"When you have excluded the impossible, whatever remains, however improbable, must be the truth." Sherlock Holmes/A Conan Doyle (Sign of the Four)
I am still trying to reconcile the positive early news from the Clover trial with my expectations that it would take a 700 mg dose of leronlimab, and an ICI, to really make a splash in metastatic colorectal cancer. I've been interrogating AI on the notion--however improbable--that it might be a good idea to start off with a 350 mg dose. Why that might be I couldn't really tell you, but I go with my hunches. I worked it over hard, and came up with the following, cut-and-pasted together into a readable narrative. Call me crazy... but it is sure interesting. Somebody had to do it!
“In oncology, fully saturating every CCR5 receptor on all cell surfaces is not always optimal. CCR5 is present on aggressive tumor cells, but it is also expressed on crucial, protective helper T-cells and antigen-presenting cells.
At 700mg: Full receptor coating completely shuts down the CCL5/CCR5 chemokine axis. While this stops regulatory T-cells (Tregs) from entering, it can inadvertently blunt the necessary trafficking of favorable immune populations into the tumor matrix.
At 350mg: This dose achieves selective, partial receptor coverage. It is highly effective at stopping tumor metastasis and halting the migration of heavy M2-suppressive macrophages, but leaves enough open signaling pathways for active cytotoxic T-cells to track and infiltrate the tumor.
When you selectively block CCL5 with a 350 mg dose of leronlimab while allowing low-level CCL3, CCL4, and CCL2 signaling, you shift the balance of the immune system within the tumor:
Stopping Immune Evasion (CCL5 Blockade):
[color=var(--text)]Starving the Tumor-Associated Macrophages (TAMs): High levels of CCL5 attract circulating monocytes and turn them into M2-polarized (pro-tumor) macrophages. Blocking CCL5 halts this process, allowing macrophages to shift toward an M1 (anti-tumor) profile.[/color]
Excluding Regulatory T-Cells (T-regs): CCL5 acts as a homing beacon for T-regs, which protect the tumor from immune attacks. Neutralizing CCL5 lowers this protective barrier, leaving the tumor exposed.
Activating the Immune System (Preserved CCL3/CCL4/CCL2 Signaling):
Recruiting Natural Killer (NK) and Dendritic Cells: CCL3 and CCL4 are crucial for bringing antigen-presenting dendritic cells and NK cells into the tissue. By allowing these signals to continue, the body can still deliver the cells needed to recognize and flag CRC tumor cells.
Maintaining Monocyte Movement via CCL2: While excessive CCL2 can cause issues, baseline CCL2/CCR2 signaling is necessary to bring fresh, uncompromised monocytes into the area. Once there, the lack of CCL5 signals helps them mature into tumor-fighting M1 cells rather than tumor-protecting M2 cells.”
Recall that Cytodyn is now measuring chemokines in the bloodstream, CCL5 and CCL3 and CCL4 if I recall... perhaps CCL2 and CCL8. This is going to allow the company to PROVE this:
“To validate the thesis that a sub-saturating 350 mg dose of leronlimab acts as a "selective filter"—shutting down harmful CCL5 signaling while leaving the CCL3 and CCL4 pathways functional to recruit dendritic and Natural Killer (NK) cells—investigators track specific, measurable patterns in both circulating serum protein levels and intracellular immune cell signatures.
CCL5 (RANTES) Serum Spike: An effective blockade is proven when serum CCL5 levels rise sharply (often 5x to 10x above baseline). Because leronlimab blocks the receptor, the tumor's secreted CCL5 cannot bind and clear from circulation, causing it to accumulate in the blood.
CCL3 & CCL4 Moderate Fluctuations: If the 350 mg dose is truly permissive, serum CCL3 and CCL4 levels will remain relatively stable or rise only slightly (less than 2-fold). This minimal increase proves that these chemokines are still successfully binding to the receptor, clearing from the blood, and delivering their signals to cells.”
The idea that a 350 mg dose to start with is actually the best way to utilize leronlimab in cancer is going to likely be controversial... at least on this board! But an initial dose of 350 mg would be followed by an increase to the 700mg dose for full receptor occupancy… and then an ICI, as needed, after leronlimab prepares the tumor microenvironment for maximum efficacy. We will see. Perhaps there needs to be a couple months before the dose is increased, perhaps they will identify a biomarker that will tell oncologists when to precisely step up the dose based on the patient’s specific physiology and response to all the drugs—and provide an example of truly precision medicine.
I find the above argument convincing, but this is a theoretical argument. I interrogated AI, but AI brought it up. We are early on in the game when it comes down to clinical data regarding leronlimab in human beings. Plenty of pre-clinical work and theory, but we only have 3-4 months to wait for real, unequivocal data in mCRC. Maybe 6-7 months for final trial results, and rollover data. I expect it to be the real deal... but still learning as we go. Still room for upside surprises, though... "Whatever remains, however improbable..."
Here’s the final word from AI, with a great phrase--a "superior therapeutic orchestration." I like the sound of that. And of course I'd like to hear from others of a scientific bent... Am I really crazy?
"The concept of a step-up or sequenced dosing regimen—starting oncology patients at a lower 350mg dose to modify the tumor microenvironment (TME) before transitioning to a full receptor blockade at 700mg—is biologically logical, not crazy.
In immunology and oncology, this is referred to as a biphasic or hormetic dose response, where a "sub-optimal" dose yields superior therapeutic orchestration rather than a maximizing dose. Fully saturating a receptor immediately can accidentally shut down beneficial immune pathways alongside the harmful ones.”
I am still trying to reconcile the positive early news from the Clover trial with my expectations that it would take a 700 mg dose of leronlimab, and an ICI, to really make a splash in metastatic colorectal cancer. I've been interrogating AI on the notion--however improbable--that it might be a good idea to start off with a 350 mg dose. Why that might be I couldn't really tell you, but I go with my hunches. I worked it over hard, and came up with the following, cut-and-pasted together into a readable narrative. Call me crazy... but it is sure interesting. Somebody had to do it!
“In oncology, fully saturating every CCR5 receptor on all cell surfaces is not always optimal. CCR5 is present on aggressive tumor cells, but it is also expressed on crucial, protective helper T-cells and antigen-presenting cells.
At 700mg: Full receptor coating completely shuts down the CCL5/CCR5 chemokine axis. While this stops regulatory T-cells (Tregs) from entering, it can inadvertently blunt the necessary trafficking of favorable immune populations into the tumor matrix.
At 350mg: This dose achieves selective, partial receptor coverage. It is highly effective at stopping tumor metastasis and halting the migration of heavy M2-suppressive macrophages, but leaves enough open signaling pathways for active cytotoxic T-cells to track and infiltrate the tumor.
When you selectively block CCL5 with a 350 mg dose of leronlimab while allowing low-level CCL3, CCL4, and CCL2 signaling, you shift the balance of the immune system within the tumor:
Stopping Immune Evasion (CCL5 Blockade):
[color=var(--text)]Starving the Tumor-Associated Macrophages (TAMs): High levels of CCL5 attract circulating monocytes and turn them into M2-polarized (pro-tumor) macrophages. Blocking CCL5 halts this process, allowing macrophages to shift toward an M1 (anti-tumor) profile.[/color]
Excluding Regulatory T-Cells (T-regs): CCL5 acts as a homing beacon for T-regs, which protect the tumor from immune attacks. Neutralizing CCL5 lowers this protective barrier, leaving the tumor exposed.
Activating the Immune System (Preserved CCL3/CCL4/CCL2 Signaling):
Recruiting Natural Killer (NK) and Dendritic Cells: CCL3 and CCL4 are crucial for bringing antigen-presenting dendritic cells and NK cells into the tissue. By allowing these signals to continue, the body can still deliver the cells needed to recognize and flag CRC tumor cells.
Maintaining Monocyte Movement via CCL2: While excessive CCL2 can cause issues, baseline CCL2/CCR2 signaling is necessary to bring fresh, uncompromised monocytes into the area. Once there, the lack of CCL5 signals helps them mature into tumor-fighting M1 cells rather than tumor-protecting M2 cells.”
Recall that Cytodyn is now measuring chemokines in the bloodstream, CCL5 and CCL3 and CCL4 if I recall... perhaps CCL2 and CCL8. This is going to allow the company to PROVE this:
“To validate the thesis that a sub-saturating 350 mg dose of leronlimab acts as a "selective filter"—shutting down harmful CCL5 signaling while leaving the CCL3 and CCL4 pathways functional to recruit dendritic and Natural Killer (NK) cells—investigators track specific, measurable patterns in both circulating serum protein levels and intracellular immune cell signatures.
CCL5 (RANTES) Serum Spike: An effective blockade is proven when serum CCL5 levels rise sharply (often 5x to 10x above baseline). Because leronlimab blocks the receptor, the tumor's secreted CCL5 cannot bind and clear from circulation, causing it to accumulate in the blood.
CCL3 & CCL4 Moderate Fluctuations: If the 350 mg dose is truly permissive, serum CCL3 and CCL4 levels will remain relatively stable or rise only slightly (less than 2-fold). This minimal increase proves that these chemokines are still successfully binding to the receptor, clearing from the blood, and delivering their signals to cells.”
The idea that a 350 mg dose to start with is actually the best way to utilize leronlimab in cancer is going to likely be controversial... at least on this board! But an initial dose of 350 mg would be followed by an increase to the 700mg dose for full receptor occupancy… and then an ICI, as needed, after leronlimab prepares the tumor microenvironment for maximum efficacy. We will see. Perhaps there needs to be a couple months before the dose is increased, perhaps they will identify a biomarker that will tell oncologists when to precisely step up the dose based on the patient’s specific physiology and response to all the drugs—and provide an example of truly precision medicine.
I find the above argument convincing, but this is a theoretical argument. I interrogated AI, but AI brought it up. We are early on in the game when it comes down to clinical data regarding leronlimab in human beings. Plenty of pre-clinical work and theory, but we only have 3-4 months to wait for real, unequivocal data in mCRC. Maybe 6-7 months for final trial results, and rollover data. I expect it to be the real deal... but still learning as we go. Still room for upside surprises, though... "Whatever remains, however improbable..."
Here’s the final word from AI, with a great phrase--a "superior therapeutic orchestration." I like the sound of that. And of course I'd like to hear from others of a scientific bent... Am I really crazy?
"The concept of a step-up or sequenced dosing regimen—starting oncology patients at a lower 350mg dose to modify the tumor microenvironment (TME) before transitioning to a full receptor blockade at 700mg—is biologically logical, not crazy.
In immunology and oncology, this is referred to as a biphasic or hormetic dose response, where a "sub-optimal" dose yields superior therapeutic orchestration rather than a maximizing dose. Fully saturating a receptor immediately can accidentally shut down beneficial immune pathways alongside the harmful ones.”
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