The Continuation of LL With ICI Until NED Even After Cold to Hot Transition
I think this new MOA needs to be looked at a little further. u/GarageAffectionate62 asks an amazingly important question and I'll try putting together my answer based on what I know.
The main problem is that I believe we are unsure of what exactly happens to the Tumor's regulation of CCR5 during the process of converting from Cold to Hot. We do know that PD-L1 regulation is Upregulated in this transition. But, I suspect that the CCR5 ligand, which is CCL5 aka RANTES, a ligand regulated by the tumor, is being down regulated by the tumor, as it transitions from Cold To Hot. But, I think we will see that regardless of what the tumor actually does with RANTES, it becomes imperative not to stop the administration of LL.
My reasoning is in agreement with GarageAffectionate and it goes as follows. Before any LL treatment at all, the Cold Tumor was doing very well, thriving even, through the use of the highly expressed RANTES CCR5 ligand. As we do know, RANTES converts Natural Killer Cells, CD8 Killer T Cells and M1 Macrophages into submissive tumor slaves. RANTES suppresses the ImmunoRegulation and that means the PD-1 Programmed Cell Death communication is Turned off when RANTES abounds. The slaved Killer Cells don't even bother checking for that "self" Identity card, whether or not the tumor is self or non-self.
However, when leronlimab is introduced, all of a sudden, all of the CCR5 receptors become occupied by LL and RANTES loses its grip. The Killer Cells come to a realization of who they in fact are and now begin using the PD-1 Identification method of checking for self or non-self. However, since this is a Cold tumor at first, very few tumor cells, if any, actually express PD-L1. But they soon begin to express more and more as LL continues to be administered.
It is at this point, that the Killer Cells and M1 Macrophages actually begin living up to their name. Without RANTES plugging up their CCR5 ears, the Killer Cells of our immune system have clear understanding and know to check the identity through the PD-1 identification channel. When there is no identification produced, because no PD-L1 was found or presented, then, that tumor cell is destroyed by our own white blood cell lymphatic militia. However, in a Cold Tumor, there are only a very few number of tumor cells which do produce PD-L1 and those do in fact present that identification card of PD-L1 and do subsequently survive our militia's check point.
By definition, Cold tumors express very little PD-L1 on their cell surfaces. The few tumor cells that do, may escape the massive tumor death and onslaught brought on by the introduction of LL into the tumor microenvironment which eradicates RANTES' suppressive effects. The tumor cells that do produce PD-L1 on their surfaces survive this onslaught, even to the point where they may actually reproduce. However, the tumor cells that do not produce PD-L1 are rapidly killed off by the body's Natural Killer Cells, CD8 T Killer Cells and M1 Macrophages since they did not produce that check point identification that they are self. Without that Identification Card, they are deemed Non-Self and are quickly killed by the Natural Killer Cell, CD8 Killer T Cell or M1 Macrophage.
But those that do survive, go on to replicate themselves. And those daughter cells, go on to produce PD-L1 thereby producing an ID card identifying them also as self, such that they too are passed over.
Now, since the tumor is a living mass of tissue, these PD-L1 expressing tumor cells can communicate to the inside cells of the tumor mass. The tumor mass as a whole communicates just like our own internal organs have communication. There is an intracellular communication network happening at all times between all the cells of the tumor as a whole. Therefore, the surviving PD-L1 producing tumor cells on the tumor mass whole exist because they have PD-L1 on the surface of their cells. These particular PD-L1 producing cells communicate inwardly to the cells which are located more interior to the tumor, (that are not affected by the initial LL onslaught), via intercellular communication channels instructing them to rapidly begin Upregulating their production of PD-L1 pronto.
Apparently, in these Cold Tumors, the inherent tumor cell's capacity to produce PD-L1 was always there, but was never necessary, until the point when LL was introduced and the RANTES channel was thwarted. This PD-L1 signal was always available to be enabled, but was never enabled, as it was not necessary since the tumor had learned to survive with only the use of RANTES alone. But now, after LL administration, RANTES has become useless but the tumor still needs to survive, and the surviving cells all scream and plead even to rapidly begin making PD-L1.
Throughout this process, LL is on board, and Killer Cells continue checking for the tumor cell's identity regardless of whether or not the tumor emits RANTES because LL is on board. The tumor could stop emitting RANTES since it no longer has any effect. It also could continue RANTES emission even though it has no effect. If the tumor stops emitting RANTES, the Killer Cells remain as Killer Cells because RANTES is no longer around hypnotizing. If the tumor continues to emit RANTES, the Killer Cells remain Killer Cells because LL is on board plugging the ears of CCR5 and therefore, can not "hear" its hypnotizing hum. But if LL is stopped, and RANTES is still being emitted, which I'm unsure of, then the Killer Cells could again go back to being tumor slaves.
If that would happen, then an even more virulent Tumor would be created. One that without LL around, recruits Natural Killer Cells, CD8 Killer T Cells and M1 Macrophages and turns them all into tumor slaves while also presenting a "self" identification card on its cell surface such that even if it were requested by any normal Killer cell, (though very few would even exist), it would still be allowed to slide.
Therefore, thinking this through, I agree with u/GarageAffectionate62, when he says, "If that is the case it may be more beneficial to continue leronlimab into the ICI treatment as once a tumor is able to communicate via RANTES again it could begin drawing in immune suppressive cells again possibly being the case for the one survivor without progression but not cancer free in mTNBC."
Initially, administration of LL to a Cold tumor kills off most of the tumor, but the parts of it that survive do produce PD-L1. With repeat administration of LL, more and more of the non-producing PD-L1 tumor cells get killed off while, the PD-L1 producing cells become increasingly more prevalent within the tumor mass as they induce more interior tumor cells to ramp up their PD-L1 production. At a certain point, or threshold, a PD-L1 inhibitor, ICI is introduced and interferes with the identification card presented to the Killer Cells. Now, these PD-L1 presenting tumor cells are also killed off because their identification card has been interfered with. Therefore the Killer Cell destroys that tumor cell as well.
However, if the tumor cell is able to produce RANTES again, and recruit via this communication call, the Killer Cells and hypnotize them back into being tumor slaves, then, again, a checkpoint identification would not even be required and PD-1 would be ignored entirely. Because tumor slaves don't bother checking, everybody get's let through the gate. This must not be allowed to even happen and can only be prevented if LL remains on board at all times, maybe not at the same dosage, as tumor burden is reduced, but still present. With LL on board, even if the tumor again goes back to producing RANTES, LL would be there to plug the ears of the CCR5 receptors of the Killer Cells and they would remain as Killer Cells forcing them to go through the check point gate.
So, I think based on all of this, leronlimab should not be stopped, until there is NED, no evidence of disease and a complete collapse of the tumor presence. Until there is no evidence of its existence. Otherwise, if any resurgent tumor cell begins to put out RANTES, then the Killer Cells could convert to slaves and help to build it up all over again.
Posted Jul 8, 2025, 11:05 AM UTC