Well Ken, after a little research, I think you are absolutely right about the ability of leronlimab to address metastasis in all solid tumors... even in CCR5-negative cancers. And the reason--which is pretty obvious, and yet I missed it totally in our first go-round--is that the drug works on the immune cells themselves, which are mostly CCR5-positive. Independent of the status of the primary tumor.
You know the rest--modifying immune suppression in the tumor microenvironment by blocking the upregulation of myeloid-derived suppressor cells, macrophage polarization from M2 back to tumor-gobbling M1s, and re-energizing exhausted T-cells. And stressing out circulating tumor cells which induces the expression of PD-L1, so that crucial element of leronlimab's MOA will also work in CCR5-negative or low cancers (!).
It gets better--in a paper by the Oregon State gang from 2022 I found this quote: "Indeed, the frequency of CCR5-positive cells change longitudinally in response to inflammatory and homeostatic stimuli..." Google AI got downright poetic about this, stating "CCR5 expression on immune cells is highly dynamic within the tumor microenvironment (TME), generally increasing in response to the inflammatory, hypoxic, and chaotic conditions created by tumor cells to facilitate the recruitment of pro-tumorigenic immune cells."
In a different paper, (Raghavakaimal, with Daniel Adams of CreativBio listed as co-author), they really get into the nitty-gritty of how metastasis happens in the human body:
"Condelis et al. have suggested that mobile tumor cells do not move independently into circulation during metastatic spread, but that the process of CTC movement into the circulatory system is driven by tumor-associated macrophages (TAMs). In their analysis, it was found that motile macrophages bind to tumor cells at primary tumors and the TAMs then move into circulation via transendothelial migration, pulling tumor cells with them. Furthermore, CAMLs have been shown to exhibit pro-angiogenic markers and may act as “soil” cells in metastatic cancer spread. This pro-angiogenic activity of CAMLs enhances the vascularization of tumors and could allow for soil-and-seed CAMLs and CTCs to enhance the spread of aggressive disease."
(Soil-and-seed, prime-and-pair... what alliterations are they going to come up with next? And yes, TAMs are CCR5-positive).
Well Ken, I'd say all of the above makes a compelling case for "leronlimab becoming an adjuvant for all first line treatment vs. aggressive solid-tumor cancers." All-comers is a phrase we'll probably hear more about. You called it--take a bow!
Here's the references:
https://www.frontiersin.org/journals/immunolo...8/full#B23
Short 1st quote (Chang is the lead author, co-authors include Helen Wu, Gabriela Webb, and Jonah Sacha. Describes in detail the development of the Receptor Occupancy assay. Incredibly dense though... Honestly, I just read the abstract, intro, and discussion).
https://pmc.ncbi.nlm.nih.gov/articles/PMC9125938/#Sec14
This is the longer quote about TAMs and metastasis (Raghavakaimal and Daniel Adams)
You know the rest--modifying immune suppression in the tumor microenvironment by blocking the upregulation of myeloid-derived suppressor cells, macrophage polarization from M2 back to tumor-gobbling M1s, and re-energizing exhausted T-cells. And stressing out circulating tumor cells which induces the expression of PD-L1, so that crucial element of leronlimab's MOA will also work in CCR5-negative or low cancers (!).
It gets better--in a paper by the Oregon State gang from 2022 I found this quote: "Indeed, the frequency of CCR5-positive cells change longitudinally in response to inflammatory and homeostatic stimuli..." Google AI got downright poetic about this, stating "CCR5 expression on immune cells is highly dynamic within the tumor microenvironment (TME), generally increasing in response to the inflammatory, hypoxic, and chaotic conditions created by tumor cells to facilitate the recruitment of pro-tumorigenic immune cells."
In a different paper, (Raghavakaimal, with Daniel Adams of CreativBio listed as co-author), they really get into the nitty-gritty of how metastasis happens in the human body:
"Condelis et al. have suggested that mobile tumor cells do not move independently into circulation during metastatic spread, but that the process of CTC movement into the circulatory system is driven by tumor-associated macrophages (TAMs). In their analysis, it was found that motile macrophages bind to tumor cells at primary tumors and the TAMs then move into circulation via transendothelial migration, pulling tumor cells with them. Furthermore, CAMLs have been shown to exhibit pro-angiogenic markers and may act as “soil” cells in metastatic cancer spread. This pro-angiogenic activity of CAMLs enhances the vascularization of tumors and could allow for soil-and-seed CAMLs and CTCs to enhance the spread of aggressive disease."
(Soil-and-seed, prime-and-pair... what alliterations are they going to come up with next? And yes, TAMs are CCR5-positive).
Well Ken, I'd say all of the above makes a compelling case for "leronlimab becoming an adjuvant for all first line treatment vs. aggressive solid-tumor cancers." All-comers is a phrase we'll probably hear more about. You called it--take a bow!
Here's the references:
https://www.frontiersin.org/journals/immunolo...8/full#B23
Short 1st quote (Chang is the lead author, co-authors include Helen Wu, Gabriela Webb, and Jonah Sacha. Describes in detail the development of the Receptor Occupancy assay. Incredibly dense though... Honestly, I just read the abstract, intro, and discussion).
https://pmc.ncbi.nlm.nih.gov/articles/PMC9125938/#Sec14
This is the longer quote about TAMs and metastasis (Raghavakaimal and Daniel Adams)
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