Don't really know what I'm talking about here, but perhaps a great opportunity to learn something
The PD1 pathway involves both the PD-L1 ligand as well as the PD-1 receptor.
I am not sure how exactly opdivo works. it could bind to the PD-1 receptor, thus blocking the binding of the PD-L1 ligand.
Or it could bind to the PD-L1 ligand, thus blocking the ligand from binding the receptor.
I think the problem in cancer is that the cancer cells emit PDL1 ligand, which binds the PD-1 receptor on CD8 cytotoxic t-cells and thus the CD8s get the message to "stand down". Thus the cancer cells are sending a message to the CD8s, which could kill the cancer cells, to go away. But again I am not sure.
So I think the PD1/PDL1 immunotherapies are purely targeted at CD8s, and purely for the purpose of keeping the CD8s turned on and aggressively attacking cancer cells.
Leronlimab does not participate in the PD1/PDL1 pathway, and perhaps leronlimab does not even hit the same kinds of t-cells as the PD1/PDL1 drugs.
And that's where I am hoping to learn more not only about leronlimab but PD1/PDL1 as well.
I have always been confused as to the particular action of Leronlimab.
What exactly does it do to cells and which cells does it hit?
We know for certain from HIV that LL binds CCR5 on the CD4 t-cells. The primary HIV replication pathway is through CCR5 into the CD4s.
One problem in cancer is that there are too many CD4 Tregs in the Tumor Microenvironment (TME) and that the CD4 Tregs are suppressing CD8 activity inside the TME.
It seems to me that LL hitting the Tregs and preventing them from migrating to the TME is helpful because then the Tregs will not suppress the CD8s.
But if LL is also hitting CCR5 on the CD8 cytotoxic killer cells and stopping them from migrating into the TME, then that's not good cuz the CD8s can kill cancer cells.
But the benefit of Leronlimab in cancer may have absolutely nothing to do with LL hitting the T-cells.
At least a few experiments have, at least hypothetically, shown that LL binding CCR5 on the cancer cells prevents the cancer cells from migrating away from the primary tumor and causing metastases, which is what kills the patient. If only a primary tumor, the patient survives with at worst a surgery every year or two to reduce the size of the primary tumor.
And then there is the issue of the macrophages inside the tumor microenvironment.
Possibly leronlimab converts the macrophages inside the tumor microenvironment from immunosuppressive to the other state (I forget which is M1 and M2) where the macrophages eat tumor cells? And macrophage migration or not to the TME might also be a function of LL hitting CCR5?
So it seems to me a lot of possiblities here for LL to work better with PD1/PDL1 immunotherapies.
They may hit completely different cells.
But I am just going from memory and I don't have all the pieces
Does anyone know if pancreatic cancer has CCR5 overexpression?
The PD1 pathway involves both the PD-L1 ligand as well as the PD-1 receptor.
I am not sure how exactly opdivo works. it could bind to the PD-1 receptor, thus blocking the binding of the PD-L1 ligand.
Or it could bind to the PD-L1 ligand, thus blocking the ligand from binding the receptor.
I think the problem in cancer is that the cancer cells emit PDL1 ligand, which binds the PD-1 receptor on CD8 cytotoxic t-cells and thus the CD8s get the message to "stand down". Thus the cancer cells are sending a message to the CD8s, which could kill the cancer cells, to go away. But again I am not sure.
So I think the PD1/PDL1 immunotherapies are purely targeted at CD8s, and purely for the purpose of keeping the CD8s turned on and aggressively attacking cancer cells.
Leronlimab does not participate in the PD1/PDL1 pathway, and perhaps leronlimab does not even hit the same kinds of t-cells as the PD1/PDL1 drugs.
And that's where I am hoping to learn more not only about leronlimab but PD1/PDL1 as well.
I have always been confused as to the particular action of Leronlimab.
What exactly does it do to cells and which cells does it hit?
We know for certain from HIV that LL binds CCR5 on the CD4 t-cells. The primary HIV replication pathway is through CCR5 into the CD4s.
One problem in cancer is that there are too many CD4 Tregs in the Tumor Microenvironment (TME) and that the CD4 Tregs are suppressing CD8 activity inside the TME.
It seems to me that LL hitting the Tregs and preventing them from migrating to the TME is helpful because then the Tregs will not suppress the CD8s.
But if LL is also hitting CCR5 on the CD8 cytotoxic killer cells and stopping them from migrating into the TME, then that's not good cuz the CD8s can kill cancer cells.
But the benefit of Leronlimab in cancer may have absolutely nothing to do with LL hitting the T-cells.
At least a few experiments have, at least hypothetically, shown that LL binding CCR5 on the cancer cells prevents the cancer cells from migrating away from the primary tumor and causing metastases, which is what kills the patient. If only a primary tumor, the patient survives with at worst a surgery every year or two to reduce the size of the primary tumor.
And then there is the issue of the macrophages inside the tumor microenvironment.
Possibly leronlimab converts the macrophages inside the tumor microenvironment from immunosuppressive to the other state (I forget which is M1 and M2) where the macrophages eat tumor cells? And macrophage migration or not to the TME might also be a function of LL hitting CCR5?
So it seems to me a lot of possiblities here for LL to work better with PD1/PDL1 immunotherapies.
They may hit completely different cells.
But I am just going from memory and I don't have all the pieces
Does anyone know if pancreatic cancer has CCR5 overexpression?
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