The perplexing and intricate secret formula for control of nsclc
The latest results from START if nothing else confirm what an ultimate detective story figuring out the complexities of finding how to control nsclc is. Theories abide, clues abide...but the mystery is still not solved. Here, a smart guy gives his theory as to the possible why of the extreme differences in survival the s-CRT vs. c-CRT arms had in the trial.
From Dr. Rick (scaram(o)uche from silicone investor MB) (pretty smart guy but his own words, “I haven't been near a lab since the mid-90s. I should be considered as a well-informed layman”)
“I would love for Red to be correct (tip of iceberg, benefit of cancer patients) and thus I've modeled that sCRT-Treg > cCRT-Treg, and that immunization of sCRT patients leads to profound tolerance. The effects of focal radiation on the induction of profound regional tolerance are well known.”
nature.com
Chemoradiotherapy can Induce Alterations in Immune Regulatory Cells
In addition to the direct radiation-induced genetic damage and enhanced cross-presentation of tumor antigens, radiation can also affect immune regulatory circuits. There is evidence for radiation-induced modulation of effector versus CD4+CD25+ Tregs ratios,23 and this may have protracted and profound effects on the composition and function of T-cell populations. The mechanism behind this is unknown, but may involve a differential sensitivity of these T-cell subsets to radiation-induced reactive oxygen species (ROS). This view is compatible with our observation that Tregs are more resistant to ROS-induced cell death as compared with T effectors, and Tregs maintain their suppressive function under conditions of high oxidative stress including radiation exposure.24 The molecular mechanism behind this resistance of Tregs to oxidative stress may be related to the finding that human Tregs express and secrete higher levels of thioredoxin-1, a major antioxidative molecule.25 Radiation-induced immune suppression could therefore, at least in part, be explained by preferential induction of apoptosis in T-effector cells by ROS and sparing of Tregs through a thioredoxin-dependent mechanism.
plosone.org
This may have resulted from direct radiation-induced genetic damage as well as to generation of an imbalance in T reg vs. T effector populations. Indeed, except for a single report which indicated an increase in putative T regs (CD4+CD25+) cells in individuals exposed to irradiation at Chernobyl [7], the function of regulatory T cells has not been examined in survivors of ionizing radiation. Preferential survival of Tregs relative to T effectors following sublethal ? irradiation could have profound effects on the composition and function of T cell populations for a prolonged time after exposure [8], [9], [10]. It is interesting to note that T regs also accumulate in aged humans [11] and mice [12] and that this has been associated with generalized impaired immune function [10]. Indeed, the alterations in T cell populations observed in victims of ionizing radiation exposure, including increased memory and T reg subsets, have been described as similar to the effects of aging [13], [1]. Thus, selective inhibition or depletion of adaptive T regs could potentially address the immunologic lesions observed both in aging and following ? radiation exposure.
There are several points Dr. Rick brings up in his thesis as to why s-CRT vs. c-CRT survival differed so much in START.
His thesis if I understand him correctly is that radiation given alone some 50 days after chemotherapy has started (ie s-CRT) leaves the patient with a weakened immune system with a high ratio of cells from the immune system which lesson the immune response to an antigen or non-self like cancer (ie T-reg cells) as compared to T killer cells (the cells which attack the cancer.
Whereas, in the case where Chemotherapy and radiotherapy are done at the same time (c-CRT) the ratio of suppressors to killers is less....there are more good cells to kill the cancer which are activated by the l-blp-25 vaccine.
As a layman, myself, why does the same radiation dose given with chemotherapy not suppress the immune response as it does when chemo is given followed by radiation?
Lower tumor burden is established. Timing seems to be critical. The secret formula to fighting nsclc is indeed intricate and hard to solve. |
