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.
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)
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.
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
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.
Diagnosed 11 May 2011 (100% FiSH, 155% PCR)
with b2a2 BCR-ABL fusion transcript coding for the 210kDa BCR-ABL protein
Sprycel: 20 mg per day - taken at lights out with Quercetin and/or Magnesium Taurate
6-8 grams Curcumin C3 complex.
2015 PCR: < 0.01% (M.D. Anderson scale)
2016 PCR: < 0.01% (M.D. Anderson scale)
March 2017 PCR: 0.01% (M.D. Anderson scale)
June 2017 PCR: "undetected"
September 2017 PCR: "undetected"