CDiddy and dfw, My understanding is that the tu
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Posted On: 09/03/2020 8:58:10 PM
CDiddy and dfw,
My understanding is that the tumor cells needs to have significant expression of CCR5 for inclusion in the trial. I believe that most cancers release CCL5 to traffic/attract tumor associated macrophages support the tumor microenvironment (still looking for a definitive answer) but that this is a separate issue from metastasis. Creating a micro environment is “defending the homeland” as opposed to “establishing new colonies”. Similar but not the same.
Cancer cells release CCL5/RANTES attracting macrophages, which are polarized into a pro-inflammatory/tumor supporting state and co-opted to facilitate angiogenesis necessary to support tumor growth. This helps maintain a favorable tumor micro environment and evade destruction by macrophages and natural killer cells as well as providing the necessary nutrient and oxygen for a growing tumor.
However, cancer cells successfully metastasize through over-expressions of CCR5 (RANTES/CCL5 receptor). This over expression (a requirement for inclusion in the basket trial), enhance tumor cell migration and reduces apoptosis (programmed cell death in damaged/malignant cells). The highly CCR5 expressing cancer cells have an increased directional migratory ability which allows them to penetrate surrounding tissue, rather than remaining in the original tumor (this aggressive/invasive tumor characterization).
It is interesting and frightening that cancer cells use both parts of this pathway to their advantage.
Good news (again!) that leronlimab addresses both issues by blocking CCR5 on the enabling macrophages (tumor associated macrophages) as well as on the tumor cells, inhibiting their ability to migrate/metastasize and avoid their just death (apropos) as well as their ability to turn tumor fighting macrophages into the tumor associated macrophages.
Here is an article referencing metastasis and CCR5 blocking in glioblastoma, a typically deviating brain cancer.
The discussion indicates that CCR5 inhibition (leronlimab), by interrupting macrophage depolarization, may likely have anti tumor properties, even in the absence of high tumor CCR5 expression.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC...n_sectitle
This research is very well written, but obviously over the heads of most of us (I’ll keep chipping away at it. Very compelling reading).
I hope this helps.
I will try to clarify as best I am able, with the help of our many talented colleagues here.
My understanding is that the tumor cells needs to have significant expression of CCR5 for inclusion in the trial. I believe that most cancers release CCL5 to traffic/attract tumor associated macrophages support the tumor microenvironment (still looking for a definitive answer) but that this is a separate issue from metastasis. Creating a micro environment is “defending the homeland” as opposed to “establishing new colonies”. Similar but not the same.
Cancer cells release CCL5/RANTES attracting macrophages, which are polarized into a pro-inflammatory/tumor supporting state and co-opted to facilitate angiogenesis necessary to support tumor growth. This helps maintain a favorable tumor micro environment and evade destruction by macrophages and natural killer cells as well as providing the necessary nutrient and oxygen for a growing tumor.
However, cancer cells successfully metastasize through over-expressions of CCR5 (RANTES/CCL5 receptor). This over expression (a requirement for inclusion in the basket trial), enhance tumor cell migration and reduces apoptosis (programmed cell death in damaged/malignant cells). The highly CCR5 expressing cancer cells have an increased directional migratory ability which allows them to penetrate surrounding tissue, rather than remaining in the original tumor (this aggressive/invasive tumor characterization).
It is interesting and frightening that cancer cells use both parts of this pathway to their advantage.
Good news (again!) that leronlimab addresses both issues by blocking CCR5 on the enabling macrophages (tumor associated macrophages) as well as on the tumor cells, inhibiting their ability to migrate/metastasize and avoid their just death (apropos) as well as their ability to turn tumor fighting macrophages into the tumor associated macrophages.
Here is an article referencing metastasis and CCR5 blocking in glioblastoma, a typically deviating brain cancer.
The discussion indicates that CCR5 inhibition (leronlimab), by interrupting macrophage depolarization, may likely have anti tumor properties, even in the absence of high tumor CCR5 expression.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC...n_sectitle
This research is very well written, but obviously over the heads of most of us (I’ll keep chipping away at it. Very compelling reading).
I hope this helps.
I will try to clarify as best I am able, with the help of our many talented colleagues here.
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