GLIOBLASTOMA

A HYPOTHETICAL REGRESSION PROTOCOL

agents
1. Fenofibrate 160mg one daily and 2 daily on saturday and sunday
2. Metfromin ER 500mg one daily
3. Cimetidine 800mg one daily (with the metformin)
4. Tadalafil 10 mg one daily
5. Fluoxetine 40mg one daily
6. Minocycline 100mg daily Monday to Thursday(start 2 months after start the protocol)
7. Celecoxib 400mg once a day (with the tadalafil)
8. Keppra XR 1000mg one daily(add valproic acid if need second agent)
9. Beta glucan 700mg/vitamin C 500mg-- three daily on friday saturday and sunday
10. Citrulline 750mg 2 daily on friday saturday and sunday
11. Sufurophane 60mg one daily (with the metformin)
12. Lipoic acid 300mg/b-complex 50 one daily (with the narcan)
13. Narcan 4.5mg one daily
14. Melatonin 3mg one daily at bedtime
15. Temozolamide std dosing along w/std radiation(??do cyclophos. Once done w/temodar???)
16. Keytruda to impair PD-1 and help set off regression event
17. Cylcophosphamide ??(parenteral) 50mg/kg q 6 day metronomic dosing to help/w regression
18. Curcumin phytosome 500mg 2 daily (on fri sat and sun take 2 caps three times a day)
19. Acyclovir 800mg tid po (inhibit TDO and IDO)
Make sure selenium and vitamin D levels are robust. (upper 10 percent of normality)
Some cryoablation(helium/argon gas?)of GBM should be considered due to
immunomodulation induced by cryonecrosis and cryoapoptosis.
http://www.hindawi.com/journals/bmri/2014/236939/ discusses effects of cryoablation
http://www.ncbi.nlm.nih.gov/pubmed/21214292 discusses immune effects of cryoablation
http://www.ncbi.nlm.nih.gov/pubmed/22379849 cryoablation of gliomas
I suspect ,even just adding combo of high dose curcumin phytosome + some dose of
episodic fludarabine or bid acyclovir(to degrade/impair IDO) + beta glucan(po or IM) +
Ipilimumab + pembrolizumab may result in an improvement in outcomes in GBM.

Simplified Protocol
1. Curcumin Phytosome 1000mg Tid po
2. 1,3 1-6 PGG Beta Glucan 4mg /kg IM q week x 4 then q 4 weeks
3. Fluoxetine 60mg daily po
4. Fenofibrate 320mg daily po
5. Tadalafil 10mg daily po
6. Celecoxib 400mg daily po
7. Cimetidine 800mg po daily po
8. Sulfurophane 60mg bid po
9. minocycline 100mg daily M-Th (start 2 months after start the cimetidine)
10. Ipilimumab standard dosing
11. Pembrolizumab standard dosing
12. Cylophosphamide?? maybe?? metonomic dosing 50mg/kg q 6 days x 1-2 month.
13. Temozolamide and Radiation use a standard course of chemo/rad
14. Transcranial helium-argon cryoablation?? and radiation to degrade the glio before
neurosurg to remove glio . Be on protocol for 2 months before remove the glio.
15. Acyclovir 800mg bid po (to inhibit TDO and IDO)
16. Dexamethasone ,keppra for the usual reasons.
For seizure control if need second agent then add valproic acid.
I think a cytokine storm may be crucial to the regression initiation because of the
immune changes that accompany the storm. Favorite drink = warm brewed green tea
(japan or china version ) drank slowly(a sipping tea) over 20-30 min three times daily
to help blunt IDO issues. Only 100mg EGCG absorbed/cup from tongue to end of
esophagus and only 10 % of that crosses BBB hence tid.
Consider EGCG containing gum as well and EGCG containing mints.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925358/ acyclovir impairs TDO and IDO
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050125/ fudarabine really knocks down IDO
SIMPLEST VERSION
17. Curcumin Phytosome 1000mg Tid po
18. 1,3 1-6 PGG Beta Glucan 4mg /kg IM q week x 4 then q 4 weeks
19. Fluoxetine 60mg daily po
20. Fenofibrate 320mg daily po
21. Tadalafil 10mg daily po
22. Metformin XR 500mg daily po
23. Sulfurophane 60mg bid po
24. Cimetidine 800mg daily po
25. Acyclovir 800mg bid po
26. Ipilimumab standard dosing
27. Pembrolizumab standard dosing
28. Temozolamide/Radiation standard dosing

GOAL
The goal is to cause a metabolic catastrophe in the glioblastoma cells and sensitize them to
standard radiation and chemo and damage/differentiate/kill the cancer stem cells so no more
self renewal, and make the immune system be robust enough to set off a regression event,
and initiate an immune memory event to prevent recurrence when used in combination with
standard therapy. Impairing IDO and TDO are critical to the success of the protocol.
Certain aspects of the MDSC depletion protocol should also help prevent recurrence, hence its
inclusion in this pdf.

Explanations
Fluoxetine: This should help selectively kill GBM cells . It induces transmembrane calcium influx and
subsequent GBM cell death via interactions with AMPARs . It interacts with GluR-1 subunit of the
AMPAR and causes mitochondrial membrane damage and sets off the intrinsic apoptosis pathways
with increased caspase 3, 9 and cytochrome C and PARP. The AMPARs are overexpressed in GBM so
the killing is selective to GBM cells. Fluoxetine should also markedly decrease expression of MGMT
in GBM and disrupt NfkB/p65 signaling and decrease its activity in regulating the MGMT expression
in GBM cells and sensitize the GBM to temozolamide. MGMT is involved in DNA repair.
The GBM cell death in the animal studies w/ fluoxetine was similar when they received
temozolamide. and the two together dramatically suppressed tumor growth. The combo also really
decrease the proliferation marker Ki-67. By opening the BBB a bit , the fluoxetine should help increase
brain levels of metformin and cimetidine and curcumin and fenofibrate.
It is also a good p-glycoprotein inhibitor and so should should help to improve BBB penetration of the
other agents . Sertraline(Zoloft) will open BBB as well, and so will bradykinin.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467135/ nice article on fluoxetine effect on GBM
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4550181/ good on fluoxetine and GBM
http://www.ncbi.nlm.nih.gov/pubmed/16055945/ nice on selectivity of SSRI on brain tumors.

Fenofibrate: The end result of fenofibrate in GBM is a metabolic catastrophe .Its Actions are really
complex , but it basically forces the GBM to make use of beta oxidation instead of glycolosis then
damages complex I of the electron transport chain making it impossible for the GBM to make use of
ETC. with time, (72 hrs of 50microM exposure), a metabolic catastrophe hits the GBM cells .
Its effects are selective to GBM probably because GBM cells cannot convert the Fenofibrate to
Fenofibric acid so the Fenofibrate accumulates in the mitochondrial fraction and leads to problems.
Question is can we get to 50microM in brain with oral dosing. Well the piperine should inhibit its
gluceronidation and lead to higher serum levels and the fluoxetine and tadalafil should help to open the
BBB/BTB and maybe allow for better brain penetration.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4694890/ good explanation of fenofibrate in GBM
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295376/ nice explanation of the mechanisms of the
fenofibrate induced metabolic catastrophe in GBM cells and why it is specific to GBM cells.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3409008/ explains how fenofibrate and triggers
BIM-mediated apoptosis in GBM cells--(hint it involves nuclear translocation FoxO3A
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4735548/ so fenofibrate reprograms GBM metabolic
pathways in such a way that the GBM cells suffer from an energy deficit but are still forced to produce
ketone bodies and neuroectodermal cancers cannot metabolize ketone bodies for their own benefit .
Those ketone bodies can however act as fuel for normal neurons and also act as a cytoprotective
signaling molecule for the normal neurons
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4176946/ discusses ketone bodies as signaling
molecules
Sulfurophane : sulfurophane actions are complex, it will inhibit NfkB and reduce expression of
MGMT. It also inhibits the Wnt/beta-catenin/TCF4 expression and this results in a decrease in miR-21
with the effect of enhancing the killing effect of temozolamide and really reducing the chances of
temozolamide resistance. Sulfurophane when combined with metformin should cause cancer stem cells
to lose their self renewal ability and once lost , that ability cannot be recovered. Sulfurophane also
activates ERK1/2 in a sustained fashion with the result of downregulation of mmp 2 and its activity and
upregulated CD44v6 glycoproteins with overall effect being a decrease in the invasiveness of GBM.
Sulfurophane will also upregulate calpain with then activates caspase 12 with several deleterious
downstream effects in the GBM cells. Sulfurophane can also impair complex III of the electron
transport chain and that leads to increase ROS within the mitochondria and subsequent damage leading
to activation of caspase 3 and 9 and downregulation of Bcl2, Bax and p53 gene activation. It can also
decrease the expression of DNA repair genes. It will also inhibit the expression of nanog and oct-4
which are key players in self renewal pathways in cancer stem cells. Also decreases Zeb-1 , Gli-1 and
Gli-2.
http://www.ncbi.nlm.nih.gov/pubmed/16765523 nice one on sulfurophane in GBM

Metformin: Metformin modulates many MANY signaling systems in cancer cells. From an immune
standpoint, it will enforce expression of MHC I surface antigens in tumor cells. Tumor cells will avoid
detection from cytotoxic T cells by 'retracting' their MHC I antigens from their surface. By enforcing
re-expression of those MHC I antigens on the cell surface, metformin should help to make the tumor
cell more 'visible ' to the cytotoxic T cells. Metformin with sulfurophane should downregulate WNT
systems in cancer stem cells and cause them to permanently lose self renewal abilities. The
sulfurophane will also impair PGE 2 production in MDSCs and
Metformin will also kill glioma initiating cells..
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659661/ discusses effect on glioma initiating cells.
Note the comment that metformin is the most clinically relevant drug ever reported for targeting
glioma initiating cells. Sounds like metformin easily crosses the BBB in the new reports.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395104/ discusses mechanisms of metformin in GB

Cimetidine: Cimetidine at a dose of 800mg will result in an increase in the number of Natural
Killer cells and increase the level of interleukin-2 and will decrease Tregs. Cimetidine will cause the
death of myeloid derived suppressor cells via apoptotic cell death. Myeloid derived suppressor cells are
a real problem because they are a significant player in tumor driven immuno-subversion and immunoevasion and impair Natural Killer cell functions. They can account for up to 40% of the tumor mass.
They also play a leading role in the establishment of premetastatic sites; basically building a 'nest' for
tumor cells , then putting a 'welcome home' beacon in that premetastatic nest to attract tumor cells that
may be circulating in the blood . The more myeloid derived suppressor cells in the patient with solid
tumor, the worse the prognosis, so anytime we can inactivate or kill these types of cells, we should take
the opportunity. Cimetidine will also decrease the renal tubule secretion of metformin and increase
metformin plasma levels from 25 to 50 %. This makes for a nice way to increase metformin levels
without an increase in GI side effects from oral metformin. Cimetidine should also increase the serum
level of fluoextine and that should help impair the GBM .
Cimetidine is also synergistic with Levamisole in the promotion of strong Th1 attributes.
Celebrex: Celebrex will result in a decrease in myeloid derived suppressor cells of all subtypes. The
end result of celebrex should be highly activated cytotoxic T cells and better dendritic cell based
immunotherapy because of reduced myeloid derived suppressor cell expansion. Celebrex will decrease
cox2 and pge2 within the MDSC s with multiple beneficial downstream effects.
Celecoxib will also decrease indolamine 2,3 dioxygenase and decrease treg cells.
Lipoic acid and luteolin: These inhibit IL4. IL5 and IL13 MMP2 and MMP9 . These cause a
lot of problems in solid tumor hosts. Lipoic acid basically, should cause a proton leak from pyruvate
dehydrogenase to compex I of the electron transport chain and impair the warburg effect in tumor cells.
Also decreases ROS (MDSC use ROS for immunosubversion.) If take lipoic acid then also need to take
a b-complex vitamin.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3751389/ nice one luteolin in GBM

Beta Glucan: Beta glucan should cause a reinstatement of a TH-1 dominant immune system . Its
actions are complex. A simple way to think of its actions is to understand that it 'reprograms' the
immune system to express strong and prolonged TH-1 system attributes to help with cytotoxic T cell
and dendritic cell functions , modulates several key interleukins and really decreases the numbers of
myeloid derived suppressor cells, by allowing them to differentiate into more mature cells, via the
dectin-1 receptor, that are then more of an asset to the system than a hindrance. It is not absorbed , but
interacts with the peyer's patch's macrophages in the small intestine and those macrophages pick up
some of the glucan particles, process them and then hand them off ,like a baton, to other immune cells,
who then notify the rest of the relevant immune tissues to reprogram things to a TH-1 state , because
they fear the beta glucan is the herald event to a nasty fungal infection and the human immune system
has evolved to hate fungal infections , it is just a happy accident that the same system (TH-1) , that
deals well with fungal infections also deals well with tumors. The 1,3 1-6 explains the binding and
branching traits of fungal or yeast beta glucans .
The more complex the branching traits, the better from an immuno-modulatory standpoint. Bacterial
beta glucans have 1,4 instead of 1,3 . The Vitamin C is included in the protocol because it has a
synergistic effect with the Beta glucan in reprogramming the immune system. If one had the IM
version of beta glucan ---that would work quicker ( I think mayo got theirs from Biothera in
Minnesota).http://www.biothera.com/investors/fact_sheet.html this just has address info on biothera --i
think that Mayo got their injectable form of 1,3 1-6 beta glucan for use in their CLL monoclonal study
from biothera out of Egan MN.
You need robust TH1 attributes to respond to any monoclonal antibody in
any useful way and remember
monoclonals will really increase IL-6 levels and that IL6 then helps to drive
resistance to the monoclonal so consider either minocycline or
tolcilizumab or siltuximab as well to deal with the IL6 issues.
But cant use minocycline for 2 months after start protocol and chemo.

Naltrexone: Naltrexone will increase maturation of bone marrow dendritic cells and and help shift
the immune system towards the TH1 side . It is synergistic with the lipoic acid.
At 4.5 mg dose , the naltrexone should not cause opioid withdraw in the patient who is on opioid .
http://www.ncbi.nlm.nih.gov/pubmed/24455776 discusses low dose naltrexone and its effects on the
immune system

Melatonin: It will help maintain IL12 levels which should help maintain a TH1 dominant
system. Also MDSCs use ROS production as a serious mechanism for immunosubversion and so as a
very robust antioxidant , melatonin will diminish ROS in the system.
It will also directly augment NK activity. In GBM it should sensitize the GBM to TRAIL mediated cell
death and decrease Glioma initiating cells.
http://www.ncbi.nlm.nih.gov/pubmed/19632770 explains TRAIL cell death and melatonin
http://www.ncbi.nlm.nih.gov/pubmed/19632770 discusses the proapoptotic effects of melatonin in
cancer in general.
http://www.ncbi.nlm.nih.gov/pubmed/23551342 effectiveness of melatonin in inhibiting HIF-1alpha in
GBM
http://www.ncbi.nlm.nih.gov/pubmed/17332917 explain why want to inhibit HIF-1alpha in GBM
http://www.ncbi.nlm.nih.gov/pubmed/25163989 some nice effects of melatonin in GBMdecreased
clonogenicty and decreased glioblastoma initiating cells as well as decreased tumor bulk.
Minocycline: Minocycline will inhibit interleukin-6 and down regulate the expression of the
interleukin-6 receptor. It also will inhibit matrixmetalloproteinase-2 and 9. Tumors use MMP2 and
MMP9 to enhance invasion into tissues when establishing metastatic sites. Interleukin-6 is the
instigator of many many problems in cancer patients , from cachexia to immuno-subversion.
Interleukin-6 will blunt the TH-1 immune response and enhance the TH-2 immune response in solid
tumor patients, so anytime we can inhibit interleukin-6 in the cancer patient , we should take the
opportunity. Minocycline has many other more complex actions , but from an immune standpoint , the
above is a good summary. Il-6 and MDSCs are the main drivers of cachexia in my opinion and so
minocycline at 100mg qd, should nullify the effect of IL-6 on cachexia, while the other MDSC
depleting agents should deal nicely with the MDSC issues as they apply to cachexia.
Minocycline will also profoundly downregulate the IL6 receptor and the expression of GP130.
It will decrease Mcl-1 as well. Question w/ GBM is would the mino prevent transmigration of
neutrophils across the BBB and could that be a problem...also would it blunt the effect of cimetidine on
the MDSCs since cimetidine kills them via apoptosis.
http://www.ncbi.nlm.nih.gov/pubmed/21079420 minocycline inhibits glioma growth by inducing
autophagy.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4519695/ discusses how GBM uses mmp9 and how
minocycline impairs the GBM
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748919/ so minocycline will cause endoplasmic
reticulum stress in GBM
http://www.ncbi.nlm.nih.gov/pubmed/21324352 minocycline blocks the increase in matrix type-1
matrix metalloproteinase(MT1-MMP) in gliomas

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718387/ explains how Glios exploit the MT1-MMP

system

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741958/ nice one the controversy of microglial

actions in gliomas
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3408253/ microglia supports tumor expansion.
Well mino is good at decreasing microglial activation and so maybe helps dampen the microglia.
http://www.tandfonline.com/doi/abs/10.4161/auto.7.2.14043#aHR0cDovL3d3dy50YW5kZm9ubGluZS
5jb20vZG9pL3BkZi8xMC40MTYxL2F1dG8uNy4yLjE0MDQzQEBAMA== mino will cause lots of
problems for GBMs -----need to use minocycline , but need to figure out when and how.
http://onlinelibrary.wiley.com/doi/10.1002/ijc.28908/pdf explaines mino
efects on GBM

Citrulline: selectively, should provide arginine to T cells via their arginosuccinate synthase and
so helps avoid the MDSC induced arginine depletion induced immunosupression of the cytotoxic t
cells. Oral Citrulline is metabolized to a much lesser extent than oral arginine and the MDSCs should
not be able to use citrulline as a substrate for arginase-1 ,like they would be able to do with oral
arginine supplementation.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4516994/ explains how citrulline improves T-cell
function in Arginine depleted state

Tadalafil: Tadalafil will inhibit arginase-1 within the myeloid derived suppressor cell and impair its
function. Arginase-1 depletes arginine and induces arginine depleted immunosupression of the T-cells.
In GBM, it will also increase permeability of the blood tumor barrier to chemo meds.
Abstinence from Bisphenol-A , MSG, Methylparabens and Parabens and
Fructose: Bisphenol-A and MSG will shift the immune system towards TH-2 expression. TH-2
shifting is one of the immunosubversion tools solid tumors use to avoid detection. Methylparabens and
Parabens will increase expression of Mtor signaling system and impair the expression of P53 signaling
system; Two things one would never want to do in a solid tumor because it will make the tumor more
aggressive.
Bisphenol-A and Methylparabens and Parabens are also xenoestrogenic agents and so one could
overcome the protection of antiestrogenic therapies with even moderate exposures. Fructose is the
sugar tumors prefer. They grow faster when exposed to fructose. For the protocol, just assume
Bisphenol-A is present in all plastic and metal and aluminum food and beverage containers and on all

thermal receipts and duplicate checks and in most hand lotions and abstain from exposure to these
things. Also, for the protocol, simply assume that methylparabens and parabens are
in all shampoos/cosmetics and hair conditioner agents and gel based under arm deodorants unless the
bottle states otherwise.

Vitamin D: Vitamin is a complex immunomodulatory agent . It is also a master regulator of myc

signaling systems and myc is a real problem in GBM .
It is also key player in activation of T-cells. Just making certain it is with in the
normal range(upper 10 percent) should suffice.
Vitamin D actions are complex . We do not want profound deficiency state
because of increased myc issues , but there also is data that robust levels may shift the immune system
toward the TH2 system and that would be undesirable in this protocol as we prefer strong TH1
attributes in the protocol. Also decrease ROS. Aim for a serum level of 60-70.

Given that IDO(indoleamine 2,3- dioxygenase) is the cause of tryptophan depleted immunosuppression
and is upregulated in solid tumor hosts, and given that EGCG and resveratrol and curcumin are IDO
inhibitors, the favorite drink should be green tea(china/japan variety) and golden milk(curcumin)
drank warm and slow over 30 min bid and the favorite treat should be EGCG in the gum or mint
(sencha brand) form as EGCG is mainly absorbed from sublingual to the end of esophagus .
Also given that fludarabine degrades IDO, may want to consider that as well.
IDO will make it impossible for the immune system to coat the solid tumor with complement and can
also change CD8 T-cells into a T-reg cell phenotype among other bad things so it needs to be
impaired /depleted
One cannot overstate the importance of these IDO actions on the maintenance of the solid tumor's
immune privilege. For any chance of regression in GBM, IDO must be impaired and depleted at the
functional , transcriptional , and regulatory level as well causing its degradation and curcumin , egcg
and fludarabine and resveratrol should help achieve that goal. Methyl tryptophan is another helpful
agent, but the protocol was created to make use of agents easily obtainable and methyl tryptophan is
not easily obtainable.

Curcumin: Curcumin will help enforce differentiation of glioma initiating cells and represses their self
renewal ability by initiating differentiation cascades within the glioma initiating cells.
It will also drive the glioma initiating cells into autophagy and decreases their clonogenic ability.
It will sensitize the GBM to temozolamide therapy via improve blockade of AKT/mTor activity .
It also increased ROS production within the GBM cells. Curcumins ability to decrease GBM cell
survival is p53 and caspase independent and is based on its inhibition of AP-1 and NfkB via prevention
of constitutive JNK and AKT activation. It also suppresses cyclin-D1,P-NFkB, BclXL, P-AKT, VGEF,
and augments the activity of ceramides. Curcumin does so many things , better to add a link to a very
nice article on curcumin mechanisms in cancer cells. Curcumin will help restore the immune system ,

restores the CD4/CD8 T-cell populations, reverse the type 2 cytokine bias, reduce Treg cell populations
and suppress T-cell apoptosis. Problem is bioavail issues the phytosome version, high dose, and
piperine will help with this issue, but got to be kinda careful with piperine as can increase levels of
other agents and that can be helpful or not helpful depending on the agent affected.
That is why take curcumin/piperine combo on the weekends only.
Curcumin is also a good inhibitor of indolamine 2,3 dioxygenase
Indolamine 2,3 dioxygenase is CRITICAL to GMB for immunosubversion.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758121/ this article explains in great detail the
various mechanisms curcumin makes use of to impair solid tumor.
http://www.ncbi.nlm.nih.gov/pubmed/16416600/ more curcumin mechanisms in gliomas
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4691004/ curcumin also affects miR-21 with serious
beneficial downstream effects.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4155674/ miR-21 is a real problem child in GBM

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603973/ curcumin restoration of the immune system

this is seriously nice article.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003225/ explains how curcumin reverses T-cell
related immune dysfunction in the tumor bearing host. VERY GOOD ARTICLE
http://www.healthyandnaturalworld.com/turmeric-golden-milk-recipe/ shows how to make curcumin
paste and how to make golden curcumin milk the coconut oil will dissolve curcumin (10mg/ml) and
because coconut oil is a medium chain triglyceride , should get absorbed passively and diffusely
along the gi tract....so maybe one way to improve bioavail of curcumin( question is would adding 20mg
piperine help with absorption of golden milk curcumin.)
: this is a monoclonal to the programmed death receptor-1 . It should impair the
function of PD-L1 and help with impair the immunosubversion GBM uses to avoid the immune
system.
Pembrolizumab

EGCG: Egcg will inhibit indolamine 2,3 dioxygenase at a functional level and at a transcriptional
level. It will inhibit the endoplasmic reticulum chaperone GRP78 . GRP78 contributes to
temozolamide resistance and is a prosurvival component of the endoplasmic reticulum stress response
system and is upregulated in GBM. Egcg inhibits the stem cell characteristics of glioma initiating cells.
And has synergistic effect when combined with temozolamidein the animal studies.
Egcg also downregulates p-glycoprotein expression inhibits neurosphere formation and cell migration
cleaves PARP and downregulates Bcl2 and IL6, IL8,MCP-1 MMP2 and MMP9 and
RANTES,thioredoxin-1 and ceruloplasmin, p-AKT and induces/augments Trail mediated
apoptosis in the cell model and also decreases the invasiveness of glios.

http://www.ncbi.nlm.nih.gov/pubmed/21257259 discusses egcg effect on ER.

http://www.ncbi.nlm.nih.gov/pubmed/25544670 egcg synergistic effects with anticancer agents
http://www.ncbi.nlm.nih.gov/pubmed/10719174 egcg inhibits mmp2 and mmp9 in glios.
http://www.ncbi.nlm.nih.gov/pubmed/11853893 explains effect of egcg on MMPs
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2718387/ recall that GBMs exploit the MMP system to
expand and invade tissue so good idea to inhibit that ability if one can.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4384709/ good one egcg effects

http://www.ncbi.nlm.nih.gov/pubmed/17942911 discusses GRP78 /BiP as a target in the unfolded

protein response system ---impair it and you increase effectiveness of temozolamide and 5-FU.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3721410/ good article for an explanation of how egcg
interacts with GRP78......
http://www.ncbi.nlm.nih.gov/pubmed/18948169 discusses how egcg augments trail mediated cell
death in GBM
http://www.ncbi.nlm.nih.gov/pubmed/21479441 very nice one on effects of egcg in gliomas -ACYCLOVIR: Inhibits TDO and IDO and crosses the BBB.
http://jneuroinflammation.biomedcentral.com/articles/10.1186/1742-2094-7-44 acyclovir
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2925358/ the pmc version

refs
http://jco.ascopubs.org/content/28/12/2051.full

prolonged low dose temozolamide

http://www.ncbi.nlm.nih.gov/pubmed/25434389 nice one on prolonged use of temozolamide

discusses MGMT methylation issue as well ----well valproic acid is a good HDAC inhibitor
http://www.ncbi.nlm.nih.gov/pubmed/15488325 discuses statin use in GBM

http://www.ncbi.nlm.nih.gov/pubmed/20044596 basically dont use high dose statin in GBMstatins

have complex effects in GBM and needs more study before use.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711082/ explains complexity of statin effects on
GMB
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3893468/ nice one on synergism between celebrex and
fluastatin in astrocytoma
http://www.ncbi.nlm.nih.gov/pubmed/23707077 explains atrovastatin ability to decrease GBM
invasion
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3163617/ discusses possibility of using statins as
anticancer agents in GBM
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3755070/ nice one on inhibitors of invasion in GBM
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373250/ valproic acid can sensitize the GBM to
temozolamide via downregulation of MGMT expression. Well VPA actions are complex in GBM , but
if need a second seizure med then maybe add valproic acid.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736617/ targeting autophagy helps sensitize to
temozolamide
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736617/figure/Fig1/ nice diagram of resistance
mechanisms to temozolamide

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4736617/figure/Fig2/ nice diagram on modulation of

autophagy
http://www.ncbi.nlm.nih.gov/pubmed/25681668/ discusses the synergism between temozlamide and
chloroquine(chloroquine inhibits autophagy)

http://www.ncbi.nlm.nih.gov/pubmed/25528635 chloroquine inhibits mitochondrial autophagy

http://www.ncbi.nlm.nih.gov/pubmed/22788764/ discusses targeting MGMT in glos --- well fluoxetine

and valproic acid impair MGMT
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4506397/ effect of dexamthasone on immune situation
in GBM ---basically best to get wean off of the dexamethasone ,
but SLOWLY so as to avoid adrenal crisis
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705875/ makes the argument that the immune
distortions may have been more from radiation than the dexamethasone.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4705876/ response to the above argument. Well, it is a

complex matter...and the effects of dexamethasone are very complex, ..but maybe best to slowly wean
from the dexamethasone if able .
http://www.ncbi.nlm.nih.gov/pubmed/17804742 explains how silibinin can recover trail sensitivity in
Trail resistant gliomas..
http://www.ncbi.nlm.nih.gov/pubmed/18172319 just an interesting one on Trail and arsenic trioxide in
gliomas
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492080/ immunosuppressive mechanisms in GBM
http://www.ncbi.nlm.nih.gov/pubmed/26748069 mechanisms of curcumin in GBM
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3128477/ explains beta glucans

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4198934/ discusses mechanisms of glioma formation

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924543/ discusses the effect of intermittent
metronomic dosing on the immune system in GBM they used parenteral cyclophosphamide at
140mg/kg in the animal study with nice effects.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4162810/ discusses use of metronomic dosing on an

every 6 day schedule works the best to set off extensive tumor regression and stimulate various
immune responses.... well some relapsed over time I think that just points to need for additional
immune modulating agents and MDSC depletion agents like beta glucan, cimetidine.celebrex,
cialis..ect as well as agents to either kill or strip the glioma stem cell of their self renewal
ability(sufurophane and metformin).
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC508583/ this article supports the idea of bystander
effects of cylophosphamide and importance of adoptive immunity input .

http://www.ncbi.nlm.nih.gov/pubmed/17255288 another good one on the importance of the cytokine

storm during the rebound phase after drug induced lymphodepletion.
It improved adoptively transferred immune cells.
http://www.ncbi.nlm.nih.gov/pubmed/26137402 metronomic cyclophosphamide induced eradication
of large implanted glioma and set off immune memory event I think they used the q6 dosing at
140mg/kg. Tumor regression leading to tumor ablation was seen after use of several cycles.
Rejection of the tumor re-challenge was associated with increase in cytotoxic T cells consistent with
the induction of specific long term Cd8 T-cells antitumor memory ( --also recall that the metformin
should help make the CD8 memory cells live longer by basically reprogramming their metabolism.)
Also recall that the end result of celebrex should be more hyperactivated cytotoxic T-cells.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485826/ here is the PMC version of the above article.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4678703/ nice explanation of indolamine2,3

dioxygenase mechanisms in solid tumor escape strategies.
You really HAVE to deplete indolamine 2,3 dioxygenase if want regression event to occur

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4182350/ so when target IDO, PD-L1 and CTLA-4 all

then animals with GBM turned into long term survivors... I think this supports the thinking that
multimechanistic approach to GBM is essential to eradication ,regression and immune memory.

https://en.wikipedia.org/wiki/Ipilimumab nice wiki explanation of ipilimumab as a monoclonal to

CTLA-4\\

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4105871/ another good on what happens when deplete

indolamine 2,3 dioxygenase...... it helps a lot.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3698523/ discusses the critical nature of IDO in tumor
immunosubversion

http://www.ncbi.nlm.nih.gov/pubmed/21611872 interesting one on immune effects on

cylophosphamide and vaccines

http://www.ncbi.nlm.nih.gov/pubmed/18540827 explains some mechanisms of cyclophosphamide

immune modulation ---- I think it should be an agent used in the protocol.

http://www.ncbi.nlm.nih.gov/pubmed/15585981 discusses the innate immune system and GBM

http://www.ncbi.nlm.nih.gov/pubmed/19944963 discusses t-cell anergy and other problems in GBM

immune resistance..... makes one think about Effects of IDO, ARGINASE-1 , MDSCs and cysteine
tryptophan and arginine depletion effects on the CNS t-cells.

http://www.ncbi.nlm.nih.gov/pubmed/21611872/ discusses the immunomodulatroy effects of

cyclophosphamide as relates to use of cancer vaccines.

http://www.ncbi.nlm.nih.gov/pubmed/21148486 discusses effect of cylophosphamide on TH17 system

http://www.ncbi.nlm.nih.gov/pubmed/23424024 beta glucan effect on MDSCs

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2970627/ oral beta glucan does help antitumor

immunity

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3471954/ more about beta glucan

http://www.ncbi.nlm.nih.gov/pubmed/17407102 discusses GITR --- beta glucan and narcan both affect
GITR

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4104995/ combining PDL1 inhibition and GITR

triggering in the cancer host
http://www.ncbi.nlm.nih.gov/pubmed/20198327 decreasing Tregs helps immune system

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3413251/ discusses modulation of gitr in cancer

therapy

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4467135/ fluoxetine causes apoptosis in GBM

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466510/ fenofibrate kills GBM
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3466539/ another one on fenofibrate
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4295376/ discusses the mechanisms of the metabolic
catastrophe induced by fenofibrate in GBM--- this a great article!
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2912247/ more on the mechanisms of fenofibrate

http://www.ncbi.nlm.nih.gov/pubmed/24493576 another very good one on fenofibrate use in GBM

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4655242/ metformin targets cancer stem cells in GBM
http://www.ncbi.nlm.nih.gov/pubmed/26431379 discusses more mechanisms of metformin in GBM
http://www.ncbi.nlm.nih.gov/pubmed/24965413 metformin with sorafenib kills GBM stem cells
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395104/ metformin makes temozolamide and
radiation more effective in GBM
http://www.ncbi.nlm.nih.gov/pubmed/26329695 metformin does influence survival in GBM

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294381/ nice one on repositioning metformin as

antitumor agent in GBM stem cells

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3570504/ another good one metformin in GBM

clearly it has effects

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3587450/ sorafenib and GBM stem cells and depletes

them ---good because current treatment for GBM enriches the tumor with cancer stem cells (a
very bad thing)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2852467/ sorafenib kills GBM cells

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268104/ ReDo cimetidine as an anticancer agent

http://www.ncbi.nlm.nih.gov/pubmed/16596218 cimetidine use in GBM

http://www.ncbi.nlm.nih.gov/pubmed/15871514 cimetidine combined with temozolamide

http://astrocytomaoptions.com/repurposed-drugs/ just interesting

http://www.ncbi.nlm.nih.gov/pubmed/?term=cimetidine+and+mdsc+and+fas cimetidine kills MDSCs

http://www.ncbi.nlm.nih.gov/pubmed/25303541 pde 5 inbhibitors combined with celebrex

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4398314/ celexecob and pde5 inhibitors
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2632551/ pde5 inhibitors increase blood tumor barrier
permeability for chemo in GBM ...recall that bradykinin also opens the BBB --http://www.ncbi.nlm.nih.gov/pubmed/24651037 interesting
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118163/ tadalafil impairs MDSC function
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322895/ tadalafil reduces MDSC and Treg cells
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662416/ discusses MDSCs
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4662416/ discusses immune system and MDSCs
http://www.ncbi.nlm.nih.gov/pubmed/26700461 t-cell and MDSC interacts
http://www.ncbi.nlm.nih.gov/pubmed/26546453 long term regression of GBM in animals with
keytruda
http://www.ncbi.nlm.nih.gov/pubmed/26578623 discusses MDSC in GBM
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4485826/ interesting article

http://www.ncbi.nlm.nih.gov/pubmed/24215283 MDSCs in GBM

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564242/ MDSC and tumors relationship
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940696/ keppra makes GBM more sensitive to
temozolamide
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4667941/ valproic acid in GBM
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1855204/ explains how hedgehog controls CSCs
http://www.ncbi.nlm.nih.gov/pubmed/26648123 sulfurophane reverses TMZ resistance

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928692/ discusses the gli/nanog/p53 nework and its

effects on cancer stem cells.
http://www.ncbi.nlm.nih.gov/pubmed/25991372 sulfurophane improves TMZ therapy

http://www.ncbi.nlm.nih.gov/pubmed/20633539 discusses the effect of miR-21 on TMZ resistance

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3938755/ sulfurophane inhibits GBM invasion

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4491563/ sulfurophane effect on ROS production

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3461003/ discusses sulfurophane ability to modulate

self renewal in cancer stem cells....it is a sonic hedgehog inhibitor
http://www.ncbi.nlm.nih.gov/pubmed/22406999 discusses sonic hedgehog signaling in GBM

http://www.ncbi.nlm.nih.gov/pubmed/23544423 discusses the role of the gli proteins in GBM ---well

sulfurophane modulates Gli proteins.

http://www.ncbi.nlm.nih.gov/pubmed/22114144 sonic hedgehog and gli interactions...sulfurophane

modulates Nanog and

http://www.ncbi.nlm.nih.gov/pubmed/23129257 sulfurophane effects on sonic hedgehog

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928692/ so nanog is essential to cancer stem cells in
GBM
http://www.ncbi.nlm.nih.gov/pubmed/16765523 multiple mechanisms in use with sulfurophane in
GBM

http://www.ncbi.nlm.nih.gov/pubmed/26853447 discusses effects of dietary phytochemicals in cancer

stem cells
http://www.ncbi.nlm.nih.gov/pubmed/24463298 curcumin messes with self renewal pathways in CSCs
--- fyi so does sulfurophane
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862133/ discusses mechanism of sufurophane in
cancer stem cells ---they lose ability of self renewal.
http://www.ncbi.nlm.nih.gov/pubmed/20530687 sulfurophane + sorafenib kills cancer stem cells.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3661162/ just interesting
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3500324/ sulfurophane and PGE2 synthase
http://www.ncbi.nlm.nih.gov/pubmed/23017139 PGE2 effect on MDSCs

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217352/ PGE2 + COX2 = lots of MDSCs so good to

recall that celebrex will inhibit cox2 and PGE2 and sulfurophane will inhibit PGE2 synthase within the
MDSC

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368153/ nice one on MDSCs

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1069076/ regression mechanisms
http://www.ncbi.nlm.nih.gov/pubmed/11313376/ interesting

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019895/ NICE one on MDSCs and ways to impair

them in cancer patient.
http://www.ncbi.nlm.nih.gov/pubmed/20388795/ 5-FU will kill MDSCs
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805057/?report=classic this is why supplement with
cysteine
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0049744 very good one on effect of
sulfurophane on MDSCs
http://www.ncbi.nlm.nih.gov/pubmed/15568289 explains why citrulline is needed.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4470044/ discusses some antitumor effects of lipoic
acid .
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3665298/ epigenetic effects of curcumin in GBM
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4627233/ mechanisms of curcumin in GBM
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640558/ nanoformulations of curcumin
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2758121/ curcumin and cancer

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603973/ curcumin and its immune effects

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003225/ curcumin reverses the t-cell mediated

immune problems in tumor host
http://www.ncbi.nlm.nih.gov/pubmed/24165291 curcumin mechanismsin gliomas
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2862867/ curcumin effects on stem cells
http://www.ncbi.nlm.nih.gov/pubmed/21138870 curcumin and JAK and STAT3 in GBM
http://www.ncbi.nlm.nih.gov/pubmed/19306372 STAT3 inhibition in GBM
http://www.ncbi.nlm.nih.gov/pubmed/26637846 curcumin use in GBM
http://www.ncbi.nlm.nih.gov/pubmed/26275397 targeting GBM with phytochemicals
http://www.ncbi.nlm.nih.gov/pubmed/26239619 curcumin and TMZ
http://www.ncbi.nlm.nih.gov/pubmed/25792385 curcumin sensitizes GBM to radiation.
http://www.ncbi.nlm.nih.gov/pubmed/25542083 a good one on TMZ/curcumin combo
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3635906/ nice one on resveratrol
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3248209/ blocking nfkb helps
http://www.ncbi.nlm.nih.gov/pubmed/21423202 block nfkb and it helps

http://www.ncbi.nlm.nih.gov/pubmed/21040711 nfkb inhibitors

http://www.ncbi.nlm.nih.gov/pubmed/26151775 Let-7 and Myc are real issues in GBM ---they mess
with glucose metabolism
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799884/ discusses the signaling systems that are
messed up in glioblastoma
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2940679/ discusses mTor activity in GBM and ways to
impair it --- recall that metformin is a pretty good mTor inhibitor

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3180897/ discusses ampk as a target in GBM--metformin affects AMPK but limited by BBB penetration need to see if p-glycoprotein inhibition
would improve metformin penetration across the BBBB
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3268186/ discusses PGP issues at BBB

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4600488/#B62 discusses various ways to inhibit pgp

efflux at BBB----looks like fluoxetine is a moderate pgp inhibitor. good reason to be on prozac.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3773671/ discusses verapamil as pgp inhibitor.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2856671/ nice article on pde5 inhibitors effect on BBB

in tumors increase permeability of BBB in brain tumor but not in normal brain tissue...that is a good
thing.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2632551/ discusses sildenafil and bradykinin as agents

to open the BBB.
http://www.ncbi.nlm.nih.gov/pubmed/12438524 discusses ways to affect the BBB

http://astrocytomaoptions.com/the-blood-brain-barrier/ discusses BBB and fluoxetine and verapamil

---probably all GBM folks should be on Prozac 40mg daily and if HTN then verapamil as well

http://www.ncbi.nlm.nih.gov/pubmed/19879382 discusses the dysregulated signaling systems in GBM

http://www.ncbi.nlm.nih.gov/pubmed/19618852 roles for glutamate receptors in GBM

http://www.ncbi.nlm.nih.gov/pubmed/25818339discusse immune evasion in cancer---I think it supports

notion that TH1 shifting, increase NK cells would help---some the bioavail issues with curcumin can be
overcome with the Phytosome version of curcumin and also by taking piperine with the curcumin.

http://www.ncbi.nlm.nih.gov/pubmed/22327882 supports the idea that depleting T-reg cells

helps( recall that cimetidine will decrease Tregs)

http://www.ncbi.nlm.nih.gov/pubmed/15032595/ discusses t-cell memory effects

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4674000/ discusses metformin ability to reverse

warburg effect

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610988/ explains how methylene blue reverses the

warburg effect in GBM cells.
http://www.ncbi.nlm.nih.gov/pubmed/12172541 discusses blockade of AMPA receptors in GBM
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4226667/ discusses drug cocktail for GBM
http://www.ncbi.nlm.nih.gov/pubmed/20652724 another one on drug cocktails for GBM
http://www.ncbi.nlm.nih.gov/pubmed/22560712/ discusses artesunate in GBM

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3813417/ discusses drug -drug interactions in GBM

http://www.ncbi.nlm.nih.gov/pubmed/22639159/ discusses GMB immunosubversion
http://www.ncbi.nlm.nih.gov/pubmed/24582432 tregs play big role in GBM immunosubversion.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3500434/ Indolamine 2,3 dioxygenase is a huge
problem in the GBM immune system --- well curcumin is a very good inhibitor of IDO and egcg is a
moderate inhibitor of IDO. Fludarabine will degrade IDO.
http://www.ncbi.nlm.nih.gov/pubmed/26636389 makes a good argument to inhibit IDO in GBM
patient.
http://www.ncbi.nlm.nih.gov/pubmed/25054303 discusses tryptophan metabolism in GBM

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641522/ indolamine 2,3 dioxygenase plays a

CRITICAL role in GBM immunosubversion.
http://www.ncbi.nlm.nih.gov/pubmed/23144293 MUST INHIBIT IDO!!
it is the cause of too many issues.

http://www.ncbi.nlm.nih.gov/pubmed/23090118 discusses tryptophan catabolism in GBM

http://www.ncbi.nlm.nih.gov/pubmed/26140242 discusses how cancer reprograms the immune system.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4050125/ explains how fludarabine impairs IDO
http://www.ncbi.nlm.nih.gov/pubmed/19075017/ curcumin inhibits IDO
http://www.ncbi.nlm.nih.gov/pubmed/17270146 egcg and IDO inhibition

http://www.ncbi.nlm.nih.gov/pubmed/19307990 cox 2 inhibitors decrease IDO and Tregs

http://www.hindawi.com/journals/ecam/2012/501796/ interesting one about using mistletoe in GBM
by downregulating GBM genes and improving NK cell GBM cell lysis.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2825688/ discusses targeting IL-6,-- recall that mino is

a good IL-6 and IL6 receptor inhibitor

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3579281/ discusses interleukins in GBM well IL-6

and IL1beta
http://www.ncbi.nlm.nih.gov/pubmed/11147905/ IL-6 as a target in GBM

http://www.ncbi.nlm.nih.gov/pubmed/26573275 interesting one on combo of luteolin and silibinin--seems they inhibit autophagy
http://www.ncbi.nlm.nih.gov/pubmed/24750786 discusses use of combo of arsenic trioxide and
metformin interesting that it mentions that metformin easily crosses the BBB. The combo induced
autophagy and apoptosis in GBM cells.

http://www.ncbi.nlm.nih.gov/pubmed/23651583 effects of resveratrol on glioma stem cells.

It promoted nanog suppression via proteosomal degradation. Just have to see if it crosses the BBB.
Also helps stabilize the BBB ---so dont want that as will make harder to get other things across it.

http://www.ncbi.nlm.nih.gov/pubmed/25382637 makes refeence to the IL-6 issue in GBM it is a

problem , so maybe episodic minocycline after 2 months--- but mino can impair transmigration of
neutrophils across BBB , so really have to be careful with mino
---i think timing will be everything with minocycline.
http://www.ncbi.nlm.nih.gov/pubmed/23877261 a nice one on the use of ATRA

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4593370/ discusses the use of combo of disulfiram and

ritonavir to inhibit IL-18 in GBM

http://www.ncbi.nlm.nih.gov/pubmed/22564423 discusses a trio of captopril/disulfiram/nefinavir to

inhibit GBM mmp2 and mmp9 ----well minocycline is a really good mmp2 and mmp9 and il6 inhibitor

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4338488/ discusses interstitial treatment for GBM

http://www.ncbi.nlm.nih.gov/pubmed/10914414 discusses the exploitation of immune mechanisms in

the treatment of CNS cancers.

http://www.ncbi.nlm.nih.gov/pubmed/15585981 discusses innate immune response in the CNS and its

role in GBM immune surveillance

http://www.ncbi.nlm.nih.gov/pubmed/19944963 discusses the mechanisms of local immunoresistance

in GBM
http://www.ncbi.nlm.nih.gov/pubmed/24563621 talks about every 6 day metronomic dosing of
cyclophosphamide and why that type of dosing is essential to activating antitumor innate immunity and
it role in regression.

MDSC DEPLETION PROTOCOL

This is a hypothetical protocol to deplete MDSCs
CAN'T USE THIS IN ANY TRANSPLANT PATIENT AS IT WOULD
CAUSE AN ACUTE REJECTION EVENT.
Agents:
1. 1,3 1-6 Beta glucan 2000mg twice a day
2. Vitamin C 500mg twice a day (take with beta glucan)
3. Cimetidine 800mg twice daily
4. Celebrex 400mg daily (inhibits COX2 and PGE2)
5. Tadalafil 10mg daily or 20mg Tuesday AM and Thursday PM ( inhibits arginase 1)
6. Sorafenib 400mg twice daily for 8 weeks every year
7. Sulfurophane 4mg twice daily ( inhibits microsomal PGE2 synthase)
8. Sunitinib 50mg daily x 1 month every 6 months x 2yrs, then 1 month per yr
9.

Minocycline 100mg daily

10. Siltuximab monoclonal to IL6 every yr ( if not going to use minocycline)

11. Melatonin 6mg at bedtime
12. Zyrtec 10 mg daily
13. Levamisole 50mg three times a day the first 3 days of every 4th month x 2 yrs
14. Niclosamide 2 gm qd and Metormin XR 750mg qd .
15. Citrulline plus Cysteine to help improve t-cell activation and impair MDSC related amino
acid depleted immunosuppressive strategies.

simplified agent list :

1. sulfurophane 4mg bid
2. metformin xr 750mg daily
3. celebrex 200mg bid x 1 month then daily.
4. cimetidine 800mg bid x 2 months then daily
5. 1,3 1-6 beta glucan 2000mg bid ( maybe alternate with the Maitake MD fraction glucan?)
6. melatonin 6mg q hs , zyrtec 10 mg at bedtime
7. tadalafil 20mg on tuesday AM and thursday PM) every other week x 1yr
8. minocycline -100mg bid x 1 yr then daily
9. sunitinib -50mg daily x 4 weeks every 6 month x 2 yrs then 2 week per yr
10. Sorafenib 400mg bid x 1 month every 6 months x 2 yrs then 2 weeks per yr

Shortest most benign list of agents that 'might' do the job.

1.
2.
3.
4.
5.
6.
7.
8.
9.

Cimetidine 800mg daily

1,3 1-6 beta glucan 1400mg daily w/500mg vitamin C for 15 days/month
Citrulline 750mg daily
Celebrex 400mg daily (with the sulfurophane)
Lipoic acid 600mg at HS and AM(with one b-complex daily)
Minocycline 100mg daily M-Th( start 2 month after start the cimetidine)
Tadalafil 5mg daily
Sulfurophane 60mg daily
Naltrexone 4.5mg at bedtime(take with the lipoic acid)

The agents underlined and in italics are for episodic use only.
The others are for daily use. Include lipoic acid and luteolin for their ability to decrease IL4 and IL13
levels. IL4 and IL 13 play roles in MDSC activation and immunosuppression.
If need a diuretic it should be amiloride. (alternative RNA splicing agent)
NO FRUCTOSE OR HIGH FRUCTOSE CORN SYRUP CONTAINING FOODS.
NO BISPHENOL-A EXPOSURE ( no thermal receipts or duplicate checks, plastic or aluminum drink
cans or bottles, no fragrances , no gel type deodorants, no eating on ANY plastic food containers ,no
soup cans , no processed foods, only use BPA free lotions and shampoos, sleep in complete darkness).
(maximize use of celebrex for pain control before adding any opioid)
Favorite drink =brewed green tea (china /japan type ) drank warm and slow over 30 minutes every day
Favorite snack is broccoli sprouts.( lot of sulfurophane it these)
Favorite mints are Green tea mints or Green tea gum for the egcg.
CAN'T USE THIS IN ANY TRANSPLANT PATIENT AS IT WOULD
CAUSE AN ACUTE REJECTION EVENT.

Consideration is given to using ATRA (all trans retinoic acid )at some point to allow the MDSCs to
complete their maturation and then become assets in the anti tumor response instead of liabilities to the
cause but ATARA has LOTS of very nasty adverse effects.

EXPLANATION OF AGENTS
protocol has never been used in humans and is so hypothetical at this point in time.
Below is a brief explanation of the main effects of the agents . The explanations of the mechanisms
have been really simplified but should suffice to afford a basic understanding of why the agents were
selected or are being considered. A deeper understanding can be obtained by reading through all of the
references.
Metformin: Metformin modulates many signaling systems in cancer cells. From an immune
standpoint, it will enforce expression of MHC I surface antigens in tumor cells. Tumor cells will avoid
detection from cytotoxic T cells by 'retracting' their MHC I antigens from their surface. By enforcing
re-expression of those MHC I antigens on the cell surface, metformin should help to make the tumor
cell more 'visible ' to the cytotoxic T cells. Metformin with sulfurophane should downregulate WNT
systems in cancer stem cells and cause them to permanently lose self renewal abilities. The
sulfurophane will also impair PGE 2 production in MDSCs. Problem is finding a pure source of
sulfurophane. That is the only reason it is not included in the protocol.
Cimetidine: Cimetidine at a dose of 800mg will result in an increase in the number of Natural
Killer cells and increase the level of interleukin-2. Cimetidine will cause the death of myeloid derived
suppressor cells via apoptotic cell death. Myeloid derived suppressor cells are a real problem because
they are a significant player in tumor driven immuno-subversion and immuno-evasion and impair
Natural Killer cell functions. They can account for up to 40% of the tumor mass. They also play a
leading role in the establishment of premetastatic sites; basically building a 'nest' for tumor cells , then
putting a 'welcome home' beacon in that premetastatic nest to attract tumor cells that may be circulating
in the blood . The more myeloid derived suppressor cells in the patient with solid tumor, the worse the
prognosis, so anytime we can inactivate or kill these types of cells, we should take the opportunity.
Cimetidine will also decrease the renal tubule secretion of metformin and increase metformin plasma
levels from 25 to 50 %. This makes for a nice way to increase metformin levels without an increase in
GI side effects from oral metformin. Cimetidine is also synergistic with Levamisole .

Celebrex: Celebrex will result in a decrease in myeloid derived suppressor cells of all subtypes. The
end result of celebrex should be highly activated cytotoxic T cells and better dendritic cell based
immunotherapy because of reduced myeloid derived suppressor cell expansion.

Levamisole: Levamisole's actions in cancer are multiple and really complex. Suffice it to say that
from
an immunomodulatory standpoint, It will partially revert the cancer driven immuno-subversion of the
immune system from a TH-2 dominant immune system towards the reinstatement of a TH-1 dominant
immune situation. The immunomodulatory effects of Levamisole are synergistic with those of
Cimetidine.

Beta Glucan: Beta glucan should cause a reinstatement of a TH-1 dominant immune system . Its
actions are complex. A simple way to think of its actions is to understand that it 'reprograms' the
immune system to express strong and prolonged TH-1 system attributes to help with cytotoxic T cell
and dendritic cell functions , modulates several key interleukins and really decreases the numbers of
myeloid derived suppressor cells. It is not absorbed , but interacts with the peyer's patch's macrophages
in the small intestine and those macrophages pick up some of the glucan particles, process them and
then hand them off ,like a baton, to other immune cells, who then notify the rest of the relevant immune
tissues to reprogram things to a TH-1 state , because they fear the beta glucan is the herald event to a
nasty fungal infection and the human immune system has evolved to hate fungal infections , it is just a
happy accident that the same system (TH-1) , that deals well with fungal infections also deals well with
tumors. The 1,3 1-6 explains the binding and branching traits of fungal or yeast beta glucans .The more
complex the branching traits, the better from an immuno-modulatory standpoint. Bacterial beta
glucans have 1,4 instead of 1,3 . The Vitamin C is included in the protocol because it has a synergistic
effect with the Beta glucan in reprogramming the immune system. If one had the IM version of
betaglucan ---that would be fine to use ( I think mayo got theirs from Biothera in minnesota)
I think You need robust TH1 attributes to respond to any monoclonal
antibody in any useful way.

http://www.biothera.com/investors/fact_sheet.html this just has address info on biothera I think,

Mayo got their injectable form of PGG1,3 1-6 beta glucan for use in their CLL monoclonal study from
biothera out of Egan MN.

Dipyridamole: Dipyridamole will impair the ability of the tumor cells to 'hide' from the Natural
Killer cells by coating themselves with platelets. Tumor cells ,when in the blood stream like to 'cloak'
themselves with platelets to avoid having their antigens detected by the immune system. The
dipyridamole partially removes this ability by modulating several signaling systems on the platelets so
they no longer 'adhere' to the tumor cells. This ,then, exposes the tumor cells surface antigens. It will
also decrease the number of tumor associated macrophages and myeloid derived suppressor cells
infiltrating the primary tumor . It is notable that the higher the platelet counts in many solid tumor
patients, the worse the outcome.

Minocycline: Minocycline will inhibit interleukin-6 and down regulate the expression of the
interleukin-6 receptor. It also will inhibit matrixmetalloproteinase-2 and 9. Tumors use MMP2 and
MMP9 to enhance invasion into tissues when establishing metastatic sites. Interleukin-6 is the
instigator of many many problems in cancer patients , from cachexia to immuno-subversion.
Interleukin-6 will blunt the TH-1 immune response and enhance the TH-2 immune response in solid
tumor patients, so anytime we can inhibit interleukin-6 in the cancer patient , we should take the
opportunity. Minocycline has many other more complex actions , but from an immune standpoint , the
above is a good summary. Il-6 and MDSCs are the main drivers of cachexia in my opinion and so
minocycline at 100mg qd, should nullify the effect of IL-6 on cachexia, while the other MDSC
depleting agents should deal nicely with the MDSC issues as they apply to cachexia.

5-Fluorouracil: 5-FU will kill myeloid derived suppressor cells . Unless using it at full dose for
formally treating a cancer, low dose is recommended for the protocol. Maybe using it for 7 days every
month would be reasonable . Minocycline should prevent any 5-FU related chemobrain.
Sunitinib will cause a drastic reduction in MDSCs
Sorafenib will cause a decrease in MDSCs and also impairs cancer stem cells.
Monoclonal Antibody: A Monoclonal Antibody will help to mark the tumor cells and should
then helpto induce apoptosis in tumor cells. The protocol requires tumor cell apoptosis in order to
be effective.Which monoclonal to use will depend on the particular tumor involved. If no monoclonal
is to be found for the particular tumor, then using siltuximab against interleukin-6, and depending on
radiation or formal chemotherapy to induce apoptosis should work . Regarding the issue of
monoclonals not being very effective; I think the monoclonals will be much much more effective when
used in the context of this protocol because of the the immunomodulating effects of the various agents.
For pancreatic cancer, the monoclonal should be Herceptin if HER2 pos
(70 % of pancreatic cancers are Her2 pos)

Citrulline: selectively should help provide arginine to T cells via arginosuccinate synthase and
helps avoid arginine depletion induced immunosupression of the cytotoxic t cells. The Cysteine should
help prevent MDSC induced depletion of cysteine and should improve ability to activate cd8 cells.

Gemcitabine: Gemcitabine is an agent that kills myeloid derived suppressor cells. MAY also have
potential to also select for cancer stem cells in some cancers?(--need more studies), so if use this one
then probably should also be using metformin and sulfurophane/sorafenib in combination with
gemcitabine as that combination should kill both differentiated tumor cells and cancer stem cells, or at
least cause them to lose self renewal when they leave the mesenchymal state as a result of modulation
of WNT systems. For use in this protocol, as an agent to decrease myeloid derived suppressor cells,
one would have to be careful . Only episodic use would be advised. More information is needed with
this one. Currently it is not included in the protocol. If they are already on it for the cancer then the
toxicity to myeloid derived suppressor cells is just a very nice side effect. The sulfurophane should
also inhibit PGE2 production in MDSCs, and impair their functions.

Tadalafil: Tadalafil will inhibit arginase-1 within the myeloid derived suppressor cell and impair its
function. Arginase-1 depletes arginine and induces arginine depleted immunosupression of the T-cells.
Vitamin D: Vitamin is a complex immunomodulatory agent . It is also a master regulator of myc
signaling systems. It is also key player in activation of T-cells. Just making certain it is with in the
normal range should suffice. Vitamin D actions are complex . We do not want profound deficiency state
because of myc issues , but there also is data that robust levels may shift the immune system toward
the TH2 system and that would be undesirable in this protocol as we prefer strong TH1 attributes in the
protocol.
Abstain from Bisphenol-A , MSG, Methylparabens and Parabens and
Fructose: Bisphenol-A and
MSG will shift the immune system towards TH-2 expression. TH-2 shifting is one of the
immunosubversion tools solid tumors use to avoid detection. Methylparabens and Parabens will
increase expression of Mtor signaling system and impair the expression of P53 signaling system; Two
things one would never want to do in a solid tumor because it will make the tumor more aggressive.
Bisphenol-A and Methylparabens and Parabens are also xenoestrogenic agents and so one could
overcome the protection of antiestrogenic therapies with even moderate exposures. Fructose is the
sugar tumors prefer. They grow faster when exposed to fructose. For the protocol, just assume
Bisphenol-A is present in all plastic and metal and aluminum food and beverage containers and on all
thermal receipts and duplicate checks and in most hand lotions(unless it says bpa free) and abstain from
exposure to these things. Also, for the protocol, simply assume that methylparabens and parabens are
in all shampoos/cosmetics and hair conditioner agents and gel based under arm deodorants unless the
bottle states otherwise.

Niclosamide: Niclosamide will probably be added to the protocol and its effects are quite complex
and really beneficial, but need more information on it relating to serum levels without modifying it
with phosphate to improve bioavailability. There is some data that implies the effects of niclosamide
are achievable at nanomolar concentrations and with a 2 gram oral dose of the nonphosphate modified
drug , one can achieve micromolar concentrations. If that is the case in humans then adding it to the
protocol is a simple choice because of the effects on STAT-3 and other signaling systems.
If it turns out that the phosphate modified niclosamide molecule is needed to improve bioavailability to
achieve the desired effects then clinical availability becomes a problem because then one needs a
pharmaceutical lab to make the stuff.

Lipoic acid and luteolin: These inhibit IL4 and IL13 . These two interleukins cause a lot of
problems in solid tumor hosts.
Still thinking about what dose to use..(dose for lipoic acid would be 600mg bid?) and if use lipoic acid
then need to include a b-complex vitamin .

Refs
http://clincancerres.aacrjournals.org/content/17/7/1645/T1.expansion.html nice list of agents and
mechanisms for interfering with MDSCs
http://www.ncbi.nlm.nih.gov/pubmed/23424024 beta glucan effect on MDSC-- it drastically
downregulated MDSCs
http://www.jimmunol.org/content/192/1_Supplement/138.32 beta glucan modulates MDSCs
http://www.bloodjournal.org/content/117/25/6825?sso-checked=1 discusses beta glucan effect on
immune system esp particulate beta glucan
http://ajcn.nutrition.org/content/80/1/154.full selenium effect on immune system in polio ---it does
similar things in hiv ----suspect same thing in cancer.
http://www.ncbi.nlm.nih.gov/pubmed/9558729 selenium and immune function
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701882/ good one on MDSCs

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2810085/ discusses amiloride effect on MDSC

http://www.ncbi.nlm.nih.gov/pubmed/7638244 selenium restores age related immune cell function
--fyi it increases Il2 receptors.

http://www.ncbi.nlm.nih.gov/pubmed/23220070 cimetidine kills MDSCs via caspase related death

so that is why minocycline is gonna be episodic
http://www.ncbi.nlm.nih.gov/pubmed/22546994 nice one on regulation of MDSC death also points
to why need minocycline in some form to inhibit P38 Mapk system.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109712/ shows the retaliatory relationship between

MDSCs and activated T-cells--- ie MDSCs inhibit t-cell activation , but once activated, t-cells will kill
MDSCs via fas-fasl (recall cimetidine kills MDSCs via upregulation of fas/fasl systems.).....
..so maybe increased MDSC killing with cimetidine and activated T cellsso maybe just periodic
minocycline so as not to interfere with apoptosis.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3696683/ explains how MDSCs use BCL-XL

modulation to downregulate fas to avoid CTL killing efforts--- clever little buggers aren't they.
Wonder if hiv uses something similar. There is an agent to decrease bcl xl --- will have to retrieve the
info.
http://www.ncbi.nlm.nih.gov/pubmed/23017139 PGE 2 effect on MDSC
http://www.ncbi.nlm.nih.gov/pubmed/24762604 effect of theanine on cox2 inhibition in dendritic cells
it decreased cox2 at transcriptional and translational level. It promoted the secretion of IL-12
http://www.ncbi.nlm.nih.gov/pubmed/12631593 so good to prevent cox 2 in dendritic cells
http://www.ncbi.nlm.nih.gov/pubmed/21344174 theanine as a mast cell stabilizer
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3217352/ PGE2 and COX2 form positive feedback
loop to redirect dendritic cells differentiation to form stable MDSC populations...
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828349/ MDSC as immune system regulators

http://www.ncbi.nlm.nih.gov/pubmed/12907617/ effect of ATRA on MDSCs

http://www.ncbi.nlm.nih.gov/pubmed/19088044 ATRA allows MDSCs to complete their

differentiation process and become assets to the system.
http://www.ncbi.nlm.nih.gov/pubmed/19276286 sunitinib REALLY depletes MDSCs

http://www.ncbi.nlm.nih.gov/pubmed/18927310 sunitinib decreased tregs

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3711234/ effect of sorafenib on MDSCs and tregs

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0060817 discusses
minocycline effect on IL-6-- so we need minocycline cause it does a lot of things to impair the
formation of MDSCs , and IL-6 causes just SO MANY probs in cancer,, BUT it can also impair the
killing of MDSCs because it is antiapoptotic agent so double edge sword. Hence episodic use.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939552/ good one the effects of cox 2 inhibition on

MDSC numbers --- celebrex decreased MDSCs of all subtypes.
http://www.ncbi.nlm.nih.gov/pubmed/23017136 discusses MDSCs
http://www.ncbi.nlm.nih.gov/pubmed/23017135 more on MDSCs functions in cancer
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3519282/ l-arginine metabolism by MDSCs
http://www.ncbi.nlm.nih.gov/pubmed/23017143 MDSC mediated immunosuppression
http://www.ncbi.nlm.nih.gov/pubmed/23017136 immunosuppressive MDSC actions

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701882/ discusses the complex relationship between

MDSCs and T-cells

http://www.ncbi.nlm.nih.gov/pubmed/11313376/ mechanisms of MDSC immune dysfunction

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4019895/ a nice one on the various ways to mess with

MDSCs--- this is a really good article

http://www.ncbi.nlm.nih.gov/pubmed/20388795/ explains how 5 FU kills MDSCs

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3398024/ shows that decreasing MDSC does help

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109226/ good one on MDSC and tumor escape

mechanisms----recall that upto 40 percent of tumor mass can be MDSCs

http://www.ncbi.nlm.nih.gov/pubmed/21568934 another good one on 5-FU

http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0049744 sulfurophane
inhibits PGE2 production in MDSCs--- look what it did to microsomal prostaglandin E
synthase.....quite remarkable ...esp when consider combining SFN with a cox 2 inhibitor and an
arginase-1 inhibitor...... should be able to really hamper MDSC internal functions.

http://jem.rupress.org/content/203/12/2691 tadalafil acts as arginase-1 inhibitor in MDSCs

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368153/ good one MDSC as a target
http://www.ncbi.nlm.nih.gov/pubmed/10657677/ I think it supports the thinking that weather mets or
not ---got to remove the tumor if at all possible ...it will help impair the tumor driven
immunosubversion recall that cimetidine at 800mg bid will prevent post surgery immunosuppression
and surgery induced TH2 shifting events.
http://www.ncbi.nlm.nih.gov/pubmed/15313928/ discusses arginase-1 functions in immunosubversion
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4032940/ talks about the metabolic aspects of MDSCs
and T cells.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2805057/?report=classic discusses the cysteine
depletion by MDSCs--- might cysteine supplementation help ?

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2646404/ amino bisphosphonates breaks the MDSC

expansion issue by decreasing MM9
http://www.ncbi.nlm.nih.gov/pubmed/17617589/ crosstalk between MDSC and macrophages subvert
the immune system to the TH2 side
http://www.ncbi.nlm.nih.gov/pubmed/15634881 supports the thinking that TH1 system if helpful in
rejecting established metastatic disease
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1774314/ discusses arginine metabolism by liver
citrulline avoids this
http://nutrition.highwire.org/content/137/6/1616S.full a good on citrulline/nos/arginine
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3444824/ discusses citrulline and arginine metabolism
in mycobacteria infections
http://www.ncbi.nlm.nih.gov/pubmed/15343367 explain zeta chain function and importance.

http://www.ncbi.nlm.nih.gov/pubmed/15568289 citrulline can preserve T-cell zeta chains in arginine

depleted states. Basically the t-cells import the citrulline and convert it into arginine using their
arginosuccinate synthase to overcome arginine depleted immune suppression.
Just giving arginine will NOT lead to increased intracellular arginine levels that is why you need to
give citrulline.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2200807/ discusses the need to revert immune
tolerance in solid tumor