14 replies to this topic

[mdszj]

Hi all

 

I just ran across this new article on a treatment for ALL, using chimeric antigen receptor (CAR) T cells.  The article says that a third of the patients had Philadelphia + chromosome and T315i mutation.  A lot of the article (ok, most of it) is a little over my head, maybe Trey or someone else can interpret it more clearly and see if it may be applicable to some of the folks here.  But seems worth posting here.

 

http://www.cancerthe...=NTYwMDE0NzE3S0

 

[Trey]

The CAR T-cell research is very interesting.  The theory is to take a patient's own T-cells out, re-engineer them to make them see leukemic cells as "enemy", and reinsert them to destroy the leukemic cells.  The re-engineering of our own immune T-cells to attack specific cells is showing promise.  It is definitiely on the list of potential ways to cure CML some day, but not today. 

 

The recent research has demonstrated on a very small scale that re-engineered CAR T-cells can attack and kill some types of Ph+ ALL cells (the T315i issue is irrelevant because T315i is just a kinase mutation that can block TKI drugs from working, but it cannot protect the entire leukemic cell from destruction).  So far this CAR T-cell technology is under the category of "very interesting".

 

http://www.ascopost....-lymphomas.aspx

 

MD Anderson is teaming with pharma companies to work on the issue:

http://www.mdanderso...car-t-pact.html

 

Cancer centers engaged in CAR T clinical trials:

http://www.cancerres...ancers/leukemia

Edited by Trey, 01 June 2015 - 06:04 PM.

[scuba]

The article describes genetically engineered T-cells to specifically target Leukemia cells that exhibit cell surface proteins unique to the tumor cells. What is impressive is that these engineered cells survive with memory in the same way that our normal immune system would remember if you had the mumps or measles (or had the vaccine which does the same thing). So that if the Leukemia flares up again (in an analogous way cold sores/herpes outbreaks)  - the T-cells are armed and ready. This is the essence of our immune system in action. 

 

Dr. Carl June of Penn State pioneered this research more than 5 years ago and breakthroughs continue as others are applying these techniques:

 

http://www.uphs.upen...2014/10/ctl019/

 

I wrote Dr. June several years ago and inquired about T-cell immunotherapy for CML and he wrote back that CML has excellent treatment protocols with very high success. There are Leukemias, he mentioned (such as the ones cited in the article) for which prognosis is poor and he felt needed efforts directed there first. It was a very understanding response. 

 

But some day - there may be a T-cell immunotherapy developed for CML which may eliminate the need for toxic TKI's. It will just have to wait until the others are solved first.

 

(one side note. The speed by which these cells attack the cancer cells so that for all practical purposes the cancer is eradicated is measured in weeks. Pounds of tumor can be destroyed by these cells in that time. It is not unlike what happens when you get sick with the flu. The flu virus replicates to sickness levels and then your immune system, if functioning properly, replicates the T-Cells armed with the flu virus antigen, and then attacks the flu virus. It's a race between virus replication and T-cell replication and virus destruction. It takes about two weeks. The same time as it turns out, that researchers are reporting for T-cell immunotherapy to work. How much more powerful our immune system can be to control a replicating disease (like Cancer) when armed with the right antigen. So many proteins - all unique. It's amazing truly)

[TeddyB]

I wrote Dr. June several years ago and inquired about T-cell immunotherapy for CML and he wrote back that CML has excellent treatment protocols with very high success. There are Leukemias, he mentioned (such as the ones cited in the article) for which prognosis is poor and he felt needed efforts directed there first. It was a very understanding response. 

 

I agree, but what about CML in blast phase, not much success in treatment there, except for stem cell transplants.

Wouldnt CML patients in blast phase potentially benifit from CAR T-cell treatment if it was developed for them?

[scuba]

I agree, but what about CML in blast phase, not much success in treatment there, except for stem cell transplants.

Wouldnt CML patients in blast phase potentially benifit from CAR T-cell treatment if it was developed for them?

 

CML blast phase patients could potentially benefit from CAR T-cell treatment. i suspect the question is how many patients are in this category compared to the other Leukemias Penn State and others are trying to address. 

[Trey]

Just to be clear, CAR T does not work for CML at all right now.  It works for some types of leukemias (a few types of CLL and B-Cell ALL) which start at much lower levels in the stem cell hierarchy.  Because CML starts so high in the stem cell hierarchy, it is much harder to use this type of approach.  Although it is possible it may some day be useful for CML, after much more research and many more advances in the technology, speculating that it will work for blast phase patients is way beyond what is knowable right now.

 

But hey, why would we need this CAR T stuff since curcumin does the same thing anyway, right?  Ha ha ha.

[scuba]

Just to be clear, CAR T does not work for CML at all right now.  It works for some types of leukemias (a few types of CLL and B-Cell ALL) which start at much lower levels in the stem cell hierarchy.  Because CML starts so high in the stem cell hierarchy, it is much harder to use this type of approach.  Although it is possible it may some day be useful for CML, after much more research and many more advances in the technology, speculating that it will work for blast phase patients is way beyond what is knowable right now.

 

But hey, why would we need this CAR T stuff since curcumin does the same thing anyway, right?  Ha ha ha.

 

Just to be clear, in conversation with Dr. Carl June, an expert in CAR T technology, he specifically cited CML as a viable target. Leukemic initiating cells occur lower in the stem cell hierarchy and express antigens which could be targeted. It's the proliferating non-differentiating cells you want to reduce. The only reason they have not pursued CML is because CML already has very effective therapies, blast crisis notwithstanding.

 

And regarding Curcumin:

 

http://www.celldiv.com/content/3/1/14

 

http://www.nature.co...cmi201011a.html

 

http://mcr.aacrjourn...nt/4/7/457.long

 

Cancer, Trey, is a failure of the immune system either genetic inherited or environmentally induced. For genetic failures, immunotherapy is quite promising since the patient's own T-cells need to be modified.

 

For environmental failures where the immune system has been weakened in some manner so cancer cells are able to proliferate unchecked (including Leukemia) efforts at improving the immune system using natural anti-oxidant phytochemicals of which Curcumin is one may prove therapeutic. There is a TON of research (two above) pointing in this direction. You choose to ignore it or laugh at it because it doesn't fit your paradigm. Curcumin is not a cure - and neither are TKI's. TKI's can and do damage to the body especially affecting the heart. Curcumin is natural. TKI's are not. We don't know what the long term effects of TKI's will be. And data is beginning to emerge on the increasing risks of the second generation TKI's. 

 

It is important to note that I have never said Curcumin is a cure - ever. But Curcumin along with other agents (yes - vitamin D) just might restore sufficient T-cell performance to help keep CML in check - naturally. It also can help augment TKI's performance so that less of the drug may be needed to get a very deep response. Or no drug at all once the response is sufficiently deep and prolonged.

 

http://www.ncbi.nlm....pubmed/21774804

 

And it's safe.

 

So laugh all you want - I continue to take Curcumin in higher than normal dose - have been for years. I achieved MMR/PCRU while only taking 20mg Sprycel and Curcumin together. And now I am completely off Sprycel since February and remain PCRU (next test in two weeks) using myself to test my approach. It was interesting that while taking only Curcumin during my many drug breaks early in my treatment - there was no expansion while off Sprycel - NONE. PCR/FISH remained the same. And to my oncologists surprise, when I was finally able to resume a low dose of Sprycel (20mg), my PCR plummeted dramatically to MMR while avoiding severe myelosuppression.

 

Is the Curcumin helping - I believe it is. But without detailed, large population double blind studies repeated in more than one lab then verified and approved by the FDA we'll never know. Because there is no money to be made with natural substances in expensive FDA approved trials. Trials are rarely multi-component. They test one drug and measure response at a time. Perhaps combinations of things are needed. Only Ph.D. research done for the sake of science alone (see above references) gives a hint at Curcumin's effectiveness.

 

In a later post in a new thread I will document the many different T-cells, their function (especially both their proliferative and anti-proliferative function) and the difference between down regulating cell pathways and inhibiting cell pathways and impact on neoplasms. 

 

(*note: I did have some heart artifacts (Qt responses) that my Cardiologist said was minor. That too went away after stopping Sprycel.)

[Gail's]

Scuba, I had a question regarding recurrence of cml after TKI cessation. Is it possible that the downstream leukemia wbcs have a protective effect on the higher order stem cells? If I understand correctly, even at pcru there are still leukemia wbcs circulating and I wondered about the possibility of a supporting role. I, too, believe that all cancers have a strong connection to a weakened immune response since we're bombarded daily with carcinogens. Problem is that no matter how healthy we try to be, so many factors can lower our immune response and allow the cancer to grow.

[scuba]

Scuba, I had a question regarding recurrence of cml after TKI cessation. Is it possible that the downstream leukemia wbcs have a protective effect on the higher order stem cells? If I understand correctly, even at pcru there are still leukemia wbcs circulating and I wondered about the possibility of a supporting role. I, too, believe that all cancers have a strong connection to a weakened immune response since we're bombarded daily with carcinogens. Problem is that no matter how healthy we try to be, so many factors can lower our immune response and allow the cancer to grow.

Gail,

 

Leukemic stem cells (LSC's) live in their own private world tucked away in special bone marrow niches along with our normal blood stem cells (HSC's)

 

http://www.cell.com/...5909(15)00070-3

 

 

nourished by the extracellular fluids and connected to the Stromal cells. Special proteins called cytokines are produced by cells in our body to signal when LSC's as well as normal HSC's need to divide to produce more cells and differentiate into the different types of blood cells we need. When this occurs, the daughter cells (some are Leukemic initiating cells) are created and some head on out into the blood stream where additional expansion, storage and differentiation occurs (Spleen, Thymus and other locations).

 

Unchecked - the daughter cells of LSC's expand and expand and we have disease. We do know that TKI's seem ineffective against quiescent LSC's. And TKI's do have a difficult time killing all of the daughter cells responsible for CML expansion. I say difficult because it can take many many months before the population of CML circulating cells are diminished to CCyR levels or below.

 

Contrast that with our immune response to a virus such as flu or the Herpes variety. Flu virus expands exponentially at first causing disease. Unchecked - it can kill the host. The immune system replicates special T-cells in unprecedented numbers which ramps up to match the virus - starts outcompeting the virus rate of replication and within a couple of weeks the virus is largely gone. But this does require a healthy immune system. And after the disease burden is reduced and eliminated, you have a lot of angry T-cells hunting for the virus. So new cytokines are released which tells the excess T-cells to self destruct and/or return to patrol in a non-replicating status. It is a marvelous system of checks and balances. Proliferate, don't proliferate, attack or die (apoptosis). It's happening in our bodies all of the time.

 

http://www.niaid.nih...ges/tcells.aspx

 

CML - is left in the proliferate state with no off switch (as all cancers) - but yet, the proliferation is not constant. Remission (even natural remission) does occur. We don't know why. Something to do with these signalling cytokines perhaps or some other yet to be discovered mechanism. Anything that can affect CML rate of growth may enable the immune system to get the upper hand.

 

If a TKI was as effective as T-cells - then we would have PCRU achieved in a few days to weeks. That does not happen. We have to take our TKI's for years and years in some cases to get ahead of the CML population growth rate. Fast responders are measured in months. CML exists because our immune system failed to recognize it - sufficiently - to attack it aggressively. But it may acquire recognition slowly. This is what makes CAR-T immunotherapy so exciting. Instead of a TKI chemical, you would have an engineered T-cell that expands in the body killing cancer cells. And just like a virus getting killed in a few weeks, the same thing happens with CAR-T immunotherapy when attacking leukemia cells. The disease can be gone in a matter of weeks - although maintaining remission is not guranteed

 

(http://www.nejm.org/...22#t=articleTop)

 

 

In the case of CML, in the absence of T-cell immunity, something else is modulating CML expansion - because CML doesn't expand like a flu virus (until very late Blast stage) when first created. This is where all of this signalling comes in from cytokines. After all - leukemic cells just want to get along. They no doubt respond somewhat to the normal signals - just not well and over time, they get the better of the normal system and evolve into something really horrible - blast crisis. TKI's keep this from happening for the most part. 

 

Perhaps long enough so that normal immune function can take over. Clearly - something is keeping CML in check for 40-50% of the people who stop their TKI after achieving deep response. Could it be the cells are just quiescent - just waiting for the right signal to start the disease all over again. No one knows.

 

But to be clear - CML and cancer in general - occurs because of a failure in the immune system. Because like you said, we are bombarded with carcinogens and cancer causing radiation all of the time. Cancer cells are always being created. Our immune system protects us - most of the time. Some of us, either with an inherited genetic flaw or an environmentally induced one have a faulty immune system that allows a cancer not only to get traction, but to grow and metastasize.

 

But keeping your immune system healthy (and that does require vitamin D to be readily available since vitamin D is necessary to activate T-cells) at least helps in the fight. It's no one thing. It's complex largely because it involves so many different kinds of proteins.

[Trey]

Gail,

You asked if the lower level leukemic cells can somehow protect the high level leukemic stem cells.  The answer is "No", they do not protect them.  But they also do not attack them because they are seen as "self". 

[Gail's]

Thanks to both of you. I understand the feedback idea, but not the details obviously. I am trying to understand why LSCs can be targeted to die but not the HSCs. Probably the million $ question, because if you could kill them off, CML would be cured. What I was thinking is that maybe as the LSCs die and spill their guts out, that could be signaling the HSCs to continue or proliferate. Very simple minded thinking I'm sure but just an idea.

[rcase13]

So basically what your saying is the HSCs are profiteering and taking advantage of the poor LSCs...

[scuba]

So basically what your saying is the HSCs are profiteering and taking advantage of the poor LSCs...

 

Not at all. HSC's and LSC's behave similarly and respond to the same cytokines that call for entry into the cell cycle (division and differentiation) and come out of quiescence. It's just that descendent cells of LSC's also have the bcr-abl gene (in the case of CML) which turns on the make more white blood cells without a switch to turn off. Cytokine proteins produced elsewhere in the body which would normally tell these white cells to stop dividing are ignored and the leukemic cells keep proliferating. In addition, the normal white cells 'hear' the screaming message to stop dividing and stop. This is how our normal system gets replaced over time by the leukemic one. It's not a 100% swap out or else we would be in real trouble - just that the population of one set of cells is dominating over another population of cells due to rates of division. Over time, it just gets worse and worse.

 

http://www.ncbi.nlm....oks/NBK215924/ 

 

Tyrosine kinase inhibitors shut down the leukemic white cells, they start to disappear and the normal system starts to re-establish. When LSC's divide, they are vulnerable to TKI's. It's the act of dividing which creates the demand for ATP (energy molecule) and the TKI blocks that. So LSC's do get reduced in numbers by TKI's. The problem is that not all of the LSC's divide. Some stay quiescent. And apparently can stay that way for a very long time. That is how it is believed CML gets restarted and relapse occurs when people who are in deep PCRU remission stop therapy.

 

HSC's and LSC's are similar in function. It's the products of their cell divisions that produce normal cells in one case or cancerous ones in the other.

[Trey]

The higher the level of the cell in the blood making chain, the more "back door" survival mechanisms they have.  Disrupting the BCR-ABL pathway in lower level leukemic cells leads to cell death, but disrupting BCR-ABL in the highest level leukemic cells does not lead to cell death because they are "smarter" and simply use an alternate pathway for survival. 

[Gail's]

Thank you both, Trey and Scuba, for explaining it so I can get it. Is it possible that as LSCs die off, the HSCs go into overdrive due to the lack of their offspring? Thus contributing to continued presence of at least some LSCs. As well as the quiescent cells hanging around. Like a supply/demand system? And that's why many of us must stay on TKIs to keep the cancer in check.

I remember one of you saying that both the HSCs and LSCs are very smart, so we have to be smarter than them. Hope the means to kill off the defective HSCs will be in our future.