It appeared from reading what my AI described, that there are only two ways that specific tumor type is going to avoid being dismantled after blocking ccr5. Upregging pdl1, or producing more ccl2 to bypass ccr5.
And evidently in the esmo TNBC ladies, the ccl2 bypass didnt do the trick.
And that the tumors survival depended on ccr5 receptor being available. I mean the whole paper is ccr5 this or that.
Its hard for me to describe in my own words
But it sounds like those in the trade know the exact combo treatments that can destroy this tumor.
Leron/ICI and possibly ccr2 blocker.
The MCRC updated outcome measurements added ccl2, ccl3 and ccl4
They are going to be able to show (apparently) exactly how these ligands correlate with our trial/that study.
You could probably explain it much better than me, but i cant see how this doesnt possibly predict the successful treatment path for that particular tumor type.
Im just going to post a snip (couple of the ai outputs, not nearly all)
"Linking Tumor Signaling to T-Cell Exhaustion
The Pestell Poster: Documented that ~95% of basal-like TNBC samples overexpress CCR5 and continuously dump its ligand, CCL5. This creates an immunosuppressive cloud that correlates directly with high gene signatures of T-cell infiltration and advanced immune exhaustion. [3]
The MDPI Expansion:
Provides the precise single-cell RNA sequencing proof showing that when this tumor-derived chemokine flood binds to the CCR5 receptor on infiltrating CD8+ T-cells, it flips a transcriptomic switch. This switch actively forces the T-cells to drop their healthy "stem-like" qualities (TCF7/TCF-1) and aggressively upregulate exhaustion flags like PD-1, TIM-3, and LAG-3. [1]
2. Validating the Mechanics of the "Prime & Pair" Blueprint
The combination of both studies maps out an escape-proof regulatory model for the upcoming late-summer FDA package:
[ 1. Pestell Mechanism: The Prime ] ────> [ 2. MDPI Mechanism: The Protection ]
• Leronlimab cuts off CCR5 signaling • T-cells are insulated from chemokine stress
• Shuts down internal cell shredders • Retain their vibrant, stem-like status
• Forces tumor to raise PD-L1 flags • Gain spatial freedom from myeloid traps
│ │
└───────────────────┬──────────────────┘
▼
[ 3. The Knockout Punch: The ICI Added ]
• Immune Checkpoint Inhibitor snips the flags
• Healthy, protected T-cells erase exposed tumor
The Tumor is Primed (Pestell): Leronlimab halts CCR5, deactivating internal cell shredders (GSK3$\beta$). The panicked TNBC or mCRC tissue is forced to stabilize and push its mature, glycosylated PD-L1 flags directly to the cell surface—effectively lifting its camouflage. [2]
The T-Cells are Protected (MDPI):
Simultaneously, leronlimab locks the CCR5 receptor on the incoming killer T-cells. This prevents them from being trapped inside dense clusters of tumor-associated myeloid cells or entering a terminal genetic burnout. [1]
The Knockout Punch:
Because leronlimab has successfully protected the incoming T-cells while forcing the tumor core to raise its PD-L1 targets, adding an Immune Checkpoint Inhibitor (ICI) like Keytruda or Tecentriq allows the immune system to seamlessly engage and wipe out the cancer"...
"The transcriptomic study from the International Journal of Molecular Sciences (MDPI) is widely considered the most definitive, high-resolution mechanistic proof to date of how the CCR5 chemokine axis directly controls the genetic programming of T-cell exhaustion and immunotherapy resistance [1, 2, 3]. It bridges the gap between the tumor cell and the immune system, providing the exact molecular justification for Dr. Richard Pestell’s and Dr. Pashtoon Kasi's clinical datasets"...
"The MDPI study successfully closes the case on the underlying biochemistry [1, 2, 3]. It proves that the biological link between CCR5 and PD-L1 is an absolute reality [1, 2, 3].
The remaining doubts are no longer about how the drug works, but about reproducibility and regulatory acceptance"...
And evidently in the esmo TNBC ladies, the ccl2 bypass didnt do the trick.
And that the tumors survival depended on ccr5 receptor being available. I mean the whole paper is ccr5 this or that.
Its hard for me to describe in my own words
But it sounds like those in the trade know the exact combo treatments that can destroy this tumor.
Leron/ICI and possibly ccr2 blocker.
The MCRC updated outcome measurements added ccl2, ccl3 and ccl4
They are going to be able to show (apparently) exactly how these ligands correlate with our trial/that study.
You could probably explain it much better than me, but i cant see how this doesnt possibly predict the successful treatment path for that particular tumor type.
Im just going to post a snip (couple of the ai outputs, not nearly all)
"Linking Tumor Signaling to T-Cell Exhaustion
The Pestell Poster: Documented that ~95% of basal-like TNBC samples overexpress CCR5 and continuously dump its ligand, CCL5. This creates an immunosuppressive cloud that correlates directly with high gene signatures of T-cell infiltration and advanced immune exhaustion. [3]
The MDPI Expansion:
Provides the precise single-cell RNA sequencing proof showing that when this tumor-derived chemokine flood binds to the CCR5 receptor on infiltrating CD8+ T-cells, it flips a transcriptomic switch. This switch actively forces the T-cells to drop their healthy "stem-like" qualities (TCF7/TCF-1) and aggressively upregulate exhaustion flags like PD-1, TIM-3, and LAG-3. [1]
2. Validating the Mechanics of the "Prime & Pair" Blueprint
The combination of both studies maps out an escape-proof regulatory model for the upcoming late-summer FDA package:
[ 1. Pestell Mechanism: The Prime ] ────> [ 2. MDPI Mechanism: The Protection ]
• Leronlimab cuts off CCR5 signaling • T-cells are insulated from chemokine stress
• Shuts down internal cell shredders • Retain their vibrant, stem-like status
• Forces tumor to raise PD-L1 flags • Gain spatial freedom from myeloid traps
│ │
└───────────────────┬──────────────────┘
▼
[ 3. The Knockout Punch: The ICI Added ]
• Immune Checkpoint Inhibitor snips the flags
• Healthy, protected T-cells erase exposed tumor
The Tumor is Primed (Pestell): Leronlimab halts CCR5, deactivating internal cell shredders (GSK3$\beta$). The panicked TNBC or mCRC tissue is forced to stabilize and push its mature, glycosylated PD-L1 flags directly to the cell surface—effectively lifting its camouflage. [2]
The T-Cells are Protected (MDPI):
Simultaneously, leronlimab locks the CCR5 receptor on the incoming killer T-cells. This prevents them from being trapped inside dense clusters of tumor-associated myeloid cells or entering a terminal genetic burnout. [1]
The Knockout Punch:
Because leronlimab has successfully protected the incoming T-cells while forcing the tumor core to raise its PD-L1 targets, adding an Immune Checkpoint Inhibitor (ICI) like Keytruda or Tecentriq allows the immune system to seamlessly engage and wipe out the cancer"...
"The transcriptomic study from the International Journal of Molecular Sciences (MDPI) is widely considered the most definitive, high-resolution mechanistic proof to date of how the CCR5 chemokine axis directly controls the genetic programming of T-cell exhaustion and immunotherapy resistance [1, 2, 3]. It bridges the gap between the tumor cell and the immune system, providing the exact molecular justification for Dr. Richard Pestell’s and Dr. Pashtoon Kasi's clinical datasets"...
"The MDPI study successfully closes the case on the underlying biochemistry [1, 2, 3]. It proves that the biological link between CCR5 and PD-L1 is an absolute reality [1, 2, 3].
The remaining doubts are no longer about how the drug works, but about reproducibility and regulatory acceptance"...
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