Just a reminder. Very important to remember the m

Just a reminder. Very important to remember the mechanism of action of Leronlimab. A CCR5 Blocker. That means, Leronlimab will be helpful in indications where CCR5 is used by the disease in order to flourish. If CCR5 is blocked by LL, then the disease would no longer flourish.

This study: https://breast-cancer-research.biomedcentral....528-w#Fig2
reveals that CCR5 is not necessarily found on the Primary tumor itself. It is found on the Metastasis. On the cells called TACs. Tumor Associated Cells.

It goes on to say that, if more CCR5 is expressed, the cancer tends to be more virulent. If less CCR5 is expressed, the cancer tends to be less aggressive. When RANTES increases, so does CCR5, (Metastasis). Now, on the Primary Tumor, CCR5 tends to be downregulated, low.

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CCR5 has been found to be upregulated in aggressive breast cancer and may lead to cancer cell honing to metastatic sites [3]. CCR5 signal is found to be low to nonexistent in primary BC tumors but upregulated in secondary sites of metastasis [ 2]. CCR5 regulates cancer cell migration , which indicates that CCR5 + cells may be more migratory in nature and may promote metastasis of disease [4]. This has been shown by elevated CCR5 signal being associated with increased tumor progression in highly invasive BC subtypes (i.e., basal and HER-2) [3, 5,6,7]. Furthermore, upregulated CCR5 signaling has been positively correlated with axillary lymph node metastasis which supports the concept that CCR5 is associated with more aggressive disease spread [7, 8].

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RANTES activates CCR5 allowing BC cells to enhance their motility, invasiveness, and metastatic potential [13].

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The following is how CCL5 RANTES is used by the Tumor to do its deceiving; to hypnotize the T Regulator cells to hypnotize and convince the Natural KIller Cells, Macrophages and the Cytotoxic T cells, not to destroy the CTC circulating tumor cells, the metastasis and how it permits the intravasation of metastasis into the blood stream.

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The formation of CCR5 pools and subsequent endocytosis into the cells are indications of activation of the CCR5 motility pathway [16].

The CCR5/RANTES axis has been shown to help cancer cells recruit monocytes and stromal cells in circulation and “ educate ” them to take part in the immunosuppressive tumor microenvironment (TME) [9]. For example, CCR5 has recently been found on circulating tumor cells (CTCs) and is implicated in the activation and migration of CTCs from primary tumor sites into circulation [19,20,21]. It has been shown that macrophages drive tumor cell migration from the primary tumor site to blood vessel and aid intravasation into the blood stream (i.e., becoming CTCs), via a process defined as transendothelial migration [22,23,24,25,26,27,28]. It has been demonstrated that tumors recruit macrophages to produce a pro-tumorgenic microenvironment that downregulate the anti-tumor immune response and upregulates tumor growth [3, 9, 23].

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Although CCR5 signaling is not high in primary BC tumor sites , it could be theorized that CCR5 as a motility marker would be upregulated in migratory tumor-associated cells (TACs—CTCs and CAMLs) in circulation which could explain their motility [2, 26,27,28]. We theorize that if similar patterns of CCR5 signaling can be found in both cancer model cell lines and BC patients, then upregulation and localization of CCR5 in patients may offer novel clinical prognostic applications.

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it was determined that patients with negative or low average numbers of CCR5 pools also had fewer TACs in their blood (Fig. 4a). In comparison, patients with high average numbers of CCR5 pools had a significant twofold increase in numbers of both CTCs and CAMLs (Fig. 4b). Patients with no CCR5 pools (n = 15) averaged only 14 TACs, while patients with low CCR5 (1–9 pools, n = 11) averaged 28 TACs, and patients with high CCR5 (≥ 10 pools, n = 28) averaged 51 TACs.

This correlation between upregulated CCR5 signaling and larger populations of motile TACs in the bloodstream suggests that CCR5 could enhance the motility of more aggressive and invasive cells like TACs.

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Overall, it was determined that the presence of an average number ≥ 10 CCR5 pools on CAMLs was a highly significant predictor of worse PFS and OS

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You can be assured that Recknor would use that number of 10 to tell him, that the treatment therapy is no longer working. CTCs were not as good as a marker ast CAMLs.

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It has been shown that CCR5 signaling and the CCR5/RANTES axis in breast cancer is more upregulated in patients with more aggressive disease subtypes, though this upregulation is not commonly seen in primary breast tissue but rather in secondary sites

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CCR5 was negative in 87% (n = 13/15) of primary tumor tissue and CCR5 identifiable in only 13% (n = 2/15) of patients

CCR5 presence is mainly present on actively motile cells such as CTCs or tumor macrophages [22, 24], but is downregulated in stagnate fixed cells found at tumor masses

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Furthermore, CAMLs have been shown to exhibit proangiogenic markers and may act as “soil” cells in metastatic cancer spread [22, 23, 35]. This proangiogenic activity of CAMLs enhances the vascularization of tumors and could allow for soil-and-seed CAMLs and CTCs to enhance the spread of aggressive disease [22, 24, 38]. In addition, it has been shown in human BC, a high density of tumor-associated macrophages is correlated with poor prognosis [22, 23]. Here we find that CAMLs in the circulation of mBC patients have the hallmarks of CCR5 activation indicating the possible migratory pathway of TAM entry into circulation.

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Due to the lack of CCR5 expression in patient biopsies [2] (Additional file 1: Fig. S4), the finding of CCR5 pools in mobile circulating cells (i.e., CTCs and CAMLs) is of great interest in drug-targetable therapies. As TACs are responsible for cancer spread, patients with higher quantities of drug-targetable CCR5 may see great benefit from anti-CCR5 therapy by minimizing the spread of CTCs and/or CAMLs [3, 9, 41]. There are a number of anti-CCR5 drugs that exist in the market, including a number of CCR5 inhibitors in early phase clinical trials, i.e., leronlimab, aplaviroc, vicriviroc, and maraviroc, all of which block the CCR5 receptor and inhibit activation of the pathway [3]. As there are currently a number of ongoing clinical trials that are looking into the efficacy of anti-CCR5 therapies in a variety of different cancers (i.e., breast, colorectal, pancreatic, and non-Hodgkin lymphoma) [3, 9], the addition of a companion diagnostic that identifies CCR5 expression may be beneficial,

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While preliminary, and requiring validation in further studies, these results suggest that quantifying CCR5 signal on circulating TACs may identify patients who might respond to anti-CCR5 therapy, thus minimizing cancer spread and improving patient survival.

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I've put this here to indicate that NOW WE HAVE THE REASON WHY WE LERONLIMAB IN COMBINATON THERAPY WILL BE SO SUCCESSFUL. LERONLIMAB ADDRESSES THE METASTASIS VIA CCR5 BLOCKADE WHILE THE PARTNER DRUG ADDRESSES THE PRIMARY TUMOR VIA IT'S MOA .