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Two Chemo Agents May Thwart Immune Response to Cancer THIS COULD BE THE ONE

pete43lost_at_sea's picture
pete43lost_at_sea
Posts: 3915
Joined: Nov 2010

http://www.cancernetwork.com/gastrointestinal-cancer/content/article/10165/2117999

the good bit below, I will email this to me oncologist and immunologist. we live in exciting times.

Chronic inflammation has been previously linked to cancer initiation and progression, including over-activation of IL-1β. The differences in the response of the immune system to different chemotherapies may have to do with the mechanism of the therapy. The authors cite previous studies which show another type of chemotherapy, anthracycline, can facilitate an anticancer immune response through activation of acute inflammation and immunogenic cell death, a specific type of tumor cell death that results in an immune response.
An increase in IL-1β has also been shown in colorectal patients treated with 5-fluorouracil, according to the authors. This hints that combining inhibitors of either the inflammasome or IL-1β with either gemcitabine or 5-fluorouracil could enhance the antitumor effect. “The inhibition of this pathway could be useful to enhance the efficacy of this [chemotherapy],” said Ghiringhelli.
A phase I trial to show if an inhibitor of IL-1β can reverse the resistance to 5-fluorouracil in patients with metastatic colon cancer is currently ongoing. “That an IL-1β antagonist, already used in clinical practice, may improve the effects of existing chemotherapy regimens by reducing the immune suppression detected in this work, is compelling but depends on further experiments using drugs like 5-fluorouracil in situations as they are used in patients,” said Weber.

Lovekitties's picture
Lovekitties
Posts: 2900
Joined: Jan 2010

I could not get to the article you cited via the link you gave without signing up on that site.

I did however do a search on some of the text you gave and got to it.

Here it is for those who don't want to sign up to the cancer network site:

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Two Chemo Agents May Thwart Immune Response to Cancer

By Anna Azvolinsky, PhD1 | December 5, 2012

1Freelance Science Writer and CancerNetwork Contributor. Follow Her on Twitter

A new study shows two chemotherapy drugs prevalent in the clinic—gemcitabine and 5-fluorouracil—influence the immune response in a way that facilitates tumor growth. The research, conducted in mice, is published in Nature Medicine.

Chemical structure of gemcitabine(Drug information on gemcitabine)

François Ghiringhelli, MD, PhD, and Lionel Apetoh, PhD, of the Institut National de la Santé et de la Recherche Médicale and Centre Georges-François Leclerc in Dijon, France, and colleagues have uncovered a novel mechanism by which two chemotherapy agents activate the NLRP3 inflammasome complex within myeloid-derived suppressor cells that results in production of the cytokine interleukin (IL)-1β. This was shown by the study researchers to prevent a robust immune response against the tumor.

The experiments also showed that higher IL-1β levels led to secretion of another cytokine, IL-17, a pro-inflammatory cytokine, by CD4+ T-cells. The presence of IL-17 limited the antitumor effect of 5-fluorouracil and enhanced growth of mouse tumors. IL-17 has previously been shown to promote cancer growth and tumor progression.

“These results unravel the ambivalent effect of gemcitabine and 5-fluorouracil in the antitumor immune response,” conclude the authors in the publication.

According to Jeff Weber, MD, PhD, of the Moffitt Cancer Center in Tampa, Florida, while this study is well done and highlights the complexity of the potential counteracting effects of frequently used chemotherapy, there are also limitations. The study focused more on 5-fluorouracil than gemcitabine, and there is only modest human evidence that confirms the hypothesis.

A concern about the clinical application of this research, according to Weber, is that 5-fluorouracil is given in along with leucovorin, which enhances the activity of the chemotherapy, and is often given in combination with bevacizumab(Drug information on bevacizumab) and oxaliplatin(Drug information on oxaliplatin), which “may counteract some of the immune suppressive mechanism noted in [the study],” said Weber.

Whether chemotherapy promotes or prevents the patient’s immune system from acting on his or her cancer is a subject for debate. There has been recent evidence showing chemotherapy can systemically facilitate immunosuppression. However, there is also evidence that certain chemotherapies enhance an antitumor response by the immune system. The challenge, said Ghiringhelli, is to dissect the immune effect of different drugs in order to design better combinations to enhance the immune response.

Weber agrees. “Further studies are necessary, including expanding work with gemcitabine, to further understand the clinical implications of this outstanding work.” Because there is evidence that certain chemotherapies have a positive effect on a patient’s immunity, understanding which treatments and under which circumstances is crucial.

As a gastrointestinal cancer specialist, Ghiringhelli sought to understand the effect of these two chemotherapies, which are effective but never lead to a cure for patients. 5-fluorouracil in particular is often used to treat metastatic colon cancer. “We believe that it is important to determine the effect of this treatment on the immune system, and if it could be combined with immunotherapy to enhance its effect,” said Ghiringhelli.

The new study suggests ways to bypass the protumor growth activity of gemcitabine and 5-fluorouracil. Mice in the study that did not express integral factors of the inflammasome complex, either NLRP3 or CASP1, had a more robust antitumor effect following treatment with either chemotherapy. While the wild-type mice treated with chemotherapy died by day 30 post-treatment, 30% to 42% of the mutant mice were alive and tumor free at day 60 post-treatment. A recombinant IL-1 antagonist also enhanced the antitumor response to either chemotherapy agent in mice.

According to Ghiringhelli, this new mechanism is dependent on the type of chemotherapy, suggesting that those “that target thymidylate synthetase could mediate this effect.” 5-fluorouracil is an antimetabolite that inhibits the thymidylate synthetase required for DNA synthesis.

Chronic inflammation has been previously linked to cancer initiation and progression, including over-activation of IL-1β. The differences in the response of the immune system to different chemotherapies may have to do with the mechanism of the therapy. The authors cite previous studies which show another type of chemotherapy, anthracycline, can facilitate an anticancer immune response through activation of acute inflammation and immunogenic cell death, a specific type of tumor cell death that results in an immune response.

An increase in IL-1β has also been shown in colorectal patients treated with 5-fluorouracil, according to the authors. This hints that combining inhibitors of either the inflammasome or IL-1β with either gemcitabine or 5-fluorouracil could enhance the antitumor effect. “The inhibition of this pathway could be useful to enhance the efficacy of this [chemotherapy],” said Ghiringhelli.

A phase I trial to show if an inhibitor of IL-1β can reverse the resistance to 5-fluorouracil in patients with metastatic colon cancer is currently ongoing. “That an IL-1β antagonist, already used in clinical practice, may improve the effects of existing chemotherapy regimens by reducing the immune suppression detected in this work, is compelling but depends on further experiments using drugs like 5-fluorouracil in situations as they are used in patients,” said Weber

pete43lost_at_sea's picture
pete43lost_at_sea
Posts: 3915
Joined: Nov 2010

Dear Marie,

thanks for the reply, always at least one, it takes time and care to share these important and relevant discoveries.

I did not realise I had even joined that site, i just get the emails and this one looked pretty relevant to me and I have a few friends at the clinic , colorectals that will benefit as they are on low xeloda. I suspect they will try this line of therapy, they are risk takers like me.

I have emailed my oncologist and immunologist at the german clinic, If I need systemic avastin/5fu i think the IL-1β antagonist would likely play an important role.

It could be something this simple that could add years of quality to our lives, if we can use our immune system wisely and minimise the side effects.

I wonder why so few replies, I guess its just where everyones interest lies in different areas, possibly the short term emotional and physical issues of cancer. I am so excited by
this research, I know it will help some of my more adenturous colorectal friends within a few weeks is the real chance they will be trying this. so yes its just mice in the study, but like how similar we are. my current health I owe to mouse and rat antibodies.

Its a discovery like this that offers the potential to turn metastatic crc into a chronic long term managable illness rather than what it is currently.

if my vaccine and antibody therapies need some help, avastin/5fu will be my first line and of course I will test the antagonist. I love running my own personal clinical trials.

stopping the inflamatory cascade is the secret here. better care options exist beyond conventional but they are risky and take time and effort and money with no guarantees.

hugs and thanks,
Pete

ps since my removab I have developed a love of cheese!

Lovekitties's picture
Lovekitties
Posts: 2900
Joined: Jan 2010

I think there are possibly a couple of 'innocent' reasons why some of your posts get limited replies.

First, some of this stuff is in language that mostly doctors would understand. I know a lot of it is way over my head.

Second, there are few if any of us who have the financial capability of trying anything which is not approved by the FDA and the dratted insurance companies. While this and other things you put forth may be medically cutting edge, it is out of our reach.

So don't be discouraged by the amount of response. Most just don't know what to say.

Hugs,

Marie who loves kitties

Sundanceh's picture
Sundanceh
Posts: 4266
Joined: Jun 2009

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pete43lost_at_sea's picture
pete43lost_at_sea
Posts: 3915
Joined: Nov 2010

i am just having a winge.
empathy and understanding of where many of our friends here are at is something i struggle with as I have adapted to this illness in my own way.

one day we will have a cure, I suspect its already here and we just don't know it.

my mission is remission. the next few months are critical if my hypothesis and gamble pays off.

then I will have a workable cure based on chemo free removab and dendritic cells and some other supportive bits and pieces.

I have got friends like you and craig, and a few others, how many friends do we need, its even overwhelming to keep track of peoples stories here.

so i am now encouraged and not discouraged
thank you for your kind reply.

hugs,
Pete

dmj101's picture
dmj101
Posts: 521
Joined: Nov 2011

Pete I always follow your threads mostly as a lurker.
As Marie states most of us probably don't have access to these meds.
I know I always ask my dr about what you and others write about.. My doc's response is "you aren't that sick,,,, yet" that always make me cry abit inside. though it is offered as a blessing. Your posts to me are knowledge that there is hope out there and that someone is searching for the cure..
I like you do believe the cure is out there... we just don't know of it.
I have a feelling I a 5fu resistant but the dr won't discuss it when I ask... she tells me it is very rare.. I have only seen changes in my blood work and scans since it was stopped.
Good Luck Buddy!

pete43lost_at_sea's picture
pete43lost_at_sea
Posts: 3915
Joined: Nov 2010

its great your not that sick!

lurk away, its just nice to know someone reads these little posts.
I guess asking onc's is a starting, heck one day they might say, what a great idea lets do.

hugs,
Pete

steved
Posts: 836
Joined: Apr 2004

Thanks for this as does turn some of my understanding of drugs like xeloda on its head. However, it is very early in its development as a hypothesis that translates into clinically useful interventions. There is no evidence in humans yet that this is helpful and not on the mixed regimes eg xeloda and avastin that many of us use. I wouldn't be jumping on this as something to do yet but more something to follow as the research develops. If you jump on every band wagon that makes it to phase one trial then you will be taking a lot of unknown drugs the vast majority of which will prove unhelpful as they progress into more sophisticated and targeted trials. You also take a lot of risks around how little is know regarding the possible harmful effects of these drugs that are so early n their development.

I think that is probably the reason for the limited response to posts like this- there are so many new development and hypotheses that arise in our cancer world but so few that make it to being clinically proven and useful and so people struggle with the false hope that arises from the and the frustration with how long they take to progress through juicing through all the hoops drugs need to jump through before they can be used clinically.

I personall y really enjoy these posts (colocan is a great source of updates like this) as i don't find the time to trawl the literature myself. So thanks for posting this and feel free to ignore my cautious pessimismpete as I know you are a risk taker in this field. Keep sending the info you receive our way.

Steve

smokeyjoe
Posts: 1428
Joined: Feb 2011

Thanks for posting Pete :) Interesting.

coloCan
Posts: 1842
Joined: Oct 2009

for nontechnical explanations of current research,such as:medicalnewstoday.com
ecancer.org (which, i think,originates in England and has this version of Pete's article:ecancer.org/news/3613)
sciencecodex.com
eurekalert.org
healthcanal.com

You'll find that eventually they all cover the same items,usually.....

and here's one truly technical site that is worth exploring:plosone.org (as in Public Library of Science.....check out stuff on KRAS,for instance)

There is so much published on a daily basis coming from all over the world......just this week was news about mistletoe from Austraila,(tho Isreal reported on this over a year ago)resveratol,rice bran, "The Synergistic Effects of Combined Wnt/KRAS Inhibition in CRC Cells"-this one is sort of writing you find in plos,real technical!!!!)a potential cancer fighter in a fungus;a breath test to determine CRC;all sorts of stuff, if you're into this sort of stuff....there are always trials going on as well....

and healthday.com
today has an article:"Chemo Brain May Occur Before Treatment Even Starts"......

for those keeping track, "chemo Brain" as a consequence of Tx was not acknowledged until relatively recently.....perhaps if more researchers experienced chemo there will no longer be any doubt about the existence of "chemo brain"....Like my body,my mind has never been the same and never will be.......steve

pete43lost_at_sea's picture
pete43lost_at_sea
Posts: 3915
Joined: Nov 2010

you seem pretty smart, then you must have started out as a true genius.

good point about our bodies not being the same, heck i am just grateful to be able to use a loo in the old fashioned way again.

the challenges of life either make us stronger or weaker, hopefully we all get better with age like the fresh young dry red wine i enjoyed tonight. it got better as it went down my throat.

as i am overloaded with these crazy treatments and reading 5 books at once and documenting my experience on my blog, i am so grateful you are the unoffical research officer for our community.

as this piece jumped out at me, my friend on low dose xeloda/avastin has a few mets starting to grow. i bet its immune dysfunction, he is at the clinic now and I reckon they may try this. this issue was raised a while back but it timing is whats important to me, now i am at the immune capital of the universe, well my universe anyway.

a sincere thanks for all the great research. you are the researcher and i am the tester!
not a bad combination.

hugs,
Pete

pete43lost_at_sea's picture
pete43lost_at_sea
Posts: 3915
Joined: Nov 2010

clinical trials have good and bad points, lets not go there any time soon.

my enthusian for the antagonist is that i am studying my butt off with regard to moDC and how we can tune them in culture depending on our cd4/cd8 ratios and the various cytokines.
its an existing drug, this is just another off label use.
i have been there done that, some of my friends are likely heading down that path.

i am waiting on an answers from research scientist and some very capable adventurous doctors.

I will keep sending. thanks for replying. did you get any tumour frozen ? as an aside, it might be useful for a vaccine ? just an idea that popped into my head. as i get me crc vaccine shot monday, i cannot wait. see the othe rpost if interested.

hugs,
Pete

tanstaafl's picture
tanstaafl
Posts: 946
Joined: Oct 2010

We do try to keep inflammation, measured with the hoary old blood test, ESR aka Erythrocyte Sedimentation Rate, under control. Partly with the IV vitamin C and oral boswellia, as well as the various natural antioxidants / COX2 inhibitors recommended by LEF. Partly by removing sources of inflammation - dental, or reducing some supplements that stress the liver, like Agaricus blazei.

pete43lost_at_sea's picture
pete43lost_at_sea
Posts: 3915
Joined: Nov 2010

Did you know frankescence aka boswellia crossed blood brain barrier.
My head is full of odd opinions, that one from Dr Nestlehut, he had a brain tumour remission before DC just using boswellia. These are only herbs and spices, but they save lives. I am very glad your here.
Hugs,
Pete
Ps the Ers stuff interesting, does not the off label 5fu antagonist do more than Esr, you are on 5fu I think.
The piano has started and the glass of dry red is working again. I have started the ketogenic diet for real.

k44454445's picture
k44454445
Posts: 494
Joined: Jul 2012

hope things are going great for you. please keep on posting. i read your posts because you have new info & your posts have good medical terminology. i do have to say you keep me busy on google, but i enjoy it!
hugs from indiana to germany
judy

pete43lost_at_sea's picture
pete43lost_at_sea
Posts: 3915
Joined: Nov 2010

your so sweet.

hugs from duderstadt to indiana
pete

pete43lost_at_sea's picture
pete43lost_at_sea
Posts: 3915
Joined: Nov 2010

just started searching and exploring to find the drug and see how feasible off label use is.

I am researching what complementary therapies can minimise the negatives of 5fu. off course i want a fully engaged immune system as my vaccine program is being run in parallel with starting xeloda and avastin.

if anyone has info or interest in this post here or pm me, i want the info to present to my sydney based oncologists on the 15th.

ideally i will have the drug by then, i am supposed to start low dose xeloda and a dash of avastin on the 15th for a few weeks before returning to germany on the 4th feb.

http://www.ncbi.nlm.nih.gov/pubmed/17947302

http://www.ncbi.nlm.nih.gov/pubmed/20844880

http://www.ncbi.nlm.nih.gov/pubmed/21723691

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3437608/  this one is really educational

of course the aussie onc are stuck with clinical standards, stuff that sorry.

the german onc will also have some ideas, but i am just trying to be a pain in the ass for all the doctors that care for me.

i have heard about the trial for colorectal in this area, but i have not found any details yet.

hugs,

Pete

ps check with your medical team before taking anything. we each have a different definition of medical team.

smokeyjoe
Posts: 1428
Joined: Feb 2011

Pete   I've been wondering....have you had scans recently???   Maybe you already posted this (I've been having a hard time getting logged on to this board so I may have missed it)  

pete43lost_at_sea's picture
pete43lost_at_sea
Posts: 3915
Joined: Nov 2010

i hope you are doing well

still waiting on german pet scan report on 14dec.

the mri 14dec showed some enlargement lymph nodes.these were treatd same day chemo embolisation. i feel great and enjoying life with family and am back to germany february for more treatments.

hugs,,

pete

KathiM's picture
KathiM
Posts: 7874
Joined: Aug 2005

It's just a short train ride away....keep me posted...maybe I could come and visit...

Hugs, Kathi

pete43lost_at_sea's picture
pete43lost_at_sea
Posts: 3915
Joined: Nov 2010

i will keep you posted, and pm my email and phone.

hugs,

pete

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