Tumor's PD-L1 Upregulation
Let's talk a bit about PD-1 and PD-L1.
PD-1 is a receptor found on certain Immune System Cell walls and also is found on the cell walls of tumor cells. Our own white blood cells, specifically the CD8 Killer T-Cells, Natural Killer Cells and the M1 Type Macrophages use this inter-cellular communication method employing the PD-1 and PD-L1 pathway to kill tumor cells. As a CD8 Killer T Cell, Natural Killer Cell or M1 Type Macrophage closely approaches a suspicious cancer cell, the tumor cell needs to speak up and convince the Immune System's Killer Cell that it is actually "self" and not "invader". It can not do nothing because doing nothing means it is "invader" and would be a death sentence for the cell. So it speaks up by overexpressing PD-L1 which is its voice which immediately binds to and is heard by the CD8 Killer T Cell's PD-1 receptor. Once the Killer T Cell hears PD-L1, the Killer T Cell is de-activated and that promotes Immune Escape by the Tumor Cell.
PD-L1 to PD-1 Bio-Chemical Communication
When the PD-1 receptor on the Killer T-Cell binds to and hears the voice of PD-L1 expressed and spoken by the tumor, then the Killer T-Cell is Inhibited from its Killing capacity. When the PD-1 receptor on the Killer T-Cell does not bind or hear the voice of PD-L1, then the Killer T-Cell is Activated and subsequently destroys the Tumor Cell.
Therefore, the overexpression of PD-L1 by Tumor Cells is clearly one of their defense mechanisms which they employ to deceive our Immune System. Let's see how this was revealed in out mTNBC trials.
From the 5/15/25 mTNBC Poster Presented at ESMO Munich, in the Results section we read:
"In a post hoc analysis, the number of CTCs/CAMLs dropped in 43% (n=12/28) of patients after leronlimab induction, and upregulation of PD-L1 was seen in 81% (n=17/21) of patient’s CTCs/CAMLs (Figs 3 & 4) 5 patients treated with leronlimab are currently alive and were treated in combination, or subsequently, with immunotherapy PD-L1 checkpoint inhibitors (ICI) (Figs 4 & 5)"
From the conclusion of that poster, we read:
*"*Significant upregulation of PD-L1 in circulating cells (i.e. CTCs or CAMLs) was identified in 76% (n=16/21) of patients after leronlimab, and in 88% (n=15/17) of patients who received a 525mg or 700mg dose (Fig 4)
Patients treated with leronlimab in combination with PD-L1 ICIs had prolonged survival (Figs 4 & 5)
N=5/5 patients who induced PD-L1 in their CTCs/CAMLs and treated with ICI concurrently or subsequently with leronlimab were alive after 48 months, with n=4/5 currently NED (these n=5 patients had 4 median lines of any prior therapy)
Upregulation of PD-L1 after leronlimab along with the increased overall survival observed with the combination of leronlimab & PD-L1 ICIs warrants prospective evaluation in future mTNBC studies"
Therefore, it becomes quite clear, that these tumors did not originally produce much PD-L1. Why not? The metastatic TNBC tumor is a relatively "cold" tumor. It is a MSS or MicroSatellite Stable Tumor. In general, this MSS Type Tumor is essentially immune to the attack of the Immune System as it confounds and convinces any attacking Macrophage that it is "self". Therefore, the Immune System becomes somewhat suppressed and therefore not much inflammation is created around the tumor thereby enabling the tumor to live rent-free in breast tissues of the patient, without even putting up a fight.
However, starting day one, with the initial treatment of these patients using 525 mg or higher leronlimab, which is a CCR5 blocker, the tumor immediately finds itself requiring to put up a huge fight in order to only survive, much less proliferate. The number of CTCs and CAMLs begin to drop quickly. The magnitude of the tumors dramatically drop. The ability for the tumors to metastasize is eliminated as the RANTES communication is blocked. Angiogenesis, which led to the collateral blood supply feeding the tumors is halted and the blood circulation to and from the tumors dries up.
These tumors attacked by leronlimab, die fast and if they want to survive, something must be done very quickly. So, these mTNBC "Cold" Tumors under attack by leronlimab, had to do something if they wanted to survive. What could they do to keep themselves alive?, if they had no defenses, since RANTES was stripped from their ranks. They needed to develop a defense system which didn't have anything to do with RANTES. RANTES no longer worked because CCR5 was blocked by leronlimab. However, the remaining tumors still needed to convince the Killer Immune Lymphocytes, and M1 Macrophages not to kill them. They needed to cause these M1 Macrophages to allow the remaining leronlimab weakened tumor cells to Escape their Immune onslaught. But How?
Under extreme duress, these remaining MSS mTNBC "Cold" Tumors transformed themselves to upregulate and increase their PD-L1 expression as a defensive mechanism against leronlimab's CCR5 blockade. Essentially, these Tumors transformed themselves into "Hot" tumors and stopped speaking RANTES, and learned the PD-1 to PD-L1 language. These tumors used their newly produced PD-L1 to speak and bind to the PD-1 receptors on the cell walls of the CD8 Killer T-Cells, NK Cells and M1 Macrophages in order to convince them that they were "self" and not "invader". If they could succeed at that, then the tumors potentially could survive this fight by overcoming leronlimab's blockade of CCR5, by adopting another bio-chemical communication method which doesn't rely on RANTES. That communication method of course being PD-L1 to PD-1 which is the "Hot" method of communication.
However, it was later learned that at approximately the point, when the CTCs and CAMLs began to drop, the treating physicians have proof that leronlimab is working. It is probably, somewhere around this point when PD-L1 also begins to upregulate by the Tumor Cell. Possibly, 30-90 days following the initial drop in CTCs and the upregulation of PD-L1, leronlimab would be stopped and a PD-1 blockade would be administered. With the latter administration of the PD-1 blocker following the termination of the leronlimab, the tumor is left with no way to convince the CD8 Killer T-Cell, the Natural Killer Cell or the M1 Macrophage that it is "self". Therefore, by subsequently blocking PD-1 following the termination of the CCR5 blockade, the Immune System can no longer be fooled by the tumor's sly words. RANTES is no longer used, because the tumor switched to using PD-L1. But PD-L1 was blocked by the PD-1 blocker. So, for each and every tumor cell in the body, the Immune System was not tricked or fooled, but rather forthrightly eliminated as that tumor cell is left with no means to fool or trick the Immune System.
Did CytoDyn score with this revelation? Does CytoDyn have what it needs in this to assemble the deal of the century? Amarex could really have screwed CytoDyn had they not delivered this data, but as part of the Arbitration Settlement, the data was mandatory to be delivered and now, 5 years later, there remain these 5 patients yet alive and 4 with no evidence of disease.
Optics? Hardly. It is all in the poster, clearly presented. A solution has been found. The mechanism of action to overcome cancer's clever communication clowning craziness is clearly elucidated. CytoDyn has written the Headline.
"Long Term Survival with Leronlimab Treatment in Patients with Metastatic Triple-Negative Breast Cancer (mTNBC)"
This is CytoDyn at its finest. At the lowest of lows, it took what was given it, and worked it into an amazing common-sensical solution where the two Immuno-Therapeutic MOAs do their job as they should, but when combined in the discovered manner, can achieve the impossible, with patients still alive when they should have been dead 4 years ago.
Posted May 16, 2025, 11:14 PM UTC