“ 2.1.19. CCR5
CCR5 (C–C chemokine receptor type 5) is a seven-transmembrane GPCR highly expressed in TNBC patients. CCR5 is also a prognostic biomarker. One cohort study found that approximately 95% of TNBC patients were CCR5+, compared to the percentage of patients positive for CCR5 with other breast cancer subtypes [68]. It was observed that when the promoter region of CCR5 gets methylated, CCR5 protein results in overexpression [69]. It was further observed that overexpression of CCR5 results in increased Ca2+ signaling, which facilitates cellular migration in cancer cells. CCR5 also plays an important role in cell growth, proliferation, and the differentiation of immune cells by activating the PI3K signaling pathway, thereby inducing the activation of PDK1 and AKT [68]. Various studies showed that CCR5 overexpression is also positively associated with tumor immune cell infiltration via the activation of effector T-cells and tumor suppressor genes, and repression of YAP1 oncogenic pathways [69].
Recently, it was observed that blocking CCR5 results in anticancer activity. Such a phenomenon was showcased by the emergence of a humanized monoclonal antibody, Leronlimab (PRO 140), and CCR5 antagonist, maraviroc or vicriviroc. It was observed from the preclinical trial that the binding of Leronlimab to human CCR5 leads to the blockage of the CCR5-mediating signaling pathway, thereby preventing TNBC cell invasion [70,71].
Additionally, various in vitro and in vivo studies demonstrated that blocking or knocking down CCL5/CCR5 is harmful to metastatic tumors like TNBC, and thus limits their metastases. In May 2019, Leronlimab (PRO 140) was granted Fast Track Designation by the FDA for its application as a combination therapy with HAART for HIV-infected patients. Recently, Leronlimab has been filed as a drug of choice with the FDA for the treatment of CCR5+ mTNBC patients [72]. The filing was supported by the data from the second patient dosed with Leronlimab (Pro 140) under an emergency investigational new drug (IND) application granted by the FDA in September 2019. It was revealed that the TNBC patients receiving Leronlimab (PRO 140) exhibited no indication of metastases in the lungs and brain during the treatment [73]. In a similar context, phase Ib/II clinical study is ongoing for combining leronlimab with carboplatin (chemotherapy) for the treatment of CCR5+ mTNBC (NCT03838367). The preliminary studies showed an acceptable tolerability and efficacy with an increase in overall survival (OS) and progression-free survival (PFS) [7]. It was observed from the study that the patients who received leronlimab showed a significant 400–660% increase in 12-month PFS, as well as a 570–980% increase in 12-month OS, with a 72% decrease in circulating tumor cells [74].
Moreover, compassionate Use (NCT04313075) and the Basket Study (NCT04504942) were performed to evaluate the safety and efficacy profile of leronlimab at 12 months [75]. In compassionate study (NCT04313075) 2020, leronlimab (PRO 140) was combined with the treatment of physician’s choice (TPC) which included eribulin, gemcitabine, capecitabine, paclitaxel, nab-paclitaxel, vinorelbine, ixabepilone, or carboplatin for the treatment of CCR5+ mTNBC [76]. In the Basket Study (NCT04504942) of 2020, leronlimab (PRO 140) was administered to CCR5+ locally advanced or mTNBC patients. In this study leronlimab (PRO 140) was administered in continuation to the standard-of-care chemotherapy or radiotherapy [77].”
CCR5 (C–C chemokine receptor type 5) is a seven-transmembrane GPCR highly expressed in TNBC patients. CCR5 is also a prognostic biomarker. One cohort study found that approximately 95% of TNBC patients were CCR5+, compared to the percentage of patients positive for CCR5 with other breast cancer subtypes [68]. It was observed that when the promoter region of CCR5 gets methylated, CCR5 protein results in overexpression [69]. It was further observed that overexpression of CCR5 results in increased Ca2+ signaling, which facilitates cellular migration in cancer cells. CCR5 also plays an important role in cell growth, proliferation, and the differentiation of immune cells by activating the PI3K signaling pathway, thereby inducing the activation of PDK1 and AKT [68]. Various studies showed that CCR5 overexpression is also positively associated with tumor immune cell infiltration via the activation of effector T-cells and tumor suppressor genes, and repression of YAP1 oncogenic pathways [69].
Recently, it was observed that blocking CCR5 results in anticancer activity. Such a phenomenon was showcased by the emergence of a humanized monoclonal antibody, Leronlimab (PRO 140), and CCR5 antagonist, maraviroc or vicriviroc. It was observed from the preclinical trial that the binding of Leronlimab to human CCR5 leads to the blockage of the CCR5-mediating signaling pathway, thereby preventing TNBC cell invasion [70,71].
Additionally, various in vitro and in vivo studies demonstrated that blocking or knocking down CCL5/CCR5 is harmful to metastatic tumors like TNBC, and thus limits their metastases. In May 2019, Leronlimab (PRO 140) was granted Fast Track Designation by the FDA for its application as a combination therapy with HAART for HIV-infected patients. Recently, Leronlimab has been filed as a drug of choice with the FDA for the treatment of CCR5+ mTNBC patients [72]. The filing was supported by the data from the second patient dosed with Leronlimab (Pro 140) under an emergency investigational new drug (IND) application granted by the FDA in September 2019. It was revealed that the TNBC patients receiving Leronlimab (PRO 140) exhibited no indication of metastases in the lungs and brain during the treatment [73]. In a similar context, phase Ib/II clinical study is ongoing for combining leronlimab with carboplatin (chemotherapy) for the treatment of CCR5+ mTNBC (NCT03838367). The preliminary studies showed an acceptable tolerability and efficacy with an increase in overall survival (OS) and progression-free survival (PFS) [7]. It was observed from the study that the patients who received leronlimab showed a significant 400–660% increase in 12-month PFS, as well as a 570–980% increase in 12-month OS, with a 72% decrease in circulating tumor cells [74].
Moreover, compassionate Use (NCT04313075) and the Basket Study (NCT04504942) were performed to evaluate the safety and efficacy profile of leronlimab at 12 months [75]. In compassionate study (NCT04313075) 2020, leronlimab (PRO 140) was combined with the treatment of physician’s choice (TPC) which included eribulin, gemcitabine, capecitabine, paclitaxel, nab-paclitaxel, vinorelbine, ixabepilone, or carboplatin for the treatment of CCR5+ mTNBC [76]. In the Basket Study (NCT04504942) of 2020, leronlimab (PRO 140) was administered to CCR5+ locally advanced or mTNBC patients. In this study leronlimab (PRO 140) was administered in continuation to the standard-of-care chemotherapy or radiotherapy [77].”
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