From the Cytodyn Facebook this morning Grok's A
Post# of 157731
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Posted On: 10/07/2025 9:29:16 AM
From the Cytodyn Facebook this morning
Grok's Analysis
Leronlimab has been shown to make cold tumors hot in triple negative breast cancer where ici can better treat the tumor, why can’t miravirok do that?
Thought for 1m 16s
Both leronlimab and maraviroc are CCR5 antagonists, but they differ in their molecular structure, pharmacokinetics, and demonstrated effects in triple-negative breast cancer (TNBC). Leronlimab is a humanized IgG4 monoclonal antibody that binds to CCR5 on the surface of cells, providing prolonged blockade (typically weekly dosing) due to its long half-life. This sustained inhibition has been shown in clinical data from metastatic TNBC patients to increase PD-L1 expression on circulating tumor cells in 88% of cases at doses of 525 mg or higher, effectively inducing an inflamed tumor microenvironment—converting immunologically "cold" tumors (low T-cell infiltration and poor immunotherapy response) to "hot" ones (higher immune cell presence, making them more amenable to immune checkpoint inhibitors like anti-PD-1/PD-L1 therapies). This PD-L1 upregulation correlates with improved outcomes, such as 100% survival in patients who subsequently received ICIs, with most showing no evidence of disease.
Maraviroc, in contrast, is a small-molecule inhibitor that competitively blocks CCR5 ligand binding in an allosteric manner, requiring daily oral dosing due to its shorter half-life. While it has demonstrated anti-metastatic effects in preclinical TNBC models—such as inhibiting cell migration, invasion, and tumor dissemination by disrupting the CCL5/CCR5 axis—it has not shown the same capacity to reliably increase PD-L1 expression or convert cold tumors to hot in clinical TNBC settings. Studies indicate maraviroc can modulate the tumor microenvironment in other cancers (e.g., colorectal) by reducing immunosuppressive cells like myeloid-derived suppressor cells and promoting T-cell activity, potentially aiding in cold-to-hot conversion in those contexts. However, in TNBC specifically, it appears less potent and selective than alternatives like leronlimab or even verteporfin (another CCR5 antagonist), and no equivalent clinical evidence exists for PD-L1 induction or enhanced ICI responsiveness. This may stem from maraviroc's shorter duration of action, potential for incomplete CCR5 blockade in tumor tissues, or differences in how it stabilizes CCR5 on cell surfaces compared to an antibody like leronlimab, which may trigger unique downstream immunomodulatory effects (e.g., more robust T-cell enhancement and reduced immune evasion).
Ok then doesn’t this signal a new treatment option for these patients with metastatic disease that might be treated first with Leronlimab then a ici?
Yes, the data on leronlimab in metastatic triple-negative breast cancer (mTNBC) suggests a promising new treatment strategy, particularly for patients with immunologically "cold" tumors. Leronlimab’s ability to upregulate PD-L1 expression on tumor cells in 88% of mTNBC patients at doses of 525 mg or higher effectively converts these cold tumors to "hot" ones, enhancing the tumor microenvironment’s responsiveness to immune checkpoint inhibitors (ICIs) like anti-PD-1/PD-L1 therapies. Clinical evidence shows that mTNBC patients treated with leronlimab followed by ICIs achieved 100% survival in some cohorts, with most showing no evidence of disease, indicating a potential synergistic effect.
This sequential approach—leronlimab to inflame the tumor microenvironment followed by an ICI to capitalize on the increased PD-L1 expression and T-cell infiltration—could represent a novel therapeutic pathway for mTNBC patients, who typically face poor prognosis due to limited treatment options. The strategy leverages leronlimab’s role in disrupting the CCL5/CCR5 axis, which not only reduces tumor invasiveness but also enhances immune activation, making subsequent ICI therapy more effective. However, this approach is still investigational. While phase 2 trials and compassionate use data are encouraging, larger randomized controlled trials are needed to confirm efficacy, optimize dosing schedules, and establish safety profiles for this combination in mTNBC.
In summary, leronlimab followed by an ICI could offer a new treatment option for mTNBC, particularly for patients with metastatic disease and cold tumors, but further clinical validation is essential to integrate it into standard care.
Grok's Analysis
Leronlimab has been shown to make cold tumors hot in triple negative breast cancer where ici can better treat the tumor, why can’t miravirok do that?
Thought for 1m 16s
Both leronlimab and maraviroc are CCR5 antagonists, but they differ in their molecular structure, pharmacokinetics, and demonstrated effects in triple-negative breast cancer (TNBC). Leronlimab is a humanized IgG4 monoclonal antibody that binds to CCR5 on the surface of cells, providing prolonged blockade (typically weekly dosing) due to its long half-life. This sustained inhibition has been shown in clinical data from metastatic TNBC patients to increase PD-L1 expression on circulating tumor cells in 88% of cases at doses of 525 mg or higher, effectively inducing an inflamed tumor microenvironment—converting immunologically "cold" tumors (low T-cell infiltration and poor immunotherapy response) to "hot" ones (higher immune cell presence, making them more amenable to immune checkpoint inhibitors like anti-PD-1/PD-L1 therapies). This PD-L1 upregulation correlates with improved outcomes, such as 100% survival in patients who subsequently received ICIs, with most showing no evidence of disease.
Maraviroc, in contrast, is a small-molecule inhibitor that competitively blocks CCR5 ligand binding in an allosteric manner, requiring daily oral dosing due to its shorter half-life. While it has demonstrated anti-metastatic effects in preclinical TNBC models—such as inhibiting cell migration, invasion, and tumor dissemination by disrupting the CCL5/CCR5 axis—it has not shown the same capacity to reliably increase PD-L1 expression or convert cold tumors to hot in clinical TNBC settings. Studies indicate maraviroc can modulate the tumor microenvironment in other cancers (e.g., colorectal) by reducing immunosuppressive cells like myeloid-derived suppressor cells and promoting T-cell activity, potentially aiding in cold-to-hot conversion in those contexts. However, in TNBC specifically, it appears less potent and selective than alternatives like leronlimab or even verteporfin (another CCR5 antagonist), and no equivalent clinical evidence exists for PD-L1 induction or enhanced ICI responsiveness. This may stem from maraviroc's shorter duration of action, potential for incomplete CCR5 blockade in tumor tissues, or differences in how it stabilizes CCR5 on cell surfaces compared to an antibody like leronlimab, which may trigger unique downstream immunomodulatory effects (e.g., more robust T-cell enhancement and reduced immune evasion).
Ok then doesn’t this signal a new treatment option for these patients with metastatic disease that might be treated first with Leronlimab then a ici?
Yes, the data on leronlimab in metastatic triple-negative breast cancer (mTNBC) suggests a promising new treatment strategy, particularly for patients with immunologically "cold" tumors. Leronlimab’s ability to upregulate PD-L1 expression on tumor cells in 88% of mTNBC patients at doses of 525 mg or higher effectively converts these cold tumors to "hot" ones, enhancing the tumor microenvironment’s responsiveness to immune checkpoint inhibitors (ICIs) like anti-PD-1/PD-L1 therapies. Clinical evidence shows that mTNBC patients treated with leronlimab followed by ICIs achieved 100% survival in some cohorts, with most showing no evidence of disease, indicating a potential synergistic effect.
This sequential approach—leronlimab to inflame the tumor microenvironment followed by an ICI to capitalize on the increased PD-L1 expression and T-cell infiltration—could represent a novel therapeutic pathway for mTNBC patients, who typically face poor prognosis due to limited treatment options. The strategy leverages leronlimab’s role in disrupting the CCL5/CCR5 axis, which not only reduces tumor invasiveness but also enhances immune activation, making subsequent ICI therapy more effective. However, this approach is still investigational. While phase 2 trials and compassionate use data are encouraging, larger randomized controlled trials are needed to confirm efficacy, optimize dosing schedules, and establish safety profiles for this combination in mTNBC.
In summary, leronlimab followed by an ICI could offer a new treatment option for mTNBC, particularly for patients with metastatic disease and cold tumors, but further clinical validation is essential to integrate it into standard care.
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