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Trametes versicolor (Yun Zhi) in cancer treatment: Progress Report
University of Minnesota/Bastyr University/University of Washington
NIH NCCAM-funded Developmental Center for Research on Complementary and Alternative Medicine
LJ Standish ND PhD LAc, Cynthia A Wenner PhD, Mark R Martzen PhD, Jeff Novack PhD, Michael Verneris, MD, Dennis McKenna PhD, Gary
R Ostroff PhD, Masa Sasagawa ND, Daesong Yim PhD, Annette L Fitzpatrick PhD, Sandi Schildt BA,
Monica Olsen MS, Alicia Hill-Force BS, Randy Donelson BS, Carolyn Torkelson MD MS, Nora Disis, MD, Hailing Lu, MD, PhD, Joel Slaton MD.
CAHCIM presentationJanuary 25, 2008
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Trametes versicolorMushroom β
Glucan
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BackgroundPolysaccharide peptides extracted from the medicinal mushroom Trametes versicolor (PSK KrestinTM) have been shown to improve disease free survival in 31 randomized clinical trials
conducted in Japan,
Korea and China.
PSK (KrestinTM) was approved in 1977 as a cancer therapyby the Japanese National Health Registry and represents 25%
of the total national costs of cancer care in Japan.
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Cancer Number of Randomized Clinical Trials
Number of Patients
Stomach 22 6462 Colorectal 10 1374 Breast 5 1517 Lung 4 Articles in translation Esophageal 2 279 Nasopharyngeal 2 Articles in translation Hepatocellular 2 Articles in translation Leukemia 1 Article in translation
48 Randomized Clinical Trials in 9632 cancer patients published in Asia combining PSK with Chemotherapy
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1,3 β
glucan is likely the main active constituent
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Types of Beta Glucan -
Primary Structure
linear β1,3-glucan
β1,6 branch
β1,6 branched β1,3-glucan branch
β1, 4-glucan
Bacterial- linear β1,3-glucan (Curdlan)
Fungal- short β1,6 branched β1,3- glucan (e.g, medicinal mushrooms such
as T. versicolor, Shitake, Maitake, Ganoderma)
Yeast - long β1,6 branched β1,3- glucan (NSG and WGP Glucan)
Cereal - linear β1,3/ β1, 4-glucan (i.e.
oats, barley, rye)
Beta 1,3 GlucansBeta 1,3 Glucans
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Immunomodulatory mechanisms of action of T. versicolor
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T and B cell proliferation•
Enhancement of NK cell activity
•
Inducer of IL-2, IL-8, interferon gamma, and TNF•
Enhancement of macrophage activity
•
New idea: decrease T reg
(suppressor) cells
Reduced risk of recurrence.
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UMINN/Bastyr DCRC Research Team June 2006
Oncomycology research requires multi-disciplinary work:immunology, oncology, and natural products chemistry.
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Our Center's Hypotheses
1. T.versicolor may improve disease free survival in women with breast cancer via lymphocyte immunomodulatory mechanism.
2.
Whole T. versicolor extracts may have additional benefit beyond that of semi-purified PSK.
3.
The immunologically active constituent is beta 1,3 and beta 1,6 glucan.
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1,3 β
glucan is orally bioavailable
?
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T. versicolor has radioprotective activity in mice
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Effect of Escalating Total Body IrradiationEffect of Escalating Total Body IrradiationOn Immune Response On Immune Response
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Effect of Tv on immune response Effect of Tv on immune response during radiation therapyduring radiation therapy
Does Tv/PSK Work?Does Tv/PSK Work?
Then 4 gy
external beam RT
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T. versicolor has radioprotective activity and reduces marrow suppression in mice
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T. versicolor has radioprotective activity in mice
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T. versicolor products that are commercially available in the U.S. prevent bone marrow suppression and weight loss caused by external beam radiation exposure.
Conclusion
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Getting ready for cancer clinical trials
•
Which product? •
Standardized to which active constituent(s)?
•
Which placebo?•
Which patients?
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VPS®
Coriolus versicolor
Scientifically Proven to Support Immune Defense PSK/Japanese Formula
Dehydrated Hot Water Extract
36% beta 1-4, 1-3, 1-6 glucan (protein-bound polysaccharide)
Latin
... Coriolus versicolor, Trametes versicolor Japanese
... Kawaratake
Chinese
... Yun zhi
Common Name
... Turkey Tail
Price: 90 Vegetarian capsules $59.95
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Preparation ID
T. versicolor method of preparation
Strain Heavy Metal Concentration Endotoxin Concentration (EU/mg)Cadmium
(ppm) Lead(ppm)
Arsenic(ppm)
Mercury(ppm)
A Hot water extract of Tv fruiting body
NotDisclosed
0.053 0.52 2.000 <0.01 17.3
B Hot water extract EtOH
precipitation of Tv fruiting body
COV-1 0.130 0.70 1.00 <0.052 39
C Tv primordial biomass CV-OH1 <0.050 <0.20 <0.150 <0.01 5.24
D PSK (Kureha, Inc): hot water extract of Tv mycelium
CM-101 ND ND ND ND ND
E Powdered cold water + EtOH
extract of Tv mycelium grown on rice grain
Tv(K) ND ND ND ND ND
F Tv primordial biomass Tv(K) <0.050 <0.2 <0.2 <0.01 0.7
N Hot water extract of Tv fruiting body
Tv(K) 0.03 <0.04 <0.070 0.068 3.7
O Hot water extract of Tv mycelium
Tv(K) 0.12 <0.04 0.26 0.048 2.1
COMPANY
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BR CAPhase II
BR CA IND
Quality control assays for commercially available T. versicolor products
ProstateCA IND
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Glucatell®
Assay is sensitive and specific for β
glucan measurement but triple helical β
glucan must
be broken down to single helical form
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Glucatell®
Assay is sensitive and specific for β
glucan measurement but triple helical β
glucan must
be broken down to single helical form.
Beta glucans are detectable in OTC products, but, because they are insoluble and are difficult to expose in the plant material, they are difficult to measure.
Conclusion about beta glucans.
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Which placebo?
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Not all 'placebo' materials are immunologically inert
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Lactose and cellulose were not immunologically active, nor is the tablet coating material
Cellulose was selected for placebo material.
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Phagocytic activity is related to (1,3)-D-glucan content
“Phagocytic activity is directly related to relative concentration of (1,3)-D-glucan in polysaccharide mixtures, and that the five products we investigated appear to contain varying amounts of 1,3-glucan and this variation was shown to correlate with in vitro biological activity in a statistically significant way.”
Alex Hamill, PhDJanuary 2008
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DCRC conclusions regarding clinical trial study medication
•
Some commercially available Tv products in the U.S. are contaminated with heavy metals.
•
Both freeze dried mycelium (modern U.S. method) and hot water extracts (traditional TCM method) are immunologically active in vitro.
•
Hot water extraction of mycelium (and perhaps fruiting body) may yield more beta 1,3 glucan than freeze drying method.
•
The semi-purified PSK™
(Kureha Corporation, Japan) is the most immunologically active of the products we have evaluated.
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Observational Study Flow DiagramObservational Study Flow DiagramWhat is the challenge?What is the challenge?
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Figure 2
RBC compartment not affected by RT in breast cancer patients
3233343536373839
Hem
atoc
rit (%
)
10.5
11
11.5
12
12.5
13H
emog
lobi
n (g
/dl)
3
3.5
4
4.5
5
RB
C (t
hou/
µL)
Normal Range3.8-5
Baseline 1-3 days 2 wks 4 wks 6 wks post-radiation
Normal Range
11.5-15.5
Normal Range36 –
45
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Figure 3a
RT causes some decline in WBC
0
0.1
0.2
0.3
0.4
0.5
0.6
Mon
ocyt
es (t
hou/
µL)
0
1
2
3
4
5
6
WB
C (
thou
/µL)
0
0.01
0.02
0.030.04
0.05
0.06
Bas
ophi
ls (t
hou/
µL)
0
0.05
0.1
0.15
0.2
0.25
Eosi
noph
ils (t
hou/
µL)
Baseline 1-3 days 2 wks 4 wks 6 wks pre-
radiationpost-
radiation
Norma
lRange4.3 -
10
Norma
lRange0 –
0.5
Norma
lRange0 –
0.2
Norma
lRange0 –
0.8
P = 0.0095
P = 0.0155
P = 0.042
P = 0.328 (ns)
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Figure 3b
RT causes significant lymphopenia and loss of NK cell activity
0
5
10
15
20
25
Lytic
Uni
ts
0.40.50.60.70.80.9
11.1
Lym
phoc
ytes
(tho
u/µL
)
0
1
2
3
4
Neu
trop
hils
(tho
u/µL
)
pre-radiationBaseline 1-3 days 2 wks 4 wks 6 wks
post-radiation
NormalRange1.8 -
7
NormalRange1 –
4.8
No NormalRange est.
P = 0.0005
P = 0.11 (ns)
P = 0.032
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Figure 4.
Breast cancer patients who had wider field RT had more loss of lymphocytes and loss of NK cell activity
0
5
10
15
20
25
30
35
Mea
n N
KC
A (L
U20
) ± S
EM
0
0.2
0.4
0.6
0.8
1
1.2M
ean
lym
ph (t
hou/
µl) ±
SEM
P = .025
P = .006P = .023
P = .3 (ns)
pre-RT pre-RTpost-RT post-RT
locoregional breast only
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Figure 5. Phagocytic activity of macrophages declined after RT for breast cancer
40
50
60
70
80
FITC
- E.
col
i Upt
ake
(% o
f max
imal
)
Baseline 1-3 days 2 wks 4 wks 6 wks pre-radiation post-radiation
P = 0.165 (ns)
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0
500
1000
1500
2000
2500
3000
3500
4000
4500
TNF-
alph
a (p
g/m
L)
P = 0.0375
Figure 6. PHA-stimulated TNF – α production in PBMC at each study time point (mean ± SEM). Production levels between visit 1 (pre-radiation baseline) and visit 2 (post-radiation) were significantly different. (When the four subjects recruited from the University of Minnesota were removed from analysis p value was greater than 0.05.)
Baseline 1-3 days 2 wks 4 wks 6 wks pre-radiation post-radiation
TNF-alpha production declines in PBMCs from breast cancer patients afterStandard RT.
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• Red cell compartment unaffected
• Total WBC slight decline but ANCs
normal
•
Lymphopenia that did not return to normal within the 6-wk observational period
• NK cell activity that recovers
• phagocytic activity that recovers
• TNF-alpha production, yet, very little fatigue
Summary of Observation TrialSummary of Observation Trial
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NK cytoxicity vs. beta-1,3-D-glucan content
1
10
100
1000
0.001 0.006 0.408 1.115
beta-1,3-D-glucan content (% wt/wt)
% in
crea
se in
LU2
0
MRL FP-PB
PSKVPS
NK cytotoxicity NK cytotoxicity vsvsBetaBeta--1,3,1,3,--DD--glucan contentglucan content
Beta 1,3 GlucansBeta 1,3 Glucans
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Oral PSK inhibits tumor growthOral PSK inhibits tumor growth
0 10 20 300
500
1000
1500 PBSPSK2mgPSK10mg
Days
Tum
or S
ize
(mm
3 )
BREAST CANCER MODELBREAST CANCER MODEL
Oral administration of PSK induced tumor regression in Neu-Tg
mice.Oral gavage of PSK 2mg (●), PSK10mg (▼), or PBS (□), was given to mice three times a week for 4 weeks. Shown are tumor size (mean±sem) in control or PSK-treated mice (n=4/group).
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a case: Trametes versicolor + Rituxan
in relapsed large B cell lymphoma
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In 2001 a 58 year old Caucasian nurse practitioner diagnosed with stage II follicular CD20+ B cell lymphoma with left inguinal LAD
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CHOP + Rituxan
completed in 2002.•
Remission until 2007 with PET/CT evidence of recurrence in neck, retroperitoneum, pelvis, inguinal
•
Was offered cytoxan
+ vincristine
or Rituxan•
Four months of Rituxan
+ MRL-Coriolus
3000 mg
CT/PET resolution of neck, retroperitoneal, pelvic and inguinal nodules
Note that CR in relapse B cell lymphoma is reported at 6%.
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RituximabIn 1997, the anti-CD20 chimeric
antibody rituximab
became the first MAb
approved by the US Food and Drug Administration (FDA) for the treatment of cancer. In a single-arm, multicenter
study of 166 patients with relapsed or refractory, low-grade, or follicular non-Hodgkin's
lymphoma
(NHL), Rituximab
at a dose of 375 mg/m2 four times weekly produced an overall response (OR) rate of 48%, complete response (CR) rate of 6%, and partial response (PR) rate of 42%. Median time to progression in responders was 13.1 months.
McLaughlin P,
Grillo-Lopez AJ,
Kink BK,
et al:
Rituximab
chimeric
anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half
of patients respond to four-dose treatment program. J Clin Oncol 1998;
16:2825-2833.
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Beta glucans may augment monoclonal antibody therapy
•
Herceptin•
Rituxan
Modak
S, Koehne
G, Vickers A, O'Reilly RJ, Cheung NK. Rituximab
therapy of lymphoma is enhanced by orally administered (1-->3),(1-->4)-D-beta-glucan
Leuk
Res.
2005 Jun;29(6):679-83. MSKCC
Hong F, Hansen RD, Yan
J, Allendorf
DJ, Baran
JT, Ostroff GR, Ross GD.
Beta-glucan functions as an adjuvant for monoclonal antibody immunotherapy by recruiting tumoricidal
granulocytes as killer cells.
Cancer Res.
2003 Dec 15;63(24):9023-31.
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Prostate cancer model
Oral administration of PSK inhibits tumor growth.Three days after injection with TRAMP-C2 cells, groups of mice (n=8) were treated with oral gavage of PSK 40 mg/kg or 300 mg/kg or PBS daily for 3 weeks. Shown are tumor size (mean ±
sd) in control or PSK-treated mice.
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PSK in stage IV prostate cancer 2008
Phase I Study of Dose Escalation of PSK in Combination with Docetaxel/Dexamethasone for Metastatic Prostate Cancer (n=30)
Patients with metastases from hormone refractory prostate cancer will be enrolled to study the safety and tolerability of PSK. The first group of patients (n=10/dose group) will receive 3000 mg PSK. Subsequent groups will receive the next highest dose of 6000 mg and 9000 mg daily. They will receive a lead in of PSK alone for 3 weeks and then started on docetaxel/dexanethasone every three weeks for a total of 6 courses. Open-label PSK will continue without interruption when patients begin chemotherapy after the 3 week run-in. Patients will have blood drawn at initiation and every three weeks for CBC, LFTs, renal functions tests, PSA, immune response (innate and adaptive), and Beta 1, 3, and Beta 1, 6 glucans levels. Each group will consist of 10 patients. Each dose level will be completed before moving to the next. Evidence of level 2 toxicity in more than 1 patient per group results in termination of escalation.
PSK alone for 3 wk run-in study
PSK plusdocetaxel/dexamethasonecourse 1
Chemocourse 2
Chemocourse 3
Chemocourse 4
Chemocourse 5
Chemocourse 6
0 63 129Baseline Weeks
1815
Primary End Points• safety and tolerability• CBC• chem-23 (renal and
liver function tests)• urinalysis
Secondary End Points• NKCA• T regulatory cell• phagocytic index• TNF alpha and IFN-gamma production• PK plasma and urine• PSA for power calculations for further Phase II
OPEN LABEL PSK
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summary•
Tv
is a potent immunomodulator with effects on both
innate and adaptive immune systems•
Breast cancer RT causes immune defects that are likely to be corrected by Tv.
•
Of the commercial products, PSK™
appears to be the most active and most ready for clinical trial.
•
Beta 1,3 glucans in Tv
may augment Mab
therapy. •
Our dose escalation trial in stage I-III breast cancer is open (3000-24,000 mg)
•
A dose escalation trial in stage IV prostate cancer is pending with NCCAM
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Using Trametes in the clinic
•
NK cell functional activity assay at baseline (Focus Labs, Santa Monica –
Dynacare send out –
2 green top tubes stat)
•
If below 20 LU Rx MRL-Coriolus
1500 mg bid or tid
with food is OK.
•
Recheck NKCA in 3-6 months.
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National Center for Complementary and Alternative MedicineNational Institutes of Health
U.S. Department of Health and Human Serviceswww.nccam.nih.gov
This work was supported by a grant from: