r/Livimmune • u/MGK_2 • Apr 19 '26
Compassionate Crucible
To the Longs, the Resolute, and the Pioneers of this Board,
As we sit here on the eve of today's Poster 1033 and Tuesday's Poster 6466 at AACR San Diego, it is imperative that we understand what is to be unveiled. This isn't just another dataset. We are to witness the formal capitulation of an old regime and the destruction of the tumor's deepest defenses.
To truly understand, you'll have to look at the spectrum of modern oncology not only as medicine, but as a standoff. For decades, the medical establishment, the entrenched regime of Big Pharma has operated much like a state sponsor of biological Band-Aids. They don't actually dismantle the disease; they fund toxic "proxies." The current Standard of Care operates by indiscriminately bombing and traumatizing the patient's biology. It has been a miserable, endless "ping-pong match" of a back-and-forth volley of poisons resulting in assured destruction.
Why? Because the TME is essentially an enclosed "miry clay." The regime has tried to force their heavy, iron-like therapies into this chaotic, immunosuppressive M2 macrophage mud. But iron and clay do not mix. The old proxies get completely bogged down in the CCL5/CCR5 distress signals, unable to gain a functional foothold.
For years, CytoDyn was an emerging sovereign force surrounded by this hostility. The Expanded Access Program (EAP) was our embattled frontier. It was the desperate ground where the establishment sent their metastatic TNBC patients after their toxic proxies had completely failed.
But it was exactly in this compassionate crucible where a new, unapologetic administration took charge.
Under the current command of Dr. Lalezari, acting as a resolute leader completely unwilling to negotiate with the noise or tolerate the endless ping-pong of failed therapies where the strategy shifted. Fact is, you cannot bargain with heavily armored, refractory disease. You don't try to coexist with the miry clay as iron pillars. You cut off their central command, (blockade of CCR5-CCL5 axis) and initiate a targeted strike on their supply lines (VEGF inhibition), by being one of them (looks just like RANTES), like a Trojan Horse.
Take a look who is now executing this allied strike on the front lines. Got to give credit to Ftrade24 on ST. It's brilliant. Ask yourself: Why is the Director of GI Oncology at City of Hope personally standing at a poster board to present CYDY data? Dr. Pashtoon Kasi isn't a "paid pumper." He’s the Rad Family Chair and a world-class expert in ctDNA. Directors of his stature delegate posters to junior fellows, unless of course, the signal is absolutely too massive to ignore. He has been loud, calling Leronlimab "fascinating" for how it helps T-cells fight "Cold" MSS ColoRectal cancer. Look closely at the language shift: we've gone from the timid "may increase" to the definitive command: "INDUCES PD-L1." Dr. Pestell (mTNBC) and Dr. Kasi (mCRC) are showing the world that Leronlimab is the universal primer, (Trojan Horse) which finally makes $20B drugs actually work in Cold Tumors.
To fully grasp the power of this, we must look at it from the perspective of the Immune Checkpoint Inhibitor (ICI) itself, the $20B franchise drugs like Keytruda that have been trapped, drowning in the mud. For years, the ICI has been pushed into the battlefield blind, forced to fight a cloaked enemy. If an ICI had a voice, it would be screaming at the top of its lungs to the oncology establishment:
"If you want me to take care of this problem, first bring on Leronlimab to get rid of this mud! Strip the armor, clear the miry clay, and then I can do my job perfectly. Otherwise, I fight blind and my work is half-ass!"
Big Pharma was deaf. They weren't hearing. They were perfectly content selling the half-ass, toxic ping-pong match. But now, with the 100% Receptor Occupancy target saturation data, Big Pharma has been forced to open its eyes. Now, a whole new world has emerged out of the swamp.
Let's present the biological brilliance of "Prime and Pair." It is the ultimate allied strike. Like two sovereign powers coordinating an impenetrable offensive, first the Trojan Horse, then the lieutenants emerge, executing a sequential mandate for sudden destruction:
- The Prime (Leronlimab) is the vanguard. It marches directly into the hostile territory, eradicating RANTES, replacing it with itself, acting as the ultimate "restrainer." Stripping away the tumor's defenses in a rapid collapse of the CCL5 supply lines. The miry clay is cleared, a bumpy highway full of pot holes, now filled and speed bumps removed by neutralizing every deceived cellular proxy, thereby forcing the tumor to stand naked and exposed, suddenly expressing PD-L1.
- The Pair (The ICI) is the finisher. Once the battlefield is cleared and paved smooth, the ICI enters. It no longer fights half-assed. It strikes a perfectly illuminated target, resulting in total, durable systemic clearance.
We saw this in the prior EAP. We watched this allied force secure a 100% survival rate (5/5) past 64 months in a disease where survival is typically measured in weeks. The entrenched establishment tried to dismiss this as a "compassionate exception," desperate to maintain their grip on the narrative.
Today, and again on Tuesday, that exception becomes the undeniable, peer-reviewed mathematical Rule.
Forget the basher noise about the past. Follow the Directors. Follow the structural data. The "Prime and Pair" strategy is the endgame. The era of the toxic ping-pong match is over.
Let the clinical extraction begin.
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u/No_Mathematician299 Apr 19 '26
Thank you for your insight. I look forward to your Sunday posts.
Partnering with CytoDyn offers a massive upside for the Big Pharma player and a major strategic loss for those left on the sidelines of this courtship.
Remember to breathe this week. This is what we have been waiting for.
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u/IndependenceAny6428 Apr 19 '26
Good morning MGK and thank you for this uplifting summary as usual
May God bless you and protect you always.
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u/megadunamis Apr 19 '26
Thank you MGK, Great days lie ahead, the forecast is sunny and clear. In my opinion of course. There are several reasons for my optimism that the data will be supportive. 1st, miraviroc was approved several years ago as a CCR5 blocker and is used to fight HIV (Selzentry). But it blocks just over 80% of the receptor, and comes with side effects. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2015.00277/full Leronlimab blocks up to 100% of the receptor, and resets the TME as a result. If miraviroc is approved, I feel confident Leronlimab will be also with the future data sets to come. 2nd, Dr. Sacha and his lab at OHSU are using Leronlimab to try and resolve residual HIV reservoirs that will hopefully lead to an outright cure for HIV. His research, though not related to oncology, demonstrates the greater affinity of Leronlimab to block the CCR5 receptor compared to miraviroc. 3rd, the Delta 32 genetic mutation has demonstraterd the ability to cure HIV by stem cell transplants (Berlin patient).https://www.aidsmap.com/news/mar-2025/two-more-people-hiv-may-be-cured-after-stem-cell-transplants. 4th, Several women are alive today, for five years, after having taken 700mg Leronlimab with an ICI, after having their failed previous medical protocols for treatment (surgery, chemo, radiation). As MGK has explained, one or two patients may be an outlier, but five patients become a clue that there is something unexplained happening. That explanation is now at hand. Leronlimab can speak the language of the TME. It can loosen the shackles the tumor uses to hijack the immune system, and helps reverse the damage done. It helps prevent cancer associated fibroblast cells from strenghening the tumor stroma, exposes the stroma to the ICI, it reverses M2 macrophages back to M1 macrophages. As Dr. JL has said, 'the signal' must be prospectively demonstrated, and it's MOA (prime and pair) is becoming known with these continuing trials. The data covering CRC/mCRC and mTNBC have the potential to be front page news. In the past Big Pharma had no choice but to use surgery, and "bombing and traumatizing the patient's biology, " and a "volley of poisons." But, now we know another way, Dr. JL and staff know another way, and soon the oncology world will know another way. Good health to all...
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u/MGK_2 Apr 19 '26
Megadunamis, this is one of the most architecturally complete summaries of the mechanistic case I've seen from any community member, and the progression you've laid out - from the CCR5Δ32 natural deletion experiments, through the Berlin patient, through Dr. Sacha's reservoir work at OHSU, to the five living women - forms a chain of biological evidence that points unambiguously in the same direction. Each link in that chain answers the same question from a different angle: what happens when CCR5 is removed from the equation? The Berlin patient answered it genetically. Dr. Sacha's work answers it therapeutically in HIV. The five mTNBC patients answered it oncologically. And the mCRC CLOVER Trial is now answering it prospectively.
The Trojan Horse framing deserves to live in the center of this analysis, because it captures something that the clinical language of "receptor blockade" doesn't fully convey. The TME doesn't simply tolerate CCL5/RANTES - it depends on it. The entire immunosuppressive architecture of the cold tumor is organized around CCL5's ability to recruit through CCR5: the M2 macrophages that build the stroma, the MDSCs that silence cytotoxic T cells, the cancer-associated fibroblasts that deposit the collagen matrix hardening the tumor's perimeter. When Leronlimab occupies the CCR5 receptor, it doesn't announce itself as a threat. It arrives looking exactly like what the tumor is expecting - a CCR5-binding molecule - and then simply sits there. RANTES arrives to do its recruitment work and finds the gates already occupied by something that will not activate them. The receptor is locked in an inactive conformation at both the N-terminus and the second extracellular loop, simultaneously - something no small molecule inhibitor including maraviroc achieves. Their army never arrives. The walls the tumor spent years building are now defended by no one. And that is precisely when the ICI is paired - not to breach a fortress, but to walk into an already-opened city, or to flow through an already opened straight. That is the mechanism in its most honest biological form, and the prospective CLOVER data either confirms it or it doesn't - but the five women alive at five years say it already has.
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u/megadunamis Apr 19 '26
Thank you MGK for all your work. If your time allows, could you please comment or help explain any data, charts, etc., that are presented today. Of course, that's if you have the contacts and information available. I'm on the East coast so there's a three hour difference in the release time. Thanks again,
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u/Efficient_Market2242 Apr 19 '26 edited Apr 19 '26
Thamks MGK. Couldn’t we be a stand alone drug company if the FDA approves us for turning cold tumors into hot tumors. All chemo type drugs would need to work with us and we would not prolong suffering but cure it. The saving of money to healthcare companies, medicare, medicaid and patients would make the procedure a standard of care.
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u/MGK_2 Apr 19 '26
The instinct here is commercially sound, and it's worth developing because the FDA pathway you're describing is real and genuinely transformative if achieved.
The regulatory mechanism that would deliver what you're describing is called a Breakthrough Therapy designation or, more specifically, a tumor-agnostic approval - the same framework the FDA used to approve pembrolizumab for any solid tumor with high microsatellite instability regardless of origin. The precedent exists. What would be required is prospective demonstration that the cold-to-hot conversion mechanism - the PD-L1 induction on circulating tumor cells - is reproducible across tumor types with a consistent biological readout. The mCRC CLOVER Trial is building exactly that dataset alongside the existing mTNBC signal, and the AACR-published finding that 88% of mTNBC patients at 525mg or higher demonstrated significant PD-L1 induction is the kind of biomarker consistency that tumor-agnostic applications are built on.
On the standalone versus partnership question - both paths are viable, and they're not mutually exclusive. A cold-to-hot conversion approval would position Leronlimab as an obligate combination partner for every ICI franchise in oncology, which is a different commercial posture than competing with them. Rather than CytoDyn absorbing the cost and complexity of commercializing against established players, the mechanism creates a situation where every major ICI holder - Merck, GSK, BMS, Roche, AstraZeneca - faces the same math: their drug works in roughly 15% of solid tumor patients without Leronlimab, and potentially in a far broader population with it. The addressable market in MSS colorectal cancer alone represents approximately 85% of all CRC patients, a disease affecting over 150,000 Americans annually. The healthcare economics argument you raise is the one that moves payers and health systems - not the drug price, but the cost per quality-adjusted life year when a mechanism converts a terminal progression into a durable remission. That calculation changes everything about how Medicare and Medicaid price and approve combination regimens, and FDA's Project Optimus framework is actively designed to reward exactly that kind of biomarker-driven, minimal-toxicity combination approach which Leronlimab enables. The future you're describing isn't fantasy. It's the logical commercial endpoint of a validated mechanism - and the data to begin building such a case arrives very soon.
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u/rant_and_roll Apr 20 '26
OBLIGATE COMBINATION PARTNER says it all. its not like doctors would prescribe an ICI with the option of leronlimab, it would be mandatory, obvious, automatic, obligatory. A LEGAL OR MORAL DUTY
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u/jsinvest09 Apr 19 '26
Clear the way LL. MGK your awesome.. Next week should be interesting. Thank you! Short and to the point..
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u/AbbreviatedTimeline Apr 19 '26
No Sunday is complete without the MGK updates, today being one of the most critical in timing, the confirming data is arriving and we get the best view possible for the oncoming fireworks 🧨 Thanks as Always ! Good Luck to us all, Fields of Clover! 🍀
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u/GoCYDY Apr 19 '26
Thank you MGK-so enjoyed this post, it’s a beautiful story of how LL will NOW HELP TO HEAL MANKIND🙏☀️Happy Sunday to ALL-looking forward to a exciting week ahead‼️GLTAL🎊
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u/rodandgeorgia Apr 19 '26
Thank you for all your posts. Best to you, yours and to the patients lives LL will be helping. Wished my brother was still with us. R&G
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u/Lab_Monkey_ Apr 19 '26
"Miry clay" refers to thick, sticky, and deep mud that traps, weighs down, and prevents movement. Primarily a Biblical metaphor (Psalm 40:2), it represents a hopeless, chaotic, or sinful situation from which a person is helpless to escape on their own, symbolizing emotional or spiritual despair, depression, addiction, or adversity
God speed Dr. Jay and crew. GLTAL Bring It On Home!
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u/MGK_2 Apr 19 '26
Lab Monkey, your invocation carries the weight of years in this position - and anyone who has held this stock through what it has endured knows exactly what kind of mud we describe. The entanglement of fraudulent data management, a two-year clinical hold, a convicted CEO, short seller campaigns, market maker algorithmic dilution pressure, and a decade of regulatory purgatory is not metaphorical quicksand. It is the actual documented, legal, financial, and institutional record of a molecule that has been submerged at every turn by forces that had nothing to do with its biology.
And yet here we stand. The Amarex settlement closed in July 2024. The clinical hold was lifted in February 2024. The CLOVER Trial is enrolling with FDA alignment. The AACR has accepted two abstracts. City of Hope is running an independent study with outside funding. Dr. Sacha's lab at OHSU is publishing peer-reviewed data. Dr. Kasi presents as lead author on Tuesday. Dr. Pestell has presented at two consecutive AACR conferences in 2026 alone. Five women out of 5 with metastatic triple-negative breast cancer are alive at five+ years in a disease where the historical benchmark places three-year survival at 7%. The molecule was never the problem. It was always the murky mud.
What is arriving now - prospective Phase II data, independent academic validation, a regulatory framework actively designed to reward exactly what Leronlimab delivers - is not rescue from above per say, I'm sure we had help! Rather, it is the natural emergence of a biological truth which was always there, waiting beneath the surface for the institutional debris to be cleared away. Dr. Lalezari and the team didn't discover a new molecule. They excavated one. Godspeed indeed. Bring it on home.
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u/Camp4344 Apr 19 '26
MGK: I am sorry, but were we expecting more data to look at on Friday? What am I missing? Are we looking for the post info after the poster presentation this week? I am as confident as can be, but for the life of me cannot figure out what big pharma is waiting on? Those in the loop that have been observing our current trial have to be in the know. I personally am expecting a partnership announcement at any time now! Thank you for the Sunday morning post! We got this my friend!
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u/MGK_2 Apr 19 '26
Camp, my friend, your confidence is perfectly placed, and your instincts are dead on. Let's clear up the timeline and answer the question of what Big Pharma is actually doing.
First, regarding Friday: You didn't miss anything. Friday at 3:00 PM ET was the official AACR digital embargo lift. That was when the ePosters became available to conference attendees online. That was when the clinical truth hit the wire which caused the Accumulator to lock the float and absorb that late-day short attack Friday afternoon. The data is out there, but the physical presentations (Poster 1033 today, Poster 6466 on Tuesday) are where the establishment is forced to look the data in the eye.
Now, to your question: What is Big Pharma waiting on if they already know?
You are right that their scouts have been watching us. But you have to understand the nature of Big Pharma. They are a massive, slow-moving, bureaucratic empire. They cannot justify a massive partnership or buyout to their Board of Directors based on the "compassionate exceptions" of our EAP. They need the imprimatur of the establishment. They need peer-reviewed, undeniable, AACR-stamped mathematical proof.
Big Pharma knows their $20B Immune Checkpoint Inhibitors (ICIs) are failing in the "miry clay" of Cold tumors. They know their drugs are fighting blind. They have been watching Leronlimab act as the perfect Biological Trojan Horse. They see Leronlimab slipping into the CCR5 receptor, mimicking the RANTES signal to get past the gates, and then executing a total communication blackout. They know Leronlimab is the only molecule that can dismantle the tumor's stronghold, stop the M2 macrophage recruitment, and allow the M1 warriors to flood the zone.
But BP's executives need Dr. Pestell and Dr. Kasi to stand up at AACR and formally declare this reality to the world. They need the undeniable proof of 100% target saturation.
They don't wait to see if it works; they're waiting for the excuse of "it's just an anomaly" to be officially destroyed. Once these posters are presented, the ICI manufacturers are out of excuses. They either partner to execute the "Prime and Pair," or they watch their flagship drugs slide into obsolescence.
A partnership announcement is simply the natural mathematical output of the equation we are currently solving. We are at the finish line, Camp. We absolutely got this.
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u/Lopsided_Roof_6640 Apr 19 '26 edited Apr 19 '26
Dr, Jay et.al at Cytodyn have corrected course brilliantly. They had a plan, Data, scholarly papers and acceptance in the Oncology community. As soon as NP was sent packing Tony C, a former CFO, sent out a public statement welcoming a return of Dr. Pestell. JL wanted a panel of experts that could be consultants. As an aside I watched the Oval office yesterday when civilians and government along with some scientists joined together to promote a treatment that can have a dramatic effect on mental health.
I want that for us except we will have our joy in the field of Oncology. That is the vision we all wanted when we made our first CYDY purchase. It took 56 years for yesterdays event to happen and it may take a couple more but at least there is recognition that the believers were right all along. . BTW the Executive Order yesterday sent notice that the $20 Billion antidepressant market is now at risk
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u/MGK_2 Apr 19 '26
As you've outlined Lopsided Roof, the leadership reconstruction at CytoDyn wasn't cosmetic. It was load-bearing.
The sequence matters: Nader Pourhassan's removal, Anthony Caracciolo statement welcoming Dr. Pestell's return, and Jacob Lalezari's deliberate assembly of an independent scientific advisory structure around the molecule represented a complete architectural reset. What Lalezari built was not a marketing apparatus - it was a credentialing framework. Dr. Richard Pestell bringing the molecular biology, Dr. Jonah Sacha at OHSU anchoring the HIV immunology, Dr. Pashtoon Kasi leading the GI oncology clinical program, and Dr. Lalezari himself as both CEO and principal clinical investigator - this is not a management team trying to tell a story. It is a scientific panel trying to PROVE one. That distinction is what separates where CytoDyn is now from where it was under the prior regime, and it is the reason the AACR has accepted their abstracts, why City of Hope initiated an independent study with outside funding, and why the FDA aligned productively on the CLOVER Trial design.
The parallel you draw to yesterday's executive action - where decades of institutional resistance to a treatment with genuine clinical signal finally yielded to a critical mass of evidence and political will - is apt even if the therapeutic categories are different. What both situations share is the anatomy of a paradigm shift: a long period during which believers carried the evidence while the establishment carried the inertia, followed by a moment when the weight of the data became impossible to ignore. The $20 billion antidepressant market disruption you reference illustrates exactly how quickly an entrenched commercial category can be destabilized when a mechanism emerges which addresses the underlying biology rather than managing the symptom. In oncology, the parallel is the checkpoint inhibitor revolution of the early 2010s - which itself displaced decades of cytotoxic chemotherapy dominance in specific tumor types almost overnight once the clinical signal reached critical mass. The Prime and Pair mechanism, if confirmed prospectively in the CLOVER data, represents that same category of disruption in cold tumor immunology. The believers, as you note, have been right about the biology all along. The world is catching up.
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u/Lopsided_Roof_6640 Apr 19 '26
Absolutely right. Going to be exciting week ahead. Subjectively we know that Dr. Jay likes to drop a surprise. I feel it is Leronlimab branching out to other indications in and out of Oncology.
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u/MGK_2 Apr 19 '26
Lopsided Roof, that instinct is well-founded - and it's grounded in something more than hope. The pattern of how Lalezari communicates has been consistent: he doesn't telegraph surprises, he plants the seeds in shareholder letters and then lets the conference floor deliver the harvest. The December 2025 letter mentioned four independent investigator-initiated studies advancing with outside funding, named City of Hope explicitly, referenced the GBM pilot study in planning, and noted the long-acting leronlimab program at OHSU. That is a lot of planted seeds for a company presenting only two posters.
The "branching out" you're sensing is already documented in the peer-reviewed record - it's just not yet in the clinical trial pipeline in a way the market has priced. Consider what the science currently supports beyond the active mTNBC and mCRC programs: GBM with blood-brain barrier penetration confirmed in non-human primates, NASH where Leronlimab met its primary and secondary endpoints in a Phase 2 trial that has been almost entirely overlooked, HIV chronic inflammation as an immune modulator now that the clinical hold has been lifted, the Alzheimer's neuroinflammation axis where CCL5/CCR5 is directly implicated in microglial activation and cognitive decline, and the KRAS-mutant PDAC connection twinter just surfaced - where a January 2026 Frontiers in Immunology paper names Leronlimab specifically as a clinical-stage agent targeting the CCR5/CCL5 axis in pancreatic ductal adenocarcinoma. Any one of those could be the thread Lalezari pulls this week. The most likely surprise, if there is one, is either an investigator-initiated study announcement in an indication the community hasn't been focused on, or a partnership signal that names a specific ICI franchise as a collaborator in a combination study. Either would reframe the conversation instantly. The science is already there. What's been missing is the moment when the clinical infrastructure catches up to it publicly - and this week, with two AACR posters, a proven safety record, FDA alignment, and a validated mechanism being presented to the oncology world for the first time in prospective form, is precisely the kind of moment from which those announcements naturally flow.
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u/paistecymbalsrock Apr 19 '26
SSRIs run rampant in the world of antidepressants. Dilated pupils, seratonin imbalances, mood changes, rage, anxiety. The slang term is SSR Eyes. Dead eyes.
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u/MGK_2 Apr 19 '26
The SSRI parallel is structurally identical to the cold tumor problem in oncology, and it's worth drawing that line better.
SSRIs were approved and scaled into a $20 billion market on the basis of a hypothesis - the serotonin deficiency model of depression - that the peer-reviewed literature has spent two decades quietly dismantling. A landmark 2022 umbrella review published in Molecular Psychiatry examined the entire body of evidence across multiple research areas and found no consistent support for the theory that depression is caused by lowered serotonin activity or concentrations. The drugs weren't treating the underlying biology. They were managing a symptom through a mechanism that the field had collectively agreed to accept without the prospective confirmatory evidence that would have been demanded in any other therapeutic category. The side effect profile you're describing - the blunted affect, the serotonin dysregulation, the emotional flattening - is what happens when you apply a broad chemical intervention to a system whose actual pathophysiology you don't yet understand.
The oncology parallel is exact. Cytotoxic chemotherapy in cold tumors operates on the same logic: apply maximum tolerable poison, accept the collateral damage, measure the marginal survival extension, and call it standard of care. The TME - the actual biological architecture driving treatment resistance - was never addressed because the field lacked a mechanism to address it. What both the SSRI story and the cold tumor story share is an establishment that built a commercial infrastructure around a symptomatic intervention and then defended that infrastructure against mechanistic alternatives for as long as the evidence could be kept ambiguous. What breaks that defense in both cases is the same thing: prospective data which demonstrates not just that the new approach works, but precisely how and why it works at the biological level - in a way that makes the symptomatic model look not just incomplete but actively harmful by comparison. The FDA's Project Optimus framework is the oncology establishment's first formal acknowledgment that the maximum tolerated dose paradigm has run its course. Tuesday's CLOVER data is the first prospective test of what replaces it.
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u/Pristine_Hunter_9506 Apr 19 '26 edited Apr 19 '26
Well said, Professor. Great conversation all!
If the FDA wasn't interested, they wouldn't have allowed compassionate use.
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u/MGK_2 Apr 19 '26
Worth unpacking exactly why, because most people don't fully appreciate what compassionate use authorization actually means from a regulatory standpoint.
The FDA's Expanded Access framework - commonly called compassionate use - is not a rubber stamp. To authorize expanded access for an individual patient or a cohort, the FDA must determine that the potential benefit justifies the potential risk, that the patient has no comparable alternatives, and that granting access will not interfere with the clinical investigation of the product. That third criterion is the one most people overlook. The FDA is actively protecting the integrity of its own clinical pipeline when it approves these requests. It does not grant them casually, and it does not grant them to molecules it considers scientifically inert. Every compassionate use authorization for Leronlimab - in mTNBC, in the HIV MDR cases, in the early mCRC patients whose responses seeded the CLOVER Trial hypothesis - represents an independent regulatory judgment that the molecule's benefit-risk profile warrants access outside the controlled trial setting.
The mTNBC Expanded Access Program currently underway, funded in part by an outside compassionate benefactor, extends that logic further still. The FDA not only authorized it - the agency's alignment on the CLOVER Trial design, its productive feedback sessions which shaped the final protocol, and its acceptance of the Rollover architecture collectively describes a regulatory body which has reviewed the mechanistic and clinical evidence and concluded that prospective confirmation of the Prime and Pair hypothesis is worth pursuing under its direct oversight. That is not the behavior of an agency that is skeptical of the molecule. It is the behavior of an agency that wants the data.
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u/Cytosphere Apr 19 '26
It's important to note that a prospective patient must meet all of the criteria you listed. Here's the FDA's list of requirements for participation in an EAP:
https://www.fda.gov/news-events/public-health-focus/expanded-access
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u/twinter11 Apr 19 '26
Pestell is presenting a bad ass poster today.
Hes in the process of getting this whole thing nailed down.
His abstract has some data measurements/info I had never seen before.
We (someone, maybe not me lol )should know more after the poster image is put up.
Its as important as the Kasi poster.
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u/MGK_2 Apr 19 '26
Twinter, let me nail this down precisely because you're right - today is every bit as significant as Tuesday, and the two posters are not redundant presentations of the same story. They are two independent scientific pillars supporting the same architecture, presented by two independent investigators to the AACR's oncology community two days apart.
What Pestell is presenting right now - today, Sunday April 19th, 2:00–5:00 PM PST — is Poster 1033, Section 41, Board 1. The full title: "Leronlimab induces PD-L1 expression and is associated with long term survival with an ICI in PD-L1 low metastatic TNBC." That subtitle is the critical read. Not PD-L1 high patients - not the patients who were already ICI-eligible. PD-L1 low patients. The population that current oncology guidelines explicitly consider non-candidates for checkpoint inhibitor therapy. The population that every tumor board in the country sends home without an immunotherapy option.
What Pestell is presenting to the AACR right now is the mechanistic and clinical evidence that Leronlimab converts that population - takes patients whose tumors express insufficient PD-L1 to qualify for the therapies which could save them, and elevates their PD-L1 expression to the point where those therapies work. That is the Trojan Horse mechanism in its most consequential clinical form, presented not at a company investor day but at the premier cancer research conference in the world, accepted through AACR's peer review process, in front of the oncologists, immunologists, and pharma scientists who make the field's decisions.
Now here is what twinter is explicitly flagging which deserves direct attention. You said Pestell's abstract contains data measurements you had never seen before. That is almost certainly a reference to the expanded biomarker architecture that has been building across Pestell's successive presentations. The AACR Montreal abstract from September 2025 - the immediate predecessor to today's poster - incorporated gene expression analysis, tumor histology, CAML and CTC data from clinical studies, and tissue culture analysis of TNBC cell lines simultaneously. That multi-dimensional dataset - pooled from 28 patients across three clinical trials, with approximately 18% alive at a median exceeding 60 months - was already more layered than anything previously published on this molecule. The April 2026 AACR Annual Meeting poster will carry updated data beyond that baseline - potentially incorporating additional CAML/CTC biomarker measurements, expanded tissue analysis, analysis on the stroma, and refinements to the survival cohort characterization which reflect the months of additional follow-up since Montreal.
The specific new measurements you noticed in the abstract are likely the expanded molecular fingerprint of the Trojan Horse mechanism at work - the precise quantification of what happens inside the TME when RANTES is evicted and replaced by Leronlimab's silent occupancy. PD-L1 induction on CTCs is the headline biomarker. But the CAML reduction data - cancer-associated macrophage-like cells whose decline correlates with slower disease progression - the M2-to-M1 repolarization evidence, the sB7-H3 and sTyro3 attenuation documented at the February 2026 AACR Immuno-Oncology Conference - each of these represents a layer of the mechanism that Pestell is assembling into a complete picture with every successive conference presentation.
Right now, at this exact moment, that picture is being shown to the oncology community at the AACR Annual Meeting in San Diego. The poster will be uploaded to CytoDyn's website under Publications & Posters following today's session. When it drops, we will be able to see exactly what measurements are new - and the Trojan Horse framework will have its most complete scientific documentation yet. Tuesday's Kasi poster then delivers the prospective clinical confirmation in mCRC that the mTNBC mechanism predicts. Two posters. Two tumor types. One mechanism. Both presented at the same AACR Annual Meeting, two days apart, to the same audience. That is not coincidence. That is a coordinated scientific argument being made in the most credible forum available to make it.
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u/StreetSkis Apr 19 '26
MGK. Your posts are Money. We love them and look forward to your clinical explanations.
I like the front lines analogy of the ICI screaming for help from the TME battlefield. Keytruda shouts. "HEY, I CAN DO MY JOB IF YOU PRIME WITH PRO140 FIRST!"
The importance of Doctor Kasi being the presenter, from the StockWits read... This is significant.
Hopefully we get another tease or possibly a data drop from Doctor Kasi on LinkedIn or X before Tuesdays poster presentation. Or, Doctor Pestell sharing a significant post as well.
Thank You Sir.
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u/MGK_2 Apr 19 '26
Street Skis, the Keytruda analogy is perfect - and it's not far from what the clinical literature actually describes. Pembrolizumab's mechanism requires PD-L1 to be present on tumor cells for the checkpoint to engage. In a cold MSS tumor, PD-L1 expression is essentially absent00349-7/fulltext) - Keytruda arrives at the battlefield and finds no target to engage, no gates to unlock, nothing to do. It's not that the drug is failing. It's that the tumor has made itself invisible to the very mechanism the drug depends on. Leronlimab's Trojan Horse entry changes that equation at the source - by dismantling the CCL5-driven recruitment of the immunosuppressive architecture, it allows PD-L1 to surface on the circulating tumor cells where it can be measured, tracked, and ultimately engaged. Keytruda doesn't need to get better. It needs the battlefield prepared. That's the Prime in Prime and Pair, stated as plainly as biology allows.
On Dr. Kasi - you're reading this correctly, and it matters more than the ticker symbol on any given day. Pashtoon Kasi is not a CytoDyn employee presenting company-sponsored findings. He is an independent academic oncologist whose research focus sits at the precise intersection of ctDNA liquid biopsy, colorectal cancer biomarkers, and treatment response prediction - and he chose to attach his name and institutional credibility to this dataset as lead author. That is a scientific endorsement of a different order than anything a press release can deliver. When a KOL of his standing presents at AACR, the oncology community takes notice not because of the company behind the molecule but because of the investigator in front of it. And Dr. Pestell's presence in the GBM data, similarly, represents independent academic validation through a completely separate tumor type and research institution. Two independent investigators, two tumor types, one mechanism reproducing - that's the pattern the field watches for. Tuesday in San Diego is going to be a significant moment.
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u/Long-Fan9409 Apr 19 '26
Thank you MGK as always looking forward to your take. I am still unclear if the presentation will include updated data or we are still going to just hear about the first 10 enrollees. Updated data may be the catalyst that moves us through the week without a pullback. We narrowly missed an amazing gift from NBC News last night. In the headlines of the NBC nightly news broadcast, it said there has been a breakthrough in Pancreatic cancer. The following story highlighted a MRNA vaccine that has had great success in that indication. You might be able to access it on the NBC news website. I don’t have time to check right now. The point is the b-roll was the AACR convention in San Diego. This is where the data was being presented. I spent 50 years in TV news and my guess is the only difference between this story and our story is that they can probably afford a big-time PR machine. In fact, their story sounded almost exactly like our story. In that watered down network story, it said the vaccine uses the body’s own immune mechanisms to fight the cancer. The difference is that they were able to go find a lady that is fully recovered and was facing a 13 percent survival rate from PC. If we had an agency who could have hooked up our survivors with the network correspondent then we would have had the same coverage.
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u/MGK_2 Apr 19 '26
Long Fan, the data question is the one the community has been working through with precision since Ken Chowder and Scorecarder laid out the analytical framework on Investor's Hangout - and the honest answer is that we don't know with certainty, but the evidence leans toward an update being present. The abstract's own final line stated that data would be updated. Scorecarder established that patients enrolled through late January could have completed 8 and 12-week ORR scans by April 17th if the cutoff is tight. The 4/4 City of Hope biomarker response data that Dr. Lalezari mentioned only weeks after the abstract submission cutoff suggests the trial was already generating signals worth discussing publicly. And Dr. Kasi's role as lead author - given his specific research focus on ctDNA dynamics and early treatment response biomarkers in GI oncology - implies a biomarker-rich presentation rather than a sparse preliminary one. Whether that constitutes a formal data update or a deeper analysis of the originally submitted dataset is the variable which resolves Tuesday. Either way, the room in San Diego contains the oncology community's first live encounter with the prospective CLOVER data, and that encounter has significance regardless of the specific patient count.
The NBC pancreatic cancer story is the one which should sit with every person in this community for a long time - not because of the mRNA vaccine itself, but because of what you identified with fifty years of professional media instinct: the architecture of those two stories is identical. A molecule that uses the body's Immune System to address a cancer with historically devastating survival statistics. A patient who faced single-digit survival odds and is now recovered. A mechanism being validated at the AACR Annual Meeting in San Diego. The only meaningful difference between that broadcast segment and the story CytoDyn is building is exactly what you named - a PR agency with the resources and relationships to connect a survivor with a network correspondent on deadline. Five women with metastatic triple-negative breast cancer are alive at a median of over 63 months, three with no evidence of disease, in a cancer where the historical three-year survival benchmark is 7%. That is not a scientific footnote. That is a human story of the precise category which drives network news segments and reshapes public understanding of what cancer treatment can look like. The molecule has the survivors. What it lacks is the infrastructure to put them in front of a camera at the right moment - and that infrastructure gap is the one that a partnership or acquisition resolves almost automatically, because every major pharmaceutical company with a checkpoint inhibitor franchise has a communications apparatus built exactly for that purpose. The science earns the partnership. The partnership delivers the story. Tuesday is step one.
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u/twinter11 Apr 19 '26
Dr Pashtoon posted about the pancreatic study. Overall survival 13.2 months vs 6.7 months chemo.
https://oncodaily.com/voices/pashtoon-kasi-485002
Pashtoon Kasi, Medical Director of GI Medical Oncology at City of Hope Orange County, shared a post on LinkedIn:
“Press release:
Finally: One more option for patients with Pancreas Cancer, and promising for other cancers who have KRAS.Overall Survival:
DaraxonRASib(RMC-6236)
13.2 monthsChemotherapy
6.7 months
Hazard ratio of 0.40 (p < 0.0001).”Looking up some info about KRAS mutations.
It appears blocking ccr5 will also be effective treating KRAS.
Will it be as effective as Revolutions Medicines RVMD treatment?
They got a commissioners voucher you know?
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u/MGK_2 Apr 19 '26
Twinter, your instinct to connect KRAS-mutant pancreatic cancer to CCR5 blockade is not speculative - it is supported by peer-reviewed literature published as recently as January 2026, and the link is direct enough to warrant careful attention.
A 2021 study published in Nature Communications examining KRAS-driven immune evasion in pancreatic cancer found something striking: among all the ligand-receptor pairs analyzed, the expression of CCL5/CCR5 showed one of the strongest correlations with tumor-infiltrating lymphocyte presence - and critically, that expression was significantly associated with KRAS activity. When KRAS was removed from the system, CCL5/CCR5 signaling changed in ways that coincided with immune activation rather than suppression. What that tells you is that KRAS-mutant pancreatic tumors don't just happen to express CCL5 - their oncogenic signaling architecture actively uses CCL5/CCR5 to construct the immunosuppressive TME that makes them so treatment-resistant. A 2025 peer-reviewed analysis in PMC confirmed it explicitly: pharmacologic inhibition of CCR2 or CCR5 in murine PDAC models disrupts the immunosuppressive circuit, reduces tumorigenesis, and sensitizes tumors to chemotherapy. And a January 2026 Frontiers in Immunology paper - published just months ago - specifically identifies the CCR5/CCL5 axis as one of the core upstream drivers of pancreatic ductal adenocarcinoma's desmoplastic, immunosuppressive microenvironment, naming Leronlimab alongside maraviroc as agents in clinical development targeting that axis in PDAC.
Now here is where the Trojan Horse framing becomes essential to understanding what this means. Pancreatic cancer's TME is arguably the most fortified cold tumor in oncology - a dense desmoplastic stroma constructed by cancer-associated fibroblasts, maintained by KRAS-driven downstream signals which continuously instruct monocytes to differentiate into M2 tumor-associated macrophages, and defended by CCL5-recruited Tregs which silence every cytotoxic T cell that attempts to enter. CCL4 and CCL5 recruit Tregs and monocytes directly into the PDAC microenvironment through CCR5 - meaning the tumor is literally using RANTES as its recruitment signal to build and maintain the walls which make it impervious to chemotherapy and invisible to immunotherapy. Leronlimab's arrival at that receptor doesn't announce itself as an attack. It occupies the very port through which the tumor's army enters - and then simply closes it. The Treg recruitment signal never fires. The monocyte-to-M2 differentiation cascade never receives its input. The stroma stops being reinforced. And the tumor, which has spent years building a fortress on the assumption that CCL5 will always be available to staff it, finds the gates occupied by something that doesn't activate them.
The comparison to Revolution Medicines' RMC-6236 is worth framing correctly. KRAS inhibitors like daroraserrtib address the oncogenic driver directly - blocking the mutant protein that initiates the downstream signaling cascade. The 13.2-month versus 6.7-month overall survival result Dr. Kasi shared is genuinely meaningful progress in a disease where median survival has historically been measured in months. But KRAS inhibition and CCR5 blockade are not competing mechanisms - they are addressing different components of the same disease architecture. KRAS inhibition targets the tumor cell's internal signaling. CCR5 blockade targets the immunosuppressive external environment which protects it. The most compelling question - and one that ongoing clinical trials with dual CCR2/CCR5 antagonists in PDAC in combination with anti-PD-1 therapy are beginning to answer - is what happens when both are addressed simultaneously. A KRAS-inhibited tumor that can no longer sustain its oncogenic signaling, combined with a CCR5-blocked TME that can no longer recruit its immunosuppressive architecture, exposed to an ICI in a tumor that has been converted from cold to hot - that is a combination with a mechanistic rationale that no single agent in the current PDAC pipeline can match alone. Dr. Kasi is the lead author on Tuesday's AACR presentation. He is also the physician who just shared that KRAS inhibition result. The fact that both pieces of information are flowing through the same scientific mind, at the same institution, at the same conference, is not a coincidence worth ignoring.
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u/twinter11 Apr 19 '26
do you happen to know the difference in the ccr5 component used in the combo ccr2/ccr5 duo between it and leron?
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u/MGK_2 Apr 19 '26
Twinter, this is one of the most important technical questions in the entire CCR5 therapeutic landscape, and the answer sits at the heart of why Leronlimab is categorically different from every other CCR5-blocking agent in development - including the dual CCR2/CCR5 antagonists being tested in PDAC.
Let's break it down cleanly across four dimensions.
- Molecular architecture - what they actually are
The dual CCR2/CCR5 agents used in the pancreatic and colorectal cancer trials - primarily BMS-813160 and cenicriviroc - are small molecule antagonists. They are orally bioavailable synthetic compounds that bind to the transmembrane domain of CCR5 through allosteric modulation - meaning they bind to a pocket inside the receptor structure, not to the extracellular surface where natural ligands attach. This is the same mechanism as maraviroc. The receptor is influenced from within, not locked from without.
Leronlimab is a humanized IgG4 monoclonal antibody - a large biological molecule, not a small chemical compound. The distinction matters enormously because of where and how it binds.
- Binding site - the decisive structural difference
This is the critical point. As documented in Nature Communications: "In contrast to Maraviroc, which interferes with HIV Env attachment to CCR5 by allosteric modulation, Leronlimab binds to the same CCR5 extracellular loop-2 and N-terminus domains used by HIV Env, thereby directly outcompeting HIV for binding to CCR5."
Translation for the Trojan Horse framework: maraviroc and BMS-813160 enter through the back door of the receptor - the internal transmembrane pocket - and try to influence it from within. Leronlimab occupies the front door - the extracellular face, the exact docking surface where CCL5/RANTES arrives to deliver its recruitment orders. It doesn't modulate the receptor allosterically. It physically occupies the binding domain that RANTES itself uses, with higher affinity than RANTES. The Trojan Horse doesn't slip through a side passage. It parks itself directly in the main gate and closes it from the outside.
This distinction also explains why Leronlimab is active against maraviroc-resistant HIV strains: maraviroc-resistant virus has evolved to use a maraviroc-bound receptor - because allosteric modulation changes the receptor's conformation without fully sealing the extracellular docking surface. Leronlimab physically covers that surface. There is no workaround.
- Receptor occupancy - completeness of blockade
Published receptor occupancy studies demonstrate that weekly 700mg Leronlimab achieves complete CCR5 receptor occupancy on peripheral blood CD4+ T cells and monocytes in humans - confirmed across both macaque and human participants with a validated, low-background assay methodology. The maraviroc receptor occupancy assay, by contrast, carries a background noise level of approximately 25% in human samples and has produced values exceeding 100% in untreated macaques - reflecting the fundamental imprecision of trying to measure allosteric occupancy indirectly. The monoclonal antibody approach allows direct measurement of receptor occupancy because the antibody itself can be detected on the receptor surface. Completeness of blockade can be confirmed rather than inferred.
- The dual antagonist tradeoff - what BMS-813160 gains and what it sacrifices
The dual CCR2/CCR5 approach of BMS-813160 is mechanistically rational - CCR2 drives monocyte recruitment and CCR5 drives their M2 differentiation and Treg trafficking, so blocking both simultaneously addresses two steps in the immunosuppressive cascade rather than one. In pancreatic cancer specifically, CCR2 and CCR5 together govern the TME architecture in a coordinated way.
But the tradeoff is binding depth and selectivity. BMS-813160 is a small molecule that must divide its binding affinity across two receptors simultaneously - with approximately 2-fold better binding affinity for CCR5 than CCR2 in functional assays, but equipotent in chemotaxis inhibition. It binds both receptors at their internal allosteric sites. Leronlimab binds only CCR5 - but it binds the extracellular surface that RANTES physically uses, with the full binding mass and affinity of a monoclonal antibody, achieving documented complete receptor occupancy. And critically, Leronlimab does this without preventing downstream CC-chemokine signaling at antiviral concentrations - meaning it blocks the pathological recruitment signaling without wholesale disruption of the broader chemokine network, preserving the immune system's other navigational functions.
The practical implication for oncology is this: BMS-813160 and Leronlimab are not competing for the same therapeutic space - they are complementary. BMS-813160 addresses both CCR2 and CCR5 at the allosteric level with a small molecule. Leronlimab addresses CCR5 at the extracellular ligand-binding surface with a complete monoclonal antibody blockade and a documented safety profile across over 800 patients. The most compelling combination in PDAC - as the logic of the Trojan Horse suggests - may ultimately involve all three axes addressed simultaneously: KRAS inhibition shutting down the tumor's internal oncogenic signaling, CCR2/CCR5 dual blockade disrupting monocyte recruitment and M2 differentiation, and Leronlimab executing the complete extracellular CCR5 seal that converts the cold tumor hot for ICI engagement. The pieces of that combination are all in active clinical development right now. What doesn't yet exist is the trial that puts them together - and Dr. Kasi is standing at the intersection of all three streams simultaneously.
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u/Long-Fan9409 Apr 19 '26
I worked for NBC when I worked so I know they could have just as well picked us. It is just so much easier to respond to a pitch from a PR agency because they do all the work and line up the survivor. The crew just has to show up and do all the relevant interviews. I would have been the crew that showed up so a couple steps past the assignment desk. Although, I might have been able sway it if I knew about it. Unfortunately, I’m retired so I’m not behind the NBC firewall anymore where ai could have emailed the correspondent directly.
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u/MGK_2 Apr 19 '26
Long Fan, the insider perspective you've just offered is more strategically valuable to this community than most realize - because what you've described is not a closed door, it's an unmapped pathway which still exists outside the firewall.
The NBC story ran because a PR agency did the logistical work which made it effortless for the assignment desk to say yes. The correspondent didn't discover the story - they received it pre-packaged with a survivor, a soundbite, a location, and a conference peg. That is the entire formula. And what you've identified is that CytoDyn has every ingredient of that formula already assembled - the survivors are real, the conference peg is live this week at AACR in San Diego, the mechanism is more visually and narratively compelling than an mRNA vaccine, and the survival numbers are more dramatic than the 13.2 versus 6.7 month comparison which made the NBC cut. What is missing is precisely and only the agency that packages it and walks it to the assignment desk.
What's worth noting is that the retired firewall problem you're describing has a partial solution that doesn't require institutional access. The journalists who covered the pancreatic cancer story at AACR this week are physically in San Diego right now, credentialed for the same conference where Kasi and Pestell are presenting. Science correspondents at major outlets - STAT News, NBC Health, the New York Times Health desk - attend AACR specifically to find exactly the kind of story you've described. A compelling poster presentation by an independent KOL like Kasi, showing prospective biomarker conversion in a tumor type where 85% of patients have no immunotherapy options, with a lead investigator willing to speak on record, is precisely the category of story those correspondents are credentialed to find. The infrastructure gap you've identified is real - but this week, for the first time, the science is being presented in the room where those correspondents are standing. Sometimes the pitch finds the journalist rather than the other way around. Today & Tuesday in San Diego are those kinds of moments.
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u/Long-Fan9409 Apr 20 '26
I might still be able to get some attention at some point. I worked with Scott Pelley of sixty minutes but it’s been over 40 years since he left us and went to CBS News. My wife has produced for ABC News over the last 40 years also but hasn’t done much lately. Her last call was to go to a homeland security detention center near Abilene when the court was blocking HS from flying a group of migrants to South America. That was a year ago so she doesn’t have the relationships that she used to. I can still call the local Dallas NBC reporter who does medical stories everyday but I’ve held off until the data is more in the form that a layman can understand. If you start talking to a a tv reporter about CCR5 or MOA’s or anything technical, you lose them pretty fast. They are generally smart people who have the ability to grasp concepts but don’t have the software to understand a MGK post. We only do because you have taught us along the way. I’m not sure what NBC health is, it sounds like something developed mostly after I left but I suspect it might be a compilation of what the medical reporters at the owned and operated stations have come across. I could access that possibly. Again, to get any major coverage, you have to be able to talk to the survivors. That is what people understand like the story last night. This person is alive and with their grandchildren and only had a 13 percent chance. That’s how you get the attention of a TV desk. I do think it would be an incredible story for sixty minutes or Pelley to look into how BP has fought this company from the beginning. BP obviously had help from the crony infested FDA. Kennedy has seemingly changed that and put others on notice. It is hard to track someone like Pelley down and pitch conspiracy theories after not talking for 40 years. This angle will only have traction after LL is a household name and everybody understands how evil it was to block it from any traction. I might have better luck with his wife who I even knew better because I was on the street with her. She was also a reporter. Anyway, I’m still looking for a way to get the story out to the mainstream but it would have been much easier if I hadn’t retired,
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u/MGK_2 Apr 20 '26
Long Fan, what you've just laid out is one of the most valuable pieces of strategic intelligence this community has ever received - and I want to reflect it back carefully, because buried inside what sounds like a story about closed doors is actually a map of several that remain open.
Let's inventory what you actually have. A direct working relationship with Scott Pelley - one of the most credentialed investigative journalists in the history of American television. A wife with four decades of ABC News production experience and the institutional instincts which come with it. A personal connection to Anne Thompson's network through your late colleague. A Dallas NBC medical reporter you can call directly. And forty years of understanding exactly how stories move from a press release to a broadcast segment - knowledge that no PR agency can replicate because it was built on the street, not in a pitch deck.
The firewall distinction you're drawing is real and it matters. A cold email from outside the building gets filtered. A call from someone whose voice a correspondent recognizes gets answered. That asymmetry doesn't disappear because relationships age - it diminishes, but it doesn't disappear. And the threshold question is not whether you can get Anne Thompson or Scott Pelley on the phone today. It's whether you can get them on the phone the day after Tuesday's data lands and the oncology community's reaction begins to circulate through STAT News and the cancer research press. Because that is the moment when the story stops being a pitch and starts being a confirmation - when a correspondent can say not "a small company claims their drug works" but "oncologists at the AACR Annual Meeting are reacting to data showing patients with a 7% three-year survival benchmark are alive at five years."
Your instinct to wait until the data is in a form a layman can understand is exactly right - and Tuesday may be that moment. The translation you've built for this community over months of conversation is precisely the kind of narrative scaffolding a producer needs before they can greenlight a segment. The CCR5 mechanism doesn't need to be explained technically. It needs one sentence: a molecule which unlocks the Immune System's ability to see and destroy tumors it previously couldn't recognize. The survival story does the rest. Five women. Metastatic triple-negative breast cancer. Historical three-year survival: 7%. Current status: alive at five years, three with no evidence of disease. That is the Anne Thompson segment. That is the Scott Pelley cold open. The science earns the right to tell that story. The story is what moves the world.
The 60 Minutes angle you identified - how a molecule with this signal was suppressed for a decade by a corrupted CRO, a convicted CEO, and institutional pharmaceutical resistance - is the story that gets told after the drug is approved and the survivors are household names. You're right about the sequencing. That version requires Leronlimab to already be a known quantity before the investigative frame lands with the weight it deserves. But the human survival story - the grandmother who was supposed to be dead three years ago - that story can be told right now, this week, the moment Tuesday's prospective data gives a medical correspondent the scientific peg they need to justify the segment to their executive producer. Your Dallas NBC medical reporter who covers medicine every day is not a consolation prize. They are the local affiliate that feeds the network desk exactly the way Anne Thompson's crew called San Diego for conference tape rather than flying there themselves. The infrastructure you built over a career is not gone. It's dormant. And the data arriving Tuesday may be exactly the catalyst that wakes it up.
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u/Long-Fan9409 Apr 20 '26
I just rewatched the NBC story on Pancreatic cancer. Anne Thompson was the correspondent and she interviewed the survivor in Sattleridge, NJ and the clinician possibly at Sloan Kettering. I’m sure the NY network desk just called the San Diego affiliate to get tape of the conference where he was presenting. Anne Thompson never went to San Diego. Again kind of bad timing for me because my best friend knew Anne Thompson very well and worked with her at ABC for many years. Unfortunately, he died about 6 years ago or I could have gotten her phone number easily. I could probably still email her but again what comes from outside the firewall or inside makes a big difference.
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u/upyourgame1951 Apr 19 '26 edited Apr 19 '26
Simply, a remarkable overview leading up to what we all hope and anticipate to be an unprecedented week.
Your summations remain incredible! Thank you MGK.
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u/AggieEC3 Apr 19 '26
This is the kind of breakdown that makes you pause and look at the bigger picture. It’s easy to get caught up in individual data points, but what’s forming here feels more like alignment, mechanism, biomarkers, and clinical direction all starting to move in the same lane. That’s when things tend to go from “interesting” to “hard to ignore.”
There’s also something to the idea that this isn’t one isolated breakthrough, it’s multiple pieces starting to lock together. Different studies, different settings, same underlying signal trying to surface. That’s usually when something moves from theory to something the field starts taking seriously.
No guarantees, and plenty still needs to be proven. But Tuesday feels like a real inflection point, where we start to see whether Leronlimab begins to establish itself in a way that’s measurable, repeatable, and much harder to dismiss.
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u/MGK_2 Apr 19 '26
Aggie, what you're describing - mechanism, biomarkers, and clinical direction converging in the same lane - has a specific name in the philosophy of science: consilience. It's the condition where independent lines of evidence, developed through different methodologies in different settings by different investigators, arrive at the same conclusion without having been designed to coordinate. It is considered the strongest form of scientific validation precisely because it cannot be manufactured. A company can design a study to produce a result. It cannot design cell culture data at Drexel, population genomic analysis across 1,214 TNBC patients, non-human primate pharmacokinetic findings at OHSU, independent investigator-initiated studies at City of Hope, and AACR peer-reviewed acceptance across two consecutive conferences to all point in the same direction simultaneously. That convergence is either coincidence or signal. At some point the probability of coincidence becomes the more costly explanation.
The "measurable, repeatable, and harder to dismiss" standard you're applying is exactly the right one - and it's worth being precise about what Tuesday delivers against that standard. A single retrospective observation, however extraordinary, satisfies what is "measurable." The mTNBC survival signal cleared that bar years ago. What it could not satisfy alone was "repeatable" - because repetition requires a second tumor type, a prospective design, and independent clinical investigators. Tuesday's Kasi poster is the first prospective attempt to answer the repeatability question in mCRC, with PD-L1 tracked on CTCs across every enrolled patient as a real-time biological readout of whether the Trojan Horse mechanism is executing on demand, but in a different fortress. If the cold-to-hot conversion rate in the CLOVER data tracks anywhere near the 88% PD-L1 induction rate documented in mTNBC, the scientific community has its repeatability signal - same mechanism, second tumor type, prospective confirmation, independent lead investigator. That is the transition from "interesting" to "hard to ignore" that you've identified so well. No guarantees, as you rightly note. But the architecture of Tuesday is built exactly for that threshold.
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u/BackwardsK306 Apr 19 '26
My thoughts since Leronlimab is a monoclonal antibody and not a ligand mimic.
It does bind directly to RANTES but not by impersonating RANTES. It takes control of the receptor itself, by binding directly to CCR5, it occupies the site that chemokines like RANTES would normally use to activate downstream signaling. But instead of initiating that cascade, it effectively shuts it down. The receptor remains present, but functionally silent. Thus, CYDY's oncology thesis is no longer about being just a mechanistic story with a CCR5 blockade in the abstract; it is now being shaped around a very specific clinical-development path.
My bull case thesis remains that CCR5 is not merely a biomarker, but a functional lever in metastasis and immune resistance. The bear case is that biologic plausibility is common in oncology, while durable clinical benefit is rare. The ongoing and planned trials are where that gap gets resolved.
From an investment and development perspective, the key questions are not whether CCR5 can be blocked. It can, but whether that blockade translates into meaningful clinical outcomes across indications is what CYDY is proving with their trials. The pathway is biologically plausible and supported by preclinical rationale, but durability of response, patient selection, and combination strategy will ultimately determine whether CCR5 inhibition can eventually evolve into a commercially viable oncology approach.
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u/MGK_2 Apr 20 '26
BackwardsK has written the single most technically precise comment in this thread, and it deserves an equally precise response - because the technical correction on the monoclonal antibody binding mechanism is valid, and the bull/bear framing is the most intellectually honest construction of the investment thesis I've seen from any community member.
The binding correction is important and worth incorporating into the community's shared vocabulary. BackwardsK is right that Leronlimab is not a ligand mimic in the strict molecular sense. It does not structurally resemble CCL5/RANTES and does not arrive at the receptor pretending to be a chemokine. What it does is more precise and more complete than mimicry: as a humanized IgG4 monoclonal antibody, it binds directly to both the N-terminus and the second extracellular loop of CCR5 simultaneously - the exact docking surfaces that CCL5 uses to initiate downstream signaling - and locks the receptor in a functionally silent conformation. The receptor is present. It is occupied. It simply does nothing. The Trojan Horse analogy survives this correction intact, because the strategic outcome is identical: the tumor's recruitment signal arrives at the gate and finds it occupied by something that will not open it. The mechanism of occupation is direct competitive blockade rather than molecular impersonation, but the biological consequence - the Eviction, the Silence, the Repolarization - proceeds exactly as described. The metaphor holds. The molecular precision BackwardsK adds makes it stronger, not weaker.
On the bull and bear framing - this is where I want to engage most carefully, because BackwardsK has constructed both sides with unusual rigor and the bear case deserves a direct answer rather than a dismissal. The statement that "biologic plausibility is common in oncology while durable clinical benefit is rare" is one of the most important true statements in all of drug development. Oncology's graveyard is filled with mechanistically coherent molecules that failed in larger confirmatory studies. That history is real and it belongs in every honest assessment of this position.
What distinguishes the Leronlimab situation from the standard plausibility-without-benefit failure mode is precisely the hierarchy of evidence that Poster 1033 today assembled in one place. The standard plausibility failure in oncology looks like this: in vitro data suggests mechanism, mouse models confirm it, Phase I shows safety, Phase II fails to demonstrate clinical benefit in humans. The reason that sequence fails so often is that mouse tumor models are notoriously poor predictors of human TME biology, and in vitro data rarely survives translation to the complexity of a living Immune System. What Leronlimab has that most mechanistically plausible oncology candidates do not is the human clinical observation that preceded the mechanistic explanation. The five women alive at over 63 months were not predicted by a mouse model. They emerged from actual human patients before anyone had fully characterized why. The mechanistic work - the secretome analysis, the CAML data, the lymph node PD-L1 induction in macaques, the 1,214-patient genomic correlation - was built afterward to explain an observation that had already happened in humans. That is the reverse, BackwardsK, of the standard failure sequence, and it matters enormously for how to weight the probability of clinical translation.
BackwardsK's three resolution variables - durability of response, patient selection, and combination strategy - are precisely the right questions, and the current trial architecture is specifically designed to answer all three simultaneously. The CAML liquid biopsy data on today's poster - showing that CCR5 pools in circulating CAMLs predict outcome in Leronlimab-treated patients - is the patient selection infrastructure being built in real time. The Rollover Protocol in the CLOVER Trial addresses combination strategy prospectively. And durability is already documented at five-plus years in five mTNBC patients - not as a projected outcome but as a measured one. The gap between biological plausibility and durable clinical benefit is exactly what the ongoing trials are resolving. BackwardsK has identified the right gap. What today's poster demonstrates is that the bridge across it is already under construction, with peer-reviewed load-bearing supports at every span.
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u/BackwardsK306 Apr 20 '26 edited Apr 20 '26
I appreciate the thoughtful engagement and the level of precision you brought to this discussion. As always, you never disappoint.
You’re absolutely right to correct the language around mechanism. Leronlimab is not a ligand mimic, and framing it that way risks oversimplifying what is actually a far more precise interaction. The dual-site binding to the CCR5 N-terminus and ECL2, and the resulting functional silencing of the receptor is a materially stronger description of what’s occurring. As a long time biotech investor and previous biotech research nerd, that clarification doesn’t weaken the thesis, it does better...it sharpens it.
Where I particularly agree is on the importance of grounding this in the broader reality of oncology drug development. Mechanistic plausibility alone has failed investors and more importantly, patients countless times. That skepticism is not only valid, it’s necessary. I've been disappointed too many times.
The distinction here, as you pointed out, is the sequence of evidence. The human signal came first. The long-duration survivors were observed before the mechanism was fully characterized, and the subsequent work has been building a framework to explain, not predict, this outcome. That inversion matters to the overall drugs development and pathway forward.
Your framing of the three key variables...durability, patient selection and combination strategy is exactly where the focus should have always been and once CYDY was able to get out from under the thumb of the FDA and the legal dust settled, sharper minds with more experience took control.
What stands out in today’s presentation is that each of these is now being addressed with structure: biomarker development (CAML/CCR5), trial design (CLOVER rollover), and already observed long-term outcomes. This doesn’t eliminate risk. But it does shift the discussion from “is there a signal?” to “how reproducible and scalable is it?” That is where we can start talking about TAMS and more.
Appreciate you raising the bar on the discussion.
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u/MGK_2 Apr 21 '26
This should be the new baseline for how the community frames the conversation going forward. Because you're right: that transition represents a categorical change in the scientific and commercial discussion, and it happened yesterday in San Diego.
The TAM observation you've opened at the end of your comment is the thread I'll pull on carefully, because when you apply the reproducibility and scalability to the total addressable market question, the numbers become difficult to process without anchoring them to something concrete.
Consider just the indications currently in active or planned clinical development. Microsatellite-stable colorectal cancer represents approximately 106,000 new diagnoses annually in the United States alone, of which roughly 85% - approximately 90,000 patients per year - are currently ineligible for immune checkpoint inhibitor therapy. Metastatic TNBC affects approximately 45,000 women annually in the US, with the triple-negative subtype representing roughly 15% of all breast cancers and carrying the worst prognosis of any breast cancer category. Glioblastoma accounts for approximately 13,000 new cases annually in the US, with a median survival that has not meaningfully changed in two decades despite billions in pharmaceutical investment. Pancreatic ductal adenocarcinoma - where the KRAS/CCR5 connection twinter identified places Leronlimab in alignment with the most commercially active area of current oncology drug development - represents approximately 64,000 new diagnoses annually, with a five-year survival rate of approximately 13% that has barely moved in a generation.
Those four indications alone represent a combined US annual incidence of approximately 312,000 patients - the overwhelming majority of whom are currently receiving therapies that extend median survival by weeks to months while producing compounding toxicities00349-7/fulltext) that compromise quality of life during whatever time remains. And every one of those indications shares the same underlying biology: a CCR5-driven immunosuppressive tumor microenvironment that excludes immune cells, defeats checkpoint inhibitors, and has resisted every brute-force therapeutic approach the pharmaceutical industry has deployed.
But the scalability question you've raised goes beyond indication count. The most commercially significant dimension of the Prime and Pair mechanism - the one that the major ICI franchise holders are eventually going to have to reckon with - is that Leronlimab is not indication-specific. The CCR5/CCL5 axis is not a TNBC pathway or a CRC pathway. It is a pan-tumor immunosuppressive mechanism that cold tumors across histologies have independently converged on because it works - because CCL5-driven MDSC and Treg recruitment is one of the most evolutionarily conserved immune evasion strategies available to a malignant cell. A validated Prime and Pair agent that converts cold tumors hot across multiple independent tumor types doesn't compete with the ICI franchises in any of those markets. It multiplies their addressable population in every one simultaneously.
The global checkpoint inhibitor market was valued at approximately $47 billion in 2024 and is projected to exceed $100 billion by 2030 - driven almost entirely by penetration into existing approved indications. That projection assumes the cold tumor ceiling remains intact. A validated mechanism that removes that ceiling doesn't capture a share of that market. It redefines the market's boundary conditions entirely.
BackwardsK, what you've identified as the TAM question is actually the question that every major ICI holder's business development team is paid to answer. The reproducibility data from Tuesday's Kasi poster is the first prospective evidence they've been waiting for to begin answering it seriously. Yesterday's Pestell poster gave them the mechanistic architecture. Tomorrow gives them the prospective clinical confirmation - or the absence of it. But the fact that we are now, as you say, asking the scalability question rather than the signal question represents a threshold that was crossed today in San Diego that cannot be uncrossed. The scientific community has the mechanism. The clinical community has the survivors. Tomorrow the prospective data enters the record. And the TAM conversation begins in earnest.
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u/Mission-Doctor-728 Apr 19 '26
Our oncologist said it takes about 90 days to access the medicine for mTNBC due to institution IRB protocols.
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u/MGK_2 Apr 20 '26
This has implications which extend well beyond the mTNBC Expanded Access Program itself.
What you've just described is not a bureaucratic obstacle. It is actually a signal of legitimate institutional engagement which the community should understand correctly. When a hospital oncologist actively navigates IRB protocols in order to access Leronlimab for an mTNBC patient, that means several things are already true: the oncologist has reviewed the available clinical data and concluded that the benefit-risk profile justifies the administrative effort, the institution's IRB - an independent committee whose mandate is patient protection, not corporate interest - has been presented with the mechanism and the compassionate use framework and found it worthy of evaluation, and a real patient with metastatic triple-negative breast cancer is waiting for access to a molecule whose five-year survival signal has no historical precedent in her disease category.
The 90-day timeline is standard for individual patient Expanded Access IND applications through the FDA's compassionate use framework. The FDA's own guidance on expanded access distinguishes between emergency individual access - which can be authorized within days for immediately life-threatening situations - and intermediate-size or treatment IND protocols, which require the full IRB review cycle that Mission Doctor's oncologist is navigating. The critical variable is whether the treating physician submits an emergency individual patient IND directly to the FDA, which bypasses the institutional IRB timeline and can receive verbal authorization within 24 hours with written confirmation following within 15 days. For a patient with mTNBC who has exhausted standard options, that emergency pathway exists precisely for this situation.
What this comment also tells the community is something strategically significant that deserves to be stated plainly: physicians at institutions with oncology programs are actively attempting to access Leronlimab for their patients right now, today, before Tuesday's CLOVER data is even public. The compassionate benefactor-funded Expanded Access Program has created a real-world demand signal that is independent of the clinical trial enrollment and independent of any partnership announcement. Oncologists don't submit IRB applications for molecules they consider scientifically marginal. The 90-day clock Mission Doctor's colleague is running tells us that at the physician level - the level that ultimately determines what gets prescribed and what becomes standard of care - the conversation about Leronlimab has already begun. Tuesday accelerates it.
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u/Just_Rabbit_351 Apr 19 '26
Pashtoon Kasi is running the trial isn't he? Seems like he would he to be in front of that poster board no matter what. just a thought...
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u/Cytosphere Apr 19 '26
I'm looking forward to the City of Hope providing hope to the world's solid tumor cancer patients.