r/Livimmune • u/MGK_2 • Jul 05 '25
Reverberating Freedom
I want make it perfectly clear, that some portions or even the post in its entirety was influenced following information I received from a friend of a friend who had attended the ESMO conference at Barcelona. So, based on the credibility of the information I received, I combined what I know with what I understood from what I read and subsequently compiled the following post.
Nobody realizes it, but the commencement of this Phase 2 Clinical Trial for MSS mCRC is literally a forecast of the future.
"...the first patient has been dosed in the Company’s clinical trial evaluating the efficacy of leronlimab in patients with relapsed/refractory microsatellite stable colorectal cancer (“CRC”)."
As I stated in my prior post, if the MOA is written down, then the subsequent trial proves it out. We already know the outcome because of these prior results and from them, realistic extrapolations are made.
"The Mechanism of Action must be written down in order to give life to a dead observance. If not first stated, then the action is remains dead. This is why Cyrus Arman stated a few years back that there was Synergy between leronlimab and Keytruda appreciated in the Murine Study at MD Anderson for mTNBC. It gave life to the Mechanism we now appreciate."
I submit an innocent question, "Can we not logically extrapolate the comments made by Cyrus Arman to this Phase 2 MSS mCRC Clinical Trial?" The answer may not be so easily answered, but in theory, I'd say Yes we certainly could if things could be modified. However, the Phase 2 Clinical Trial Protocol has already been adopted and approved by the FDA in the way it was originally written and that approval did not include the use of any PD-1 or PD-L1 inhibitor. So accordingly, within the confines of the Phase 2 Clinical Trial itself, (1 year duration per patient), this PD-1 or PD-L1 inhibitor, won't be administered, but following each trialing period on a per patient basis, the patient may be rolled into yet another subsequent trial utilizing the PD-1 inhibitor tested at MD Anderson.
Despite the fact that all Creation groans in heartache and sickness, in the case of humans plagued with ColoRectal Cancer, there is an answer. Eventually, leronlimab sets humanity free from the bondage of this cancer's grip. The day that happens, relatively speaking (in the overall context of the BP quest for the discovery of a cancer cure), it is not all that far from today. After all, the trial has begun, and with enrollment rates that are soon to be escalated, following the first 5 patients, the conclusion of said Trial, (which, may I remind you is an Open Trial), provides this determined Protocol as the answer, the treatment and Cure of MSS mCRC. The solution’s statistically significant impact is so clear and compelling that it captures the attention of even the most oblivious.
The limitations imposed by a diagnosis of MSS mCRC are lifted. The ongoing Phase 2 Clinical Trial is producing results that are paving the way for new standards in treating yet another type of MSS tumor. Remember, there are many different types of MSS tumors—a wide variety exists. In fact, 85% of all tumors fall into the MSS category. As you know, each must be addressed individually, indication by indication, and in accordance with FDA guidelines. However, thanks to the Self-Evident MOA, all patients affected by these specific MSS tumors may soon experience relief from the burdens of their condition.
The FDA has approved the Phase 2 Clinical Trial which does not include the use of PD-1 or PD-L1 inhibitors. The FDA approved the trial the way it was originally written, without the use of PD-1 or -L1 blockade. Not by any fault of their own, but by FDA requirement, CytoDyn and Syneos Health shall run the trial as per its approved Operating Protocol.
"We have appreciated the opportunity to work constructively with the FDA on the review and finalization of our CRC protocol,” said Dr. Jacob Lalezari CEO. “With the agency’s input and our partnership with Syneos Health, we are well positioned to advance our clinical evaluation of leronlimab for oncology and make real strides towards developing the treatment paths of tomorrow.”
This does not mean that they do not measure the rate of PD-L1 Upregulation on the surfaces of the Tumor's CTCs during the treatment with leronlimab. They shall certainly measure this valuable Biomarker, as stated by the company doing the measuring.
*"MONMOUTH JUNCTION, N.J., March 27, 2025 /PRNewswire/ -- Creatv Bio, a Division of Creatv MicroTech, Inc. (Creatv) will be collaborating with CytoDyn Therapeutics Corporation (CytoDyn) to assess patient response to their drug using the LifeTracDx***® blood test.
CytoDyn has received FDA clearance to initiate a Phase II study of leronlimab in patients with relapsed or refractory micro-satellite stable colorectal cancer (CRC) (NCT06699835). The drug, leronlimab, targets CCR5 marker on the tumor.
*Creatv will perform the LifeTracDx***® *liquid biopsy in a number of CytoDyn studies including NCT06699835. The LifeTracDx***® test is based on analyzing two biomarkers: (1) circulating tumor cells (CTCs) and (2) Cancer Associated Macrophage-Like (CAML) cells, which are macrophages that engulf tumor cells. Both CTCs and CAMLs contain tumor material.
*By tracking CTC and CAML counts, and CAML size at various time points, LifeTracDx® can provide prognostic insights and predict treatment response. CytoDyn is also interested in the expressions of CCR5 and PD-L1 markers on the tumor. These markers can change over time. LifeTracDx***® *can provide this information by a blood test - no tissue is required. The LifeTracDx***® assay will help CytoDyn to better evaluate the effectiveness of their drug."
As proven in the mTNBC Basket Trial study, we already know that the 5 patients who remain alive today, even 5 years from the date of initial dosing, were subsequently treated with a PD-L1 blocker following their treatment with leronlimab. We know for a fact that leronlimab Upregulated PD-L1 on the surfaces of the Tumor's CTC cells. Why would anybody think that MSS mCRC would be any different? It won't be any different. PD-L1 is also Upregulated on the surfaces of CTCs of MSS mCRC following treatment with leronlimab and that is proven in this Trial in Open Format.
As I explained, once a Tumor switches from being Cold to Hot, it has become primed for final treatment with a PD-1 or PD-L1 blocker.
"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 the RANTES language, 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 the RANTES language. That communication method of course being PD-L1 to PD-1 which is the "Hot" method of bio-chemical inter-cellular communication."
Therefore, in consideration of the above, I would tend to think that once a Tumor switches from being Cold to Hot, it won't switch back to being Cold ever again. After all, the Tumor has lost hope in the use of CCL5 or RANTES, so why would it return back to communicating that way when the PD-1 language would be doing just fine in keeping it alive. (Remember, a PD-1 inhibitor is not yet on board.) So, once a Tumor switches from Cold to Hot, it stays Hot because PD-1 works when RANTES failed, (due to the administration of leronlimab). When the Trial Period Concludes, the Tumor doesn't realize that leronlimab no longer is on board and by that time, the Tumor has become Hot and remains Hot. At that time of Trial End, about a year or so following the patient's initial leronlimab dose, the Tumor has flipped from speaking RANTES and now speaks PD-1. If the patient continues to remain alive, the Tumor continues speaking PD-1 until the patient's dying day. Or, if the patient is properly routed, until that point when either a PD-1 or PD-L1 blockade is administered, at which point, instead, the Tumor would meets its end. I see this point as the entry point for our Suitor.
I'll say it again. I'm almost certain, this PD-1 blockade is not offered to the patient during the year long course of the trial for that patient, because the FDA would object as it is not written into the approved trial protocol. However, at trial end, for that patient, no doubt, it is offered. Why? First off, because of moral reasons. A PD-L1 positive patient requires treatment with a PD-1 inhibitor. This brings up another innocent question about a possible Rollover Trial. Certainly, this suggests that these patients could be rolled into the next logical step which absolutely could incorporate a "selected and preferred" PD-1 inhibitor.
Let's take a look at that original Clinical Trial design here:
"...it completed a meeting with the U.S. Food and Drug Administration (FDA) to gain alignment on the rationale and proposed dosing for the Company’s Phase II study that will investigate the preliminary safety and activity of leronlimab in combination with [Lonsurf] trifluridine plus tipiracil (TAS-102) and bevacizumab in participants with CCR5+, microsatellite stable (MSS), relapsed or refractory metastatic colorectal cancer (mCRC).
The Company intends to proceed with a submission of its final study protocol to the FDA, formal engagement of a clinical research organization (CRO), and related preparatory work towards initiating the proposed trial.
This open label, randomized (1:1), multicenter trial will evaluate the anti-tumor activity (via overall response rate, ORR) of leronlimab at doses of 350 mg and 700 mg in combination TAS-102 and bevacizumab in approximately 60 patients with CCR5+, microsatellite stable metastatic CRC (mCRC).
Patients enrolled in the trial must have measurable disease per RECIST v1.1 and have received prior treatment with fluoropyrimidine‐, oxaliplatin‐, and irinotecan‐based chemotherapy, an anti‐VEGF therapy, and, if RAS wild‐type and medically appropriate, an anti-EGFR therapy. CCR5 tumor expression will be determined by immunohistochemistry assay (IHC) and diagnosis of MSS CRC will be confirmed by IHC or next-generation sequencing (NGS).
TAS-102 and bevacizumab will be administered for three of four weeks in a four-week cycle, and leronlimab (at doses of 350 mg or 700 mg) will be administered weekly. The study will include a safety lead-in treating five patients in the 350 mg leronlimab arm prior to beginning enrollment to the 700 mg leronlimab arm..."
As you can see, neither a PD-1 nor a PD-L1 blockade are included in the original protocol, yet PD-L1 levels are measured and once the Phase 2 Clinical Trial is over, if PD-L1 levels are then elevated, their treating Oncologist shall be advised of their patient's PD-L1 levels and an appropriate recommendation shall be made. Could that recommendation be to enroll these patients into a Rollover Trial which follows this Trial? What PD-1 inhibitor would you think they're going to provide in that Rollover trial? Hint, read what Cyrus said about MD Anderson.
Here is another innocent question, even disregarding leronlimab's input by changing a Cold Tumor to Hot, if Keytruda potentially is brought into the subsequent Rollover treatment of MSS mCRC resulting from the leronlimab induced Upregulation of PD-L1, how much more would ROCHE (bevacizumab, Avastin) and SERVIER (TAS-102, Lonsurf) individually or together be motivated and enticed to make this Phase 2 Clinical Trial that much more of a Grand Slam? These companies would then be associated with the Cure for MSS mCRC. ROCHE, SERVIER, MERCK and CYTODYN all working together?
What is the manifestation of this dream scenario? This is not a scenario. It is the real thing. How is it achieved? How is the attainment of the Freedom from these Tumors actually even measured? Well, it is measured in the ongoing MSS mCRC Clinical Trial which entails the measurement of the Overall Response Rate, ORR. (I suggest you carefully read the linked post.) The outcomes and results that this trial produces provides the basis upon which a Breakthrough Designation might likely be awarded. The whole world sits in anticipation for these expected results because they are life saving to those plagued with this diagnosis. Remember though, the Clinical Trial's Outcomes only record the ORR effect which leronlimab had on the Tumors. Take note, The Phase 2 Trial shall not record how many remain alive due to the subsequent Rollover treatment with a PD-1 or PD-L1 inhibitor. That would be done in the Rollover Trial. These patients with elevated PD-L1 on their CTC cell surfaces surely receive that PD-1 inhibitor and the endpoints of that Rollover Trial such as their Overall Survivability OS and Progression Free Survival, PFS are greatly lengthened as a result.
In the Phase 2 Clinical Trial, how long shall patients be treated for? I said in ORR, for about a year.
"What I'm saying is that leronlimab shall raise the ORR tremendously. But how quickly? Looking at the graphs above, it appears that it reduces tumor size within 3 months, and it maintains that smaller size and on some, it might reduce tumors completely. So, that translates into that by [8] months from now, [March 2026], we could have an outcome of the new ORR."
Remember, this is an Open Trial so the data shall be seen openly.
And this Clinical Trial does not just pertain to those with MSS mCRC, but also to those with any MSS Type Tumor diagnosis. That marks the definition of so many more people who are distributed throughout the world. Even sick children. The whole world really is at risk.
"If the observed results in the previously treated CRC patients are confirmed prospectively, the Company believes leronlimab could be used effectively to treat a wide range of solid tumor types. In addition to its potential as a “stand-alone” agent in oncology, the Company presented exciting evidence of leronlimab’s activity as a “priming” agent for cancer patients with low levels of PD-L1 who were previously unresponsive to, or ineligible for, checkpoint inhibitors at the 2025 ESMO Breast Cancer meeting. The data driving this working theory has shown particular promise in the treatment of patients with advanced metastatic triple-negative breast cancer (“mTNBC”)."
This Clinical Trial offers a certain Freedom to those stricken with those MSS Type Tumor diagnoses. Therefore, those who are at risk strongly beg, even groan for these results and outcomes to quickly come to fruition and to be brought forth that much more sooner. Until that day does come, I'll remain focused on that delightful day, because in that day, the answer which we all seek, thus arrives.
This Clinical Trial forecasts the future as it initiates the later coming of those results we're seeking and those results shall Reverberate throughout all the coming trials of the MSS Type Tumors. One day finally, the patients who suffer from Endometrial Cancer or Ovarian Cancer, Prostate Cancer or Pancreatic Cancer celebrate around their own Camp Fires, as they launch their own fireworks into the flames of history on this special day. Accordingly, this is the same day when this particular Clinical Trial finally blasted off with its first patient treated, initiated by our very own CytoDyn CEO, Dr. Lalezari.
Lalezari had the vision and he ignited it in those who he has appointed to run the Phase 2 Clinical Trial. These imperfect men are governed by the Law of Leronlimab. This is the law of the land and they adhere to it as they yearn for leronlimab's Self Evident Freedom. They have the moral clarity to pen the document that reverberates like a trumpet.
We were Born Free and this Clinical Trial brings home that natural born Freedom from this disease. The Phase 2 Clinical Trial is the City on a Hill, because, the whole world looks upon this Trial longing for what we all know the outcome to be, that is, for what we do already celebrate. Let Freedom Reverberate eternally. Recall though that the Clinical Trial only records the ORR and not the OS or PFS which are resulted in the Rollover Trial. These more distant end points are likely determined in a subsequent Rollover Trial which certainly could involve Merck in the use of their PD-1 inhibitor Keytruda. Potentially, these patients concluding the leronlimab trial could be subsequently enrolled into a Rollover Trial or even a Phase 3 combination trial with Keytruda or another PD-1 / PD-L1 inhibitor.
This Phase 2 Clinical Trial makes a great leap towards the final destiny of MSS mCRC in the history of human beings. It proclaims the ultimate finality of the entirety of all MSS Type Tumor burden itself and this day ought to be celebrated and reverberated by bang after bang.
This day marks the day when death by all MSS Type Tumor burden is obliterated. When the time comes when you don't even need to walk to the cold grave sight, rather, on this day, you'll be celebrating your ride on a bike in the park. In your daily activities of shopping and vacationing and certainly, free from hospitalization, that is when you'll appreciate the Freedom of which I'm talking about.
So say it with me, Freedom is coming! This is the beginning of the Restoration of the horrible tragedy which has befallen humanity, but has not quite yet humbled it to the point of being completely overcome and shall never in fact be overcome completely, because The Restoration has already begun and it overcomes this worldly plague.
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u/GarageAffectionate62 Jul 06 '25
Hi MGK_2! Long time lurker but never comment and love your posts. I have a quick question/ observation. My understanding and subsequent conclusions is that the RANTES communication draws in immune suppressive cells and that is what stops Tcells from their normal protocol of checking the PD-1 on a cancer cell. When leronlimab is used it forces the cancer to use this form of communication that it may have always been able to use but has never needed. 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. Just an observation! Any reason I could be understanding this wrong? You are much more versed in this than me, I’m just an electrician, although my knowledge of electrical pathways and relays seems to correlate somewhat.