid, Junbai Wang, Geir Erland Tjønnfjord, Geir Hetland, Jon-Magnus Tangen, Anne Tierens, Jo Caers, Marilene Binsfeld, Ole Kristoffer Olstad, Anne-Marie Siebke Trøseid, Junbai Wang, Geir Erland Tjønnfjord, Geir Hetland

Abstract

Forty patients with multiple myeloma scheduled to undergo high dose chemotherapy with autologous stem cell support were randomized in a double blinded fashion to receive adjuvant treatment with the mushroom extract AndoSan, containing 82% of Agaricus blazei Murrill (19 patients) or placebo (21 patients). Intake of the study product started on the day of stem cell mobilizing chemotherapy and continued until the end of aplasia after high dose chemotherapy, a period of about seven weeks. Thirty-three patients were evaluable for all study endpoints, while all 40 included patients were evaluable for survival endpoints. In the leukapheresis product harvested after stem cell mobilisation, increased percentages of Treg cells and plasmacytoid dendritic cells were found in patients receiving AndoSan. Also, in this group, a significant increase of serum levels of IL-1ra, IL-5, and IL-7 at the end of treatment was found. Whole genome microarray showed increased expression of immunoglobulin genes, Killer Immunoglobulin Receptor (KIR) genes, and HLA genes in the Agaricus group. Furthermore, AndoSan displayed a concentration dependent antiproliferative effect on mouse myeloma cells in vitro. There were no statistically significant differences in treatment response, overall survival, and time to new treatment. The study was registered with Clinicaltrials.gov NCT00970021.

Figures

Figure 1
Figure 1
Effect of AndoSan on the proliferation of a murine multiple myeloma cell line in vitro. Proliferation of MOPC315.BM cells was assessed by 3H-labelled thymidine incorporation in the presence of different AndoSan concentrations (1.25%–20%). Results are expressed in percentage of proliferation (mean ± SD) relative to MOPC315.BM cells cultured without AndoSan (= 100%) and represent 3 independent experiments. Within each experiment, proliferation was assessed in triplicate. *P < 0.05, **P < 0.01, and ***P < 0.001 (unpaired Student's t-test).
Figure 2
Figure 2
Time to new treatment. Mean time to new treatment in the Agaricus group (n = 19) was 37.3 months (upper (blue) curve) and in the placebo group (n = 21) 31.4 months (lower (green) curve) (P = 0.47 (n.s)).
Figure 3
Figure 3
Gene expression analysis. K-means clustering algorithm. Cluster three. Several immunoglobulin related genes (IGKC, IgHV4-31, and IGKC) and genes related to Natural Killer cells, Killer Immunoglobulin Receptors (KIR2DL3 and KIR2DL4), are grouped together. These genes are more highly expressed in the Agaricus group (left column).
Figure 4
Figure 4
Ingenuity Pathway Analysis showing upregulation of genes in the HLA presentation pathway (symbols in red) in the Agaricus group and downregulation of HLA genes (symbols in green) in the placebo group.

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