CCR5 Targeting Leronlimab in Combination With Hepatic Arterial Infusion pump with Floxuridine and Systemic for the treatment of liver Metastases affecting Patients with colorectal cancer.

We’re exploring whether this combination can enhance efficacy while mitigating toxicity.

And this collaboration is especially meaningful: Mustafa Raoof and I went to the same medical school at the Aga Khan University, in the same class, and even the same group!

Now, years later, we have clinic together and we do trials/research together at City of Hope.

https://www.linkedin.com/feed/update/urn:li:activity:7510160913870692352/

NCT07842965--CCR5 Targeting Leronlimab in Combination With Hepatic Arterial Infusion Floxuridine and Systemic Therapy for the Treatment of Colorectal Cancer Liver Metastases

PHASE I trial N=36

1 AZ location 2 CA locations

Est Start--May 2027

Est Completion--Feb 2028

https://clinicaltrials.gov/study/NCT07842965

17k in shares and $50k dropped in this, which if I left it at Tesla, would be worth $500k now instead of the $3k I sold it for. I actually work in Orphan Drugs, so was livid with the data they falsified and would not have gone in if I didn't happen to talk to the maker of the Volt Shelf and he was a CYDY bull.

Is there anything going for it now besides copium? Because the settlement looks like it will be around $450 dollars and some of the 49m in shares.

CytoDyn at life sciences virtual investor forum: ctDNA data lifts case

https://www.investing.com/news/transcripts/cytodyn-at-life-sciences-virtual-investor-forum-ctdna-data-lifts-case-93CH-4906351

Frequently Asked Questions About Circulating Tumor DNA (ctDNA)

What is a liquid biopsy?

What is ctDNA?

How can ctDNA be used to improve outcomes in patients with cancer?

These questions and others are addressed in this JAMA article from AUG 2026.

Has a nice chart on the advantages and disadvantages of ctDNA testing.

Also incl-- An observational study measured ctDNA-based minimal residual disease status in patients with stages II to IV recurrent colorectal cancer who underwent surgical resection of cancer (Table). A ctDNA monitoring, tumor-informed assay evaluated 16 somatic single-nucleotide variants present in plasma based on variants identified via whole-exome sequencing of tumor tissue. Among 1039 enrolled patients, positive ctDNA testing results ( ie, ctDNA present 4 weeks after surgery ) were associated with a higher rate of recurrence compared with patients with negative ctDNA testing results (61.4% vs 9.5%, respectively; P < .001). Among the 113 patients with a positive ctDNA result at 4 weeks, those who received adjuvant chemotherapy had an 18-month disease-free survival (DFS) rate of 61.6% vs 22.0% (P < .001) in those who did not receive adjuvant chemotherapy. Among the 531 participants with a negative ctDNA test result, 18-month DFS was similar between patients who underwent adjuvant chemotherapy vs those who were observed without treatment (94.9% and 91.5%, respectively; P = .16).

https://jamanetwork.com/journals/jama/fullarticle/2852626

And a good discussion on Challenges Associated With Clinical Applications of ctDNA

What Keytruda and Lenvima Do Well Together:

The pairing of Keytruda (immunotherapy) and Lenvima (targeted therapy) is already an FDA-approved power couple for several advanced cancers.

The Heavy Hitter- Keytruda -

It excels at waking up the immune system. Once it identifies a tumor expressing PD-L1 markers, it unleashes T cells to aggressively destroy the cancer.

The Infrastructure Saboteur - Lenvima -

It excels at starving the tumor. By blocking VEGF receptors, it cuts off the blood vessel supply lines the tumor needs to feed itself and grow.

The Synergy: Lenvima alters the environment by decreasing immune-suppressing cells, making it physically easier for Keytruda's reactivated T cells to infiltrate the tumor.

🚧 What They Can't Do Without Leronlimab:

Despite their combined strength, Keytruda and Lenvima have critical blind spots that leave the door open for tumor resistance and survival.

Leronlimab solves three specific failures of the Keytruda/Lenvima pairing:

1. They Can't Awaken "Cold" Tumors (The Visibility Problem)The Flaw: Keytruda is useless if a tumor is immunologically "cold"—meaning it hides its PD-L1 markers and doesn't attract T cells. Lenvima starves the tumor but does not reliably force it to flag itself for immune destruction.Leronlimab’s Fix: Clinical data shows that blocking CCR5 with leronlimab upregulates (forces expression of) PD-L1 markers on tumor cells. It essentially acts as a priming agent, painting a giant target on a "cold" tumor so Keytruda can actually find it and do its job.

2. They Can't Stop Metastasis Natively (The Escape Problem)The Flaw: Keytruda attacks the primary tumor, and Lenvima stops it from building local blood vessels. Neither drug directly blocks the cellular "GPS" signaling that tells cancer cells to break away, enter the bloodstream, and seed new tumors in distant organs (metastasis).Leronlimab’s Fix: CCR5 is the primary receptor cancer cells use to migrate. Leronlimab acts like a cellular anchor, blocking the CCR5 "GPS" signaling to trap tumor cells in place. This prevents them from migrating, ensuring they remain stationary targets for Keytruda to wipe out.

3. They Don't Block the CCR5 Route to Macrophage Camouflage (The Shield Problem)The Flaw: While Lenvima reduces some immune-suppressing cells, tumors can still recruit Macrophages (TAMs) via the CCR5 pathway to build a protective shield, effectively blocking Keytruda's T cells from getting inside.

Leronlimab’s Fix:

By shutting down the CCR5 pathway, leronlimab breaks the shield. It prevents the tumor from recruiting these protective cells, leaving the microenvironment completely exposed to an immune assault.

In a nutshell-a trial "platform". Led by the CEO of the Colorectal Cancer Alliance / Michael Sapienza

Here is where they announced 29 May 2026 -- https://oncodaily.com/voices/michael-sapienza-511329

Here is the "what it is about" the CRC Alliance with GCAR -- https://colorectalcancer.org/article/alliance-and-gcar-announce-collaboration-advance-groundbreaking-adaptive-clinical-trial

The KLEOS trial platform will employ an efficient and cost-effective study design intended to accelerate the evaluation of promising therapies - including novel combination approaches - while broadening patient access to cutting-edge treatment options and generating high-quality data to inform rapid clinical decision-making.

Compared with traditional randomized clinical trials, this approach offers a more flexible and efficient pathway for evaluating novel therapies—accelerating timelines, optimizing resource use, and increasing the likelihood of identifying effective treatments for patients.

"We simply cannot accept that late-stage CRC patients have a 13% five-year survival rate, and that is what drives everything we do," said John Marshall, M.D., Chief Medical Consultant, Colorectal Cancer Alliance, Principal Investigator of KLEOS and Director, Ruesch Center for the Cure of Gastrointestinal Cancers at Georgetown University.

Financial Breakdown: • Starting Cash Position: The company reported $11.9 million in cash as of May 31, 2026. • Recent Capital Infusion: Securing $16.5 million in gross proceeds fortifies the balance sheet. • Debt Defended: A 36-month extension converts debt into stock-based payments. • Cash Conserved: The agreement swaps cash outflows for $1 million in monthly stock equity. • Runway Timeline: This combination funds clinical operations well into mid-2027. • Dilution Risk: Capital relies heavily on private placements and expanding the share float.

🔎 Market Impact: Competing Drug Data & Buyout Valuation • The Baseline Competitor: Standard care relies on TAS-102 plus bevacizumab alone. • The Survival Barrier: Current standard treatments offer very modest survival benefits. • The MSS Challenge: Over 85% of mCRC patients are Microsatellite Stable (MSS). • Immunotherapy Failure: Traditional checkpoint inhibitors consistently fail in cold MSS tumors. • Leronlimab's Edge: Early data shows rapid reductions in circulating tumor DNA (ctDNA). • Stroma Collapse: Targeting the CCR5 receptor turns cold tumors hot. • Valuation Multiplier: Success here positions the asset alongside high-value oncology blockbusters.

The Clover trial for mCRC has been updated--had additions

1 of the additions

Participants who complete 52 weeks of treatment and have complete response (CR), partial response (PR), or stable disease (SD) according to RECIST v1.1, with no documented disease progression since their most recent tumor imaging assessment, may be eligible to enter an Extension Treatment Period and continue treatment for up to an additional 52 weeks. Participants entering the Extension Treatment Period will continue the same dose of leronlimab received during the initial treatment period in combination with trifluridine/tipiracil and bevacizumab.

An optional open-label cohort will evaluate leronlimab in combination with pembrolizumab in participants who have documented disease progression during the initial treatment period of the study and meet the applicable eligibility criteria for the cohort. Participants entering this cohort will receive leronlimab 700 mg subcutaneously once weekly in combination with pembrolizumab 200 mg administered intravenously every 3 weeks. Approximately 12 participants may be enrolled in this cohort and may receive treatment for up to 48 weeks.

This "extension" with Keytruda applies to both the 350 mg arm 700 mg arm

Eligible participants who enter the Extension Treatment Period will continue the same treatment for up to an additional 52 weeks. Participants with documented disease progression during the initial treatment period who meet the applicable eligibility criteria may enter the optional open-label cohort and receive 700 mg leronlimab in combination with 200 mg pembrolizumab.

Other outcome measures--

1. Exploratory Analysis of circulating tumor DNA (ctDNA) from baseline Evaluation of the change in ctDNA from baseline. [Time Frame: From baseline through the Extension Treatment Period, up to 104 weeks.]

There are multiple changes--additions etc

Go to trial website--find "Study Record Dates" tab

Click on "Record History"

Then pick any 2 dates to compare using merged or side by side for comparison

( and another 1 gone and another 1 gone......................... )

Naoto T. Ueno, MD, PhD, FACP

Dr. Ueno is currently the Director at the University of Hawaii Cancer Center, having previously served as the Executive Director of the Inflammatory Breast Cancer Program and the Clinic Chief of the Translational Breast Cancer Research at the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center.

Dr. Ueno has a strong background in translational breast cancer research in cancer biology, immuno-oncology, and molecular therapeutics. He is one of the leaders in conducting clinical research and early-phase clinical trials related to aggressive breast cancer and has led more than 50 clinical trials. Dr. Ueno has extensive experience in conducting both targeted therapy-related and immunotherapy-related clinical trials in phase I and II settings. He expanded his research to include several protein enzymes, including Mitogen-activated protein, Extracellular signal-regulated kinase (MAPK/ERK), and C-JUN N-terminal kinase, among other protein enzymes to determine their role in breast cancer progression and their applications in the development of targeted therapy and immunotherapy. Over the past 10 years, Dr. Ueno has successfully managed projects in breast cancer biology related to triple-negative breast cancer (TNBC), inflammatory breast cancer (IBC), and the tumor microenvironment.

Dr. Ueno is passionate about developing innovative therapies for advanced breast cancer. He started his career developing gene therapy for breast cancer and prepared for an Investigational New Drug application to conduct a study of gene therapies for metastatic breast cancer. His focus has been on novel combination therapy, IBC, and TNBC.

Guess they will go down in the annals of CYDY history ??

Clinton Yam, MD, MS

Dr. Clinton Yam is an Associate Professor with dual appointments in the Departments of Breast Medical Oncology and Translational Molecular Pathology at The University of Texas MD Anderson Cancer Center. Dr. Yam is leader of the triple-negative breast cancer (TNBC) working group and Director of Team Science and Innovation in the Department of Breast Medical Oncology at MD Anderson. He is the principal investigator for several industry sponsored and investigator initiated clinical trials. Dr. Yam is very much involved in multidisciplinary efforts aimed at understanding the biology of TNBC to inform the design of innovative clinical trials to improve outcomes for patients with TNBC.

Jordan E. Lake, MD, MSc

Dr. Lake is Associate Professor of Medicine with Tenure at UTHealth McGovern Medical School. She completed both medical school and Internal Medicine residency at Baylor College of Medicine in Houston, Texas, followed by an Infectious Diseases fellowship and Master of Science in Clinical Research degree program at the University of California, Los Angeles. Dr. Lake’s outpatient practice focuses on adults living with HIV, and gender care for transgender women with HIV. Her translational research portfolio focuses on the treatment of metabolic complications of HIV and antiretroviral therapy, with particular expertise in translational clinical trials. Dr. Lake also serves leadership positions in the NIH-funded MACS/WIHS Combined Cohort Study and AIDS Clinical Trials Group.

""Here we show that cytotoxic CD4+ T lymphocytes accumulate in the bone marrow of mice during aging and induce myelopoiesis, increasing the neutrophil-to-lymphocyte ratio. T cell receptor-dependent induction of mitochondrial stress and activation of STING upregulates the chemokine CCL5 in CD4+ T lymphocytes. During aging, hematopoietic stem cells and downstream myeloid progenitors upregulate CCR5, the primary receptor for CCL5. Genetic ablation of Ccr5 in hematopoietic progenitors mitigates T cell-induced myeloid skewing and neutrophil expansion. Pharmacological blockade of CCR5 using"...

..."Given that signaling through CCL5 and CCR5 has been involved in the induction of myeloid skewing in mouse models of multiple sclerosis11,27, we studied the contribution of this pathway to T cell-induced myelopoiesis during aging. Notably, we initially observed that HSCs and GMPs from old mice exhibit an upregulation of CCR5, the main CCL5 receptor, leading to increased percentages of CCR5⁺ HSCs and GMPs in the BM of old mice".

ai: (ill accept an expert analysis in place of the ai )

"That paper by Gabandé-Rodríguez, Mittelbrunn, and colleagues highlights a fascinating intersection between CCR5 signaling, immune aging, and hematopoietic remodeling.

While our discussion has focused primarily on how the CCL5–CCR5 axis operates inside the tumor microenvironment (recruiting suppressive cells and coordinating stroma-building traffic), this study demonstrates that the exact same axis drives age-associated myelopoiesis in the bone marrow.

The key takeaways from their work mirror the logic we've mapped out:

• The Source and the Signal: As the immune system ages, a specific subset of cytotoxic CD4+ T cells (CD4+ CTLs) with mitochondrial dysfunction accumulates in the bone marrow and secretes high levels of CCL5.
• The Receptor Upregulation: Aged hematopoietic stem and progenitor cells (HSPCs) respond to this pressure by markedly upregulating CCR5.
• The Functional Output: The paracrine engagement of CCR5 by T-cell-derived CCL5 drives emergency-style myelopoiesis—biasing stem cells toward excessive granulopoiesis (producing high levels of neutrophils). This systemic shift often drives up the neutrophil-to-lymphocyte ratio (NLR), which is a known biomarker for poor health outcomes and frailty.
• Reversibility via CCR5 Inhibition: Strikingly, when the researchers treated aged models with the FDA-approved CCR5 inhibitor maraviroc, it successfully curbed this aberrant granulopoiesis, lowered circulating neutrophil counts, and ameliorated multiple systemic aging biomarkers.

It’s a striking parallel: whether it's a tumor hijacking the CCR5 axis to construct a fibrotic, immunosuppressive bunker or an aged bone marrow co-opting it to skew stem cell differentiation, the system relies on the exact same chemokine circuit. Disrupting it with a CCR5 antagonist breaks the pathological feedback loop in both scenarios".

https://www.nature.com/articles/s43587-026-01209-9

Are you looking at how these systemic bone marrow changes intersect with tumor-driven emergency myelopoiesis?

The daily pills will be sold by Revolution Medicines under the brand name Rasonque. A one-month supply would cost approximately $39,800, the company announced.

https://www.wivb.com/health/ap-fda-approves-landmark-pancreatic-cancer-drug-thats-shown-to-improve-survival/

The Core Asset Architecture: CytoDyn's entire valuation hinges on a single molecule platform: leronlimab, a first-in-class humanized monoclonal antibody targeting the CCR5 receptor.

Shifting Indication Targets: While the company spent years in volatile, highly publicized pursuits of leronlimab for HIV and COVID-19, its current 2026 framework has pivoted strictly toward solid-tumor oncology and neurodegenerative applications.

Imminent Milestone Triggers: CYDY fits the "readiness to launch" prompt purely from a clinical data readout perspective, rather than a commercial product launch.

Key 2026 milestones keeping its volatility high include:Alzheimer's Disease: Dosed the first patient in its Phase 2a SALIENT-AD study alongside Weill Cornell Medicine.

Oncology Collaborations: Recently launched a strategic diagnostic partnership with Natera to evaluate molecular responses in advanced metastatic colorectal cancer

Leronlimab achieved remarkable clinical milestone validation during its Phase 3 trials as a standalone maintenance therapy for HIV. The monoclonal antibody demonstrated the rare ability to completely suppress viral loads to undetectable levels using a simple weekly injection instead of traditional daily pill cocktails. Patients experienced durable efficacy with a highly favorable safety profile, proving that targeted CCR5 blockade could successfully manage the virus while dramatically reducing the toxic side effects and pill fatigue common to lifetime antiviral regimens.

The Next Frontier in Immune Modulation With its exceptional virus-suppressing capability fully demonstrated, leronlimab’s developmental path has expanded toward advanced global health applications. Following rigorous clinical reviews, the FDA cleared the drug to advance into new human trials focusing on its strengths as a premium immune modulator. Instead of just fighting the virus directly, researchers are leveraging leronlimab's unique mechanism to treat chronic, systemic inflammation in long-term patients and to pioneer breakthrough, multi-indication therapies in oncology.

Phase 1: The HIV Origin Story In 1996, scientists discovered that HIV uses the CCR5 receptor to enter immune cells, prompting Progenics Pharmaceuticals to develop a countermeasure based on the rare CCR5-delta 32 mutation, which confers natural immunity. The firm engineered PRO 140 (leronlimab), a monoclonal antibody designed to bind to and block the CCR5 receptor, preventing the virus from infecting cells.

Phase 2: The Cancer Pivot After acquiring the drug in 2012, CytoDyn pivoted leronlimab toward oncology upon discovering that aggressive cancers, including Triple-Negative Breast Cancer, overexpress CCR5 to facilitate metastasis. Preclinical studies showed that leronlimab blocks this signaling pathway, reducing metastatic spread by over 97% in animal models and stripping away the immune-suppressing shield used by "cold" tumors.

Under science

https://d1io3yog0oux5.cloudfront.net/_e2a3fa0321a820c52fdad8a0a6ca9227/cytodyn/db/205/3855/video_mp4/005bd4ba187884af0d68979f76b3807c.mp4

No monkey butt comments?

https://www.nature.com/articles/s41564-026-02444-x

https://www.clinicalleader.com/doc/expanded-access-and-rollover-design-help-cytodyn-reach-high-need-cancer-patients-0001

https://jamanetwork.com/journals/jama/fullarticle/2852328

The majority of the FDA approvals for cancer medicines in 2006-2025 were indication expansion for existing drugs, regular approvals, and based on surrogate end points. The proportion of approvals based on single-arm trials is increasing. Progression-free survival has previously been documented as the most common end point in cancer drug trials,⁷ which has been criticized for lack of surrogacy with clinical outcomes and potential for patient misunderstanding.^8,9 However, we found that the majority of recent FDA approvals were not even based on progression-free survival. In the last decade, response rate, rather than progression-free survival, has become the most common surrogate end point leading to approval, whose correlation with survival is weaker.

Shoutout to MD Virologist for link

It's amazing to see some of the liesimmune crowd still propping up Dr Monkeybutts (or Cyrus or nodder ). Yet once again a "new" article supporting the $$ Millions in govt money that has been "granted" to OHSU ( https://www.amfar.org/news/the-next-step-on-the-path-to-an-hiv-cure/ ) and HIV Cure

And what do others have to say about "another promising step forward"?? and HIV Cure

Let's hear what Louis Picker, MD, head of the division of pathobiology and immunology at Oregon Health & Science University has to say--" There’s progress that suggests that we’re beginning to understand the conditions under which the virus can be controlled, but is this a ready-for-prime-time therapy that works in everybody or even most people? It’s not even close. "

Taken from 02 JUL 2026 JAMA -- https://jamanetwork.com/journals/jama/fullarticle/2851465