Experiments of nature have revealed the peculiar importance of the G-protein–coupled receptor, C-C chemokine receptor type 5 (CCR5), in human disease since ancient times. The resurgence of interest in heterotypic signals in the onset and progression of tumorigenesis has led to the current focus on CCR5 as an exciting new therapeutic target for metastatic cancer with clinical trials now targeting breast and colon cancer. The eutopic expression of CCR5 activates calcium signaling and thereby augments regulatory T cell (Treg) differentiation and migration to sites of inflammation. The misexpression of CCR5 in epithelial cells, induced upon oncogenic transformation, hijacks this migratory phenotype. CCR5 reexpression augments resistance to DNA-damaging agents and is sufficient to induce cancer metastasis and “stemness”. Recent studies suggest important cross-talk between CCR5 signaling and immune checkpoint function. Because CCR5 on Tregs serves as the coreceptor for human immunodeficiency virus (HIV) entry, CCR5-targeted therapeutics used in HIV, [small molecules (maraviroc and vicriviroc) and a humanized mAb (leronlimab)], are now being repositioned in clinical trials as cancer therapeutics. As CCR5 is expressed on a broad array of tumors, the opportunity for therapeutic repositioning and the rationale for combination therapy approaches are reviewed herein.

CCR5 (C-C chemokine receptor type 5) is a seven transmembrane G-protein–coupled receptor (GPCR), that binds multiple ligands, CCL3 (MIP1α), CCL3L1, CCL4 (MP-1β), CCL5 (RANTES), CCL8 (MCP2), CCL11 (Eotaxin), CCL13 (MCP-4), and CCL16 (HCC-4; Fig. 1; ref. 1). Homeostatic or inflammatory chemokines, of which there are 48 in total, are low molecular weight (8–14 kDa) proteins, which are divided into four families, based on the location of the two cysteine residues located at the amino terminus (CXC, CC, XC, and CX3C; ref. 2). A total of 19 unique GPCRs interact with the 48 distinct chemokines. Upon binding of ligand, the cognate GPCR undergoes a conformational change, thereby dissociating the Gαi and the Gβγ subunits, inducing downstream signaling. Gβγ subunits activate phospholipase Cγ, to PIP2 and IP3, and a rapid increase in cytosolic Ca+2 or to diacylglycerol, inositol-1–4,5-triphosphate, protein kinase C, and inflammatory gene expression. Gαi activates adenyl cyclase. CCR5 activation of Ca+2 signaling and cellular migration is preserved in immune cells (3) and cancer cells (4, 5). Additional pathways induced by CCR5, include the PI-3′K pathway and thereby PDK1 and the serine/threonine kinase protein kinase B (AKT), which in turn induces cell survival, glycolysis, cell proliferation, growth and proliferation of progenitor and stem cells, immune cell differentiation, and the release of eIF4E to promote cap-dependent translation (Fig. 1A).

Figure 1.

CCR5 signaling in immune and cancer cells. A, Schematic representation of a T-cell–expressing CCR5 with the intracellular signaling cascade activated by cognate ligands. The diverse ligands for CCR5 are shown in green. The pathologic response induced by CCR5 on cancer cells is shown in the green box. B, The diverse types of cells expressing CCR5 are shown. C, CCR5 expression derived from The Cancer Genome Atlas (TCGA), with squares indicating upregulation in cancer versus normal tissue, shown as a calorimetric display of fold increase in expression as a HR. RNA-seq TCGA data (v2 RSEM values) were downloaded using Firebrowse and FPKM values were log2-scaled and quantile normalized (mean differences between cancer and normal tissues were calculated). D, Representative PET-MRI images from a patient receiving chemotherapy (CHT) after participation in the phase I pilot MARACON study, in which patients with advanced-stage mCRC who were refractory to standard chemotherapy were treated with maraviroc (26). White arrow, liver with metastatic lesions. Red spots, high glucose uptake typical for metastases; green, low background glucose uptake. Adapted from Cancer Cell, Vol. 29, Halama N, Zoernig I, Berthel A, Kahlert C, Klupp F, Suarez-Carmona M, et al., Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients, p. 587-601, 2016, with permission from Elsevier.

Figure 1.

CCR5 signaling in immune and cancer cells. A, Schematic representation of a T-cell–expressing CCR5 with the intracellular signaling cascade activated by cognate ligands. The diverse ligands for CCR5 are shown in green. The pathologic response induced by CCR5 on cancer cells is shown in the green box. B, The diverse types of cells expressing CCR5 are shown. C, CCR5 expression derived from The Cancer Genome Atlas (TCGA), with squares indicating upregulation in cancer versus normal tissue, shown as a calorimetric display of fold increase in expression as a HR. RNA-seq TCGA data (v2 RSEM values) were downloaded using Firebrowse and FPKM values were log2-scaled and quantile normalized (mean differences between cancer and normal tissues were calculated). D, Representative PET-MRI images from a patient receiving chemotherapy (CHT) after participation in the phase I pilot MARACON study, in which patients with advanced-stage mCRC who were refractory to standard chemotherapy were treated with maraviroc (26). White arrow, liver with metastatic lesions. Red spots, high glucose uptake typical for metastases; green, low background glucose uptake. Adapted from Cancer Cell, Vol. 29, Halama N, Zoernig I, Berthel A, Kahlert C, Klupp F, Suarez-Carmona M, et al., Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients, p. 587-601, 2016, with permission from Elsevier.

Close modal

CCR5 mediates physiologic functions of immune cells [T cells, macrophages, eosinophils, myeloid-derived suppressor cells (MDSC), microglia, and dendritic cells; Fig. 1B]. Pathologic expression of CCR5 upon cellular transformation occurs in many types of cancer (Fig. 1C). CCR5 expression induced by transformation imbues the cell with dramatic alteration in gene expression, motility, and homing behavior to metastatic sites. A naturally occurring homozygous 32 bp deletion of the CCR5 coding region (CCR5Δ32) occurs in the normal population. Individuals who carry CCR5Δ32 are healthy but have an altered immune function when exposed to pathogens, specifically with increased resistance to human immunodeficiency virus (HIV; ref. 6, 7), poxvirus (8), and the Staphylococcus aureus pore-forming leukotoxin ED (9). CCR5 is an essential coreceptor for HIV, and has been strongly implicated in cancer, in particular metastatic cancer, precancerous diseases [nonalcoholic steatohepatitis (NASH)], and cancer therapy–related disease (bone marrow transplant–related GvHD). Because CCR5Δ32 individuals are physiologically normal, whereas cancer cells selectively overexpress CCR5, recent interest has focused on targeting CCR5 to restrain cancer metastasis.

Several CCR5 antagonists developed for HIV treatment are being retasked for cancer and cancer-related diseases. The pyrimidine small-molecule CCR5 inhibitors, maraviroc and vicriviroc, and the humanized monoclonal anti-CCR5 antibody, leronlimab, have been used in HIV. Maraviroc and leronlimab achieved their primary endpoints in phase III HIV clinical trials (10–12). Leronlimab has been used in more than 760 patients with HIV, without serious adverse events related to the agent and achieved its primary efficacy endpoints in a phase III (pivotal) study (11, 13). TAK-779 is a quaternary ammonium derivative that reduced regulatory T cell (Treg) infiltration and tumor growth in a pancreatic cancer mouse model (14). Anibamine is a natural product CCR5 antagonist that reduced prostate cancer cell growth, adhesion, and invasion (15). Met-CCL5 is a competitive chemokine receptor blocker that decreased breast tumor growth and infiltrating macrophages in murine cancer models (16). Aplaviroc, a 2,5-diketopiperazine CCR5 entry inhibitor, was discontinued because of hepatotoxicity (17). A saponin, DT-13, reduced CCR5 expression, and thereby reduced cancer cell migration (18). Other approaches to reduce CCR5 include siRNA (19) and a zinc finger nuclease (20). OTR4120 and OTR4131, GAG mimetics that inhibit CCL5 binding to GAG, reduced CCL5-induced migration and invasion of hepatocellular carcinoma cells (21). INCB9471 (Incyte Corporation) was discontinued after a phase II trial for HIV (22). Cinicriviroc (TBR-652; Takeda) is a dual CCR2-CCR5 inhibitor that completed a phase IIb clinical trial for HIV and is currently being tested in NASH. In addition, a soluble receptor–based fusion protein, mCCR5-Ig, inhibits CCR5 (23).

CCR5 is overexpressed in breast cancer (4, 5), gastric adenocarcinoma (24), prostate cancer (25), colorectal carcinoma (26, 27), melanoma (28), Hodgkin lymphoma (29), head and neck cancer (30), gastric cancer (31), esophageal cancer (32), pancreatic cancer (33), acute lymphocytic leukemia (33, 34), and other tumors (Fig. 1B). In analysis of >2,200 patients with breast cancer, >50% of patient's tumors were CCR5+ and >95% of triple-negative breast cancer (TNBC) were CCR5+ (4). Higher cytoplasmic CCR5 staining correlated with poor prognosis (5). CCR5 is induced by oncogenic transformation (Ha-Ras, c-Myc, ErbB2, and c-Src; ref. 4), DNA damage (5), and CCL5 stimulation. CCR5 receptor levels correlate with poor prognosis in breast cancer and gastric adenocarcinoma (5, 23, 24). Although CCR5 binds many ligands that are overexpressed in cancer, elevated levels of the ligand CCL5 indicate poor prognosis in breast cancer (35, 36), cervical cancer (36), prostate cancer (37), ovarian cancer (38), gastric cancer (23, 39), metastatic colorectal carcinoma response to regorafenib (40), and pancreatic cancer (33). Elevated level of CCL5 in tissues or plasma is indicative of unfavorable outcome in patients with melanoma, breast, cervical, prostate, gastric, or even pancreatic cancer (41–43).

CCR5 induces cancer cell homing to metastatic sites (4, 34), augments the proinflammatory prometastatic immune phenotype (26), and enhances DNA repair (5), providing aberrant cell survival and resistance to DNA-damaging agents (see review in refs. 2 and 44).

Activating invasion and metastasis

Distinct dissociable mechanisms govern tumor invasion and metastasis (45, 46). Ectopic CCR5 expression within cancer epithelial cells is sufficient to drive cancer cell metastasis (4). CCR5-specific small-molecule inhibitors blocked metastasis of isogenic oncogene-transformed breast cancer cells in NOD/SCID mice (4) and prostate cancer metastasis in immunocompetent mice (25). CCR5 induced metastasis in p53 breast cancer cells in vivo (5). In one study, CCR5 siRNA did not reduce the metastatic phenotype of MDA-MB-231 cells in the absence of additional MDSC (47), however it must be noted that endothelial cells produce CCL5, and were shown to augmented breast cancer metastasis in another study (48).

Avoiding immune destruction

The antitumor immune response.

The ligands for CCR5 are induced in tumors, and CCR5 participates in promoting protumorigenic and prometastatic inflammation through mechanisms that are distinct from the canonical immune checkpoint (49, 50). Furthermore, there is plausible evidence for potential synergy between CCR5 inhibitors and the canonical immune checkpoint inhibitors, consistent with the current clinical trials of Pfizer and Merck, in which CCR5 inhibitors (maraviroc or vicriviroc) are combined with a checkpoint inhibitor (pembrolizumab; below). The recruitment of immune cells, including tumor-infiltrating lymphocytes (TIL), MDSCs, tumor-associated macrophages (TAM), innate lymphoid cells, Tregs (51), mesenchymal stem cells (MSC), and immature dendritic cells (DC), contributes to tumor-induced immunosuppression (52). Tumors evade immune destruction by actively inducing immune tolerance through the recruitment of CD4+CD25+Foxp3+ Tregs.

Many of these cell types express CCR5 and/or produce ligands for CCR5 (Fig. 1). For example, MSCs produce CCL3, CCCL4, and CCL5 and when mixed with either breast (47), or colon cancer cells (53), they promoted tumor metastasis. Maraviroc can reduce MDSC-induced colon cancer metastasis (53). Furthermore, CD4+Foxp3+ Tregs preferentially express CCR5 when compared with CD4+Foxp3 effector T cells, and inhibition (by TAK-779), reduced Treg migration to tumors, and reduced pancreatic tumor size (14).

Lack of CCR5 ligands is associated with reduced infiltration of antigen-specific T cells and associated metastasis (54). Tumor-derived CCL5 has also been shown to impede antitumor T-cell responses and heighten the progression of murine mammary carcinoma (55), possibly via TGFβ (56). CCR5 is part of a CCL3-CCR5/CCR1–mediated DC migration to lymph nodes and the tumor microenvironment (TME). When CD4+ T cells interact with DCs, CCL3 and CCL4 are released, which can guide CCR5-positive naïve CD8+ T cells into tissues for activation (57). CCR5 and its ligands promote the proliferation of CCR5+ polymorphonuclear (PMN)-MDSCs in the bone marrow and, later, potentiate their tumor immunosuppressive activities at the tumor site in part by inducing arginase-1. CCR5 directs the mobilization of CD11b+Gr1+Ly6Clow PMN myeloid cells from the bone marrow to promote tumor development (49). Both MDSCs subtypes (CD11b+Ly6GLy6Chi monocytic MDSCs and CD11b+Ly6G+Ly6Clow PMN-MDSCs support tumor growth and suppress antitumor immunity; ref. 49). In mice CCR5 blockade with anti-CCR5 antibody inhibited B16 melanoma growth and MDSC accumulation in tumor tissues. CCL8, an endogenous ligand of CCR5, is produced by F4/80+ macrophages in the lungs of mice with metastatic primary tumors (58). Migration of Tregs toward CCL8 ex vivo was reduced in the presence of the CCR5 inhibitor, maraviroc. Importantly, treatment of mice with maraviroc reduced the level of CCR5+ Tregs and metastatic tumor burden in the lungs (58).

TAMs express CCR5 and are comprised of an M1 to M2 spectrum of macrophages expressing variable levels of arginase, IL4, IL10, and IL13. F4/80+ macrophages are well known participants in the onset and progression of mammary tumors in murine models and strongly implicated in human cancer progression (59). Ligands from the tissue microenvironment including RANTES, recruit TAMs to the TME (60). CCL3, which binds CCR5 and CCR1, promotes tumorigenesis through recruitment of protumor macrophages into the TME (61). Genetic deletion of Ccl3 in macrophages reduced the number of lung metastasis, whereas adoptive transfer of wild-type inflammatory monocytes increased the number of lung metastasis in Ccl3-deficient mice (61). Additional ligands, including EGF, CSF1, HGF, CCL2, CXCR4/CXCl12, and Tie2, also participate in the local TME to recruit inflammatory cells, which collectively contribute to the diversity of inflammatory subtypes seen within the TME necessary for tumor progression (62). Importantly in this regard, single-cell sequencing assessing the expansion of immune cell phenotypes and diversity of cell states within the TME evidenced CCR5 as one of the top genes correlated with activation of this variance in the breast cancer TME (63).

In addition to augmenting the noncanonical tumor-promoting immune responses, several lines of evidence suggest CCR5 and its ligands appear to participate in the canonical immune checkpoint response. The programmed cell death protein 1 (also known as CD279 and PD-1) and its ligand PD-1 ligand (PD-L1) signaling pathway is a critical immune checkpoint. PD-1 signaling is an important mechanism by which tumors escape antitumor immune responses. TILs are an important biomarker for predicting responses to PD-L1 blockade therapy. Analysis of responses to CTLA-4 and PD-1 antagonists revealed that tumors responsive to these immunotherapies tend to be infiltrated with T cells, referred to as a “T-cell–inflamed” TME (64–66). CCL5 was upregulated in PD-L1–positive melanoma tumors along with IFNγ and several IFNγ-regulated genes (67, 68). Tumor mutational burden and a T-cell–inflamed gene expression profile were independently predictive of response to the PD-1 antibody, pembrolizumab (69), and high levels of the CCR5 ligands, CCL3 and CCL4, in pretreatment tumor specimens were associated with worse patient overall survival after anti-CTLA4 and carboplatin/paclitaxel treatment in melanoma (70).

In addition, a role for MDSC has been described. CCR5high MDSCs have a higher immunosuppressive activity than CCR5low MDSCs (71), and disruption of MDSC trafficking enhances anti-PD1 therapy (72). As noted above, CCL5 promotes influx of CD8+ T cells (54) and PD-L1 expression is often associated with increased TILs. In this regard the Keynote-028 study showed that the patients with tumors with high PD-L1 expression, high expression of T-cell–inflamed genes, and high tumor mutational burden were associated with high benefit from pembrolizumab treatment across several different tumor types (73). Collectively these studies suggest that the CCR5 noncanonical immune checkpoint may intersect the canonical immune checkpoint pathway.

Induction of proliferative signaling, angiogenesis, and resistance to cell death.

CCR5 participates in angiogenesis (74, 75) and resistance to cell death (5). The requirement for CCR5 in oncogene-induced cellular proliferation was supported by elegant transgenic studies, in which MMTV-PyMT (mouse mammary tumor virus polyomavirus middle T-antigen)-induced mammary tumors were reduced in ccr5−/− mice (MMTV-PyMT; ref. 76). CCL5 exerts proangiogenic effects by promoting endothelial cell migration, spreading, neovessel formation, and VEGF secretion. Moreover, tumor cells, upon CCL5 stimulation, produce VEGF and by secreting CCL5 recruit CCR5-expressing TAMs (16, 77). CCR5 inhibitors also reduced lymphangiogenesis (78, 79).

Deregulated cellular energetics and cancer stem cells.

Tumor cells require higher rates of glucose and catabolite uptake, transfer, and utilization (80) and CCR5-induced Akt phosphorylation, stimulating glucose uptake, glycolysis, the pentose phosphate pathway, fatty acid synthesis, and glutamine metabolism (2, 81). Single-cell analysis of breast cancer cells revealed that CCR5 governs dramatic (>1,000-fold) activation of RNA abundance for PI3K/Akt, ribosomal biogenesis, and cell survival signaling pathways (5). CCR5+ breast cancer epithelial cells showed features of cancer stem cells forming mammospheres and initiated tumors with >60-fold greater efficiency in mice (5).

The CCR5 antagonists maraviroc and vicriviroc and leronlimab blocked metastasis of human breast cancer xenografts (MDA-MB-231 cells) in immunodeficient mice via the inhibition of homing, and enhanced cell killing by DNA-damaging chemotherapeutic agents (4, 5, 82). Targeting CCL5 in the bone marrow via nanoparticle-delivered expression silencing, in combination with maraviroc, augmented antitumor immunity (83). Maraviroc and vicriviroc reduced prostate cancer cell metastasis to the bones, brain, and viscera in immunocompetent mice (25). Maraviroc reduced the growth of orthotopically injected colon cancer cells in part via limiting cancer-associated fibroblast accumulation (84). In mice, an anti-CCR5 antibody inhibited B16 melanoma growth and MDSC accumulation in tumor tissues (85). TAK-779 reduced pancreatic cancer cell growth and metastasis with reduced migration of Tregs into the tumors (14). Chemokines participate in the development of NASH, which in turn may progress to hepatocellular cancer (86). Maraviroc reduced lipogenesis, insulin resistance, and β-oxidation in NASH, reduced steatosis and improved the NASH score in high-fat diet–induced NASH (87), and ameliorated the development of hepatocellular carcinoma in a murine model (88).

Growth of acute lymphoblastic leukemia cells and lymphoma was reduced by maraviroc (34). Deadly hematologic malignancies may also be treated by bone marrow transplantation. Chronic GvHD (cGvHD), which is often preceded by acute GvHD (aGvHD), continues to be a significant cause of morbidity and mortality, affecting an estimated 50% of allogeneic hematopoietic stem cell transplantation (HSCT) patients (89). CCR5+ CD146-expressing CD4 T cells (both conventional Tcon and Treg subsets) are increased in patients with cGvHD, express greater levels of T-bet and IFNγ, and contribute to cGvHD (90). Leronlimab, reduced aGvHD in a dose-response fashion in a xenogeneic mouse model of aGvHD (NOD-scid IL2Rynull mice transplanted with human bone marrow stem cells) without significantly altering engraftment (91).

In the phase I pilot MARACON study, patients with advanced stage metastatic colorectal cancer who were refractory to standard chemotherapy (26), were treated with maraviroc. All tumor samples showed reduced proliferation by Ki-67. CCR5 inhibition correlated with an anti-tumoral macrophage-polarized M1 morphology. T cells at the invasive margins of human colorectal cancer liver metastases produced CCL5, which reprogrammed immunosuppressive TAMs toward a protumorigenic phenotype. An inverse correlation was found between “immune CCR5” levels and the maturation status of tumor-infiltrating neutrophils as well as 5-year survival rates (83). From the 11 patients of the core cohort, 5 were reexposed to chemotherapy, and 3 of the 5 patients had objective partial responses comparing favorably with the historic objective response rates in patients with mCRC, on or after the third-line of chemotherapy, of around 5%–10%. A representative PET-MRI image, from a patient with advanced-stage mCRC who was refractory to standard chemotherapy, clearly showed tumor shrinkage after maraviroc treatment (Fig. 1D; ref. 26).

Three additional studies targeting CCR5 for metastatic cancer have been approved by the FDA. Each study combines a drug and a biologic for CCR5+ metastatic cancer. The first is a phase I study of pembrolizumab with maraviroc in patients with refractory microsatellite stable (MSS)-colorectal cancer. The second, a phase II study is assessing safety and efficacy of vicriviroc in combination with pembrolizumab (MK-3475) in patients with advanced metastatic MSS-colorectal cancer. The third is a phase Ib/II study for CCR5+ metastatic TNBC using carboplatin and leronlimab. The study is evaluating the impact on progression-free survival with secondary objectives to assess the overall response rate, the number of circulating tumor cells, and assess benefit based on time to new metastasis.

In studies of hepatocellular cancer prevention targeting NASH, liver fibrosis improved after 1 year of therapy with cenicriviroc, leading to the implementation of a phase III trial (AURORA; ref. 92). Tropifexor (LJN452) and cenicriviroc are being assessed for safety, tolerability, and efficacy in patients with NASH and liver fibrosis (TANDEM; NCT03517540).

Table 1.

Active clinical trials using CCR5 inhibitors

CCR5 antagonistMechanismAdministrationReference
Maraviroc UK-427857 (Pfizer) approved for HIV 2007  Maraviroc (days 1–21 of each cycle) + pembrolizumab (day 1, day 22) (i) Phase I study of pembrolizumab with maraviroc in patients with refractory MSS colorectal cancer. NCT03274804. (ii) GVHD, phase I NCT00948753. Phase II NCT02167451. 
Vicriviroc CH 417690 (Merck) Pyrimidine CCR5 inhibitor Vicriviroc + pembrolizumab (i) Phase II, vicriviroc in combination with pembrolizumab (MK-3475) in patients with advanced metastatic MSS colorectal cancer. NCT03631407. 
Leronlimab (pro-140; CytoDyn) Humanized mAb Weekly self-injection (i) Phase II study for CCR5+ TNBC using carboplatin and leronlimab NCT03838367. (ii) Phase II GVHD NCT02737306. 
CCR5 antagonistMechanismAdministrationReference
Maraviroc UK-427857 (Pfizer) approved for HIV 2007  Maraviroc (days 1–21 of each cycle) + pembrolizumab (day 1, day 22) (i) Phase I study of pembrolizumab with maraviroc in patients with refractory MSS colorectal cancer. NCT03274804. (ii) GVHD, phase I NCT00948753. Phase II NCT02167451. 
Vicriviroc CH 417690 (Merck) Pyrimidine CCR5 inhibitor Vicriviroc + pembrolizumab (i) Phase II, vicriviroc in combination with pembrolizumab (MK-3475) in patients with advanced metastatic MSS colorectal cancer. NCT03631407. 
Leronlimab (pro-140; CytoDyn) Humanized mAb Weekly self-injection (i) Phase II study for CCR5+ TNBC using carboplatin and leronlimab NCT03838367. (ii) Phase II GVHD NCT02737306. 

Valuable progress has been made with CCR5 inhibitors in treatment of bone marrow transplant–related GvHD. In a trial of reduced intensity allo-HSCT with standard GvHD prophylaxis plus maraviroc compared with a contemporary control cohort receiving standard GvHD prophylaxis alone (NCT01785810), maraviroc treatment was associated with a lower incidence of aGvHD without increased risk of disease relapse (93), extending earlier studies with maraviroc suggesting a role for CCR5 in aGvHD. Maraviroc is also being assessed for GvHD prophylaxis in pediatric and adult stem cell transplant recipients (NCT02167451). Leronlimab has been deployed in a clinical trial of GvHD because of the dramatic reduction of aGvHD in a murine model (91). An open-label, single-arm, phase II multicenter study of the safety and efficacy of leronlimab (Pro-140) for prophylaxis of aGvHD in patients undergoing reduced intensity conditioning allogeneic stem cell transplantation was initiated (NCT02737306).

The retasking of CCR5 inhibitors for cancer prevention and treatment of metastatic cancer leverages the substantial prior clinical experience with these compounds and their known safety profiles in patients with HIV. Several additional agents, when combined with CCR5 inhibitors have shown promise in preclinical studies including an anti-IL6 receptor antibody for TNBC and PD-L1 inhibitors in gastric and colon cancer. The finding that CCR5 inhibitors enhance cancer cell killing mediated by radiation and DNA-damaging chemotherapeutic agents (5) suggests the potential for combining these biological agents with chemotherapeutics to potentially reduce the dose-dependent side effects of chemotherapy.

X. Jiao is the principal investigator and reports receiving a commercial research grant from CytoDyn. N. Halama reports receiving a commercial research grant from Bristol-Myers Squibb, Ono Pharma, and NOXXON Pharma, has ownership interest (including stock, patents, etc.) in CCR5 Inhibitor IP owned by University Clinic Heidelberg, and is a consultant/advisory board member for Merck Serono. D. Jaeger reports having ownership of relevant IP for CCR5 Inhibition of University of Heidelberg. R.G. Pestell is chief medical officer at, reports receiving commercial research grants from, has ownership interest (including stock, patents, etc.) in, and is a consultant/advisory board member for CytoDyn. No potential conflicts of interest were disclosed by the other authors.

This work was supported in part by DOD Breakthrough Breast Cancer Research Program grant award and by NIH R01CA132115 (all to R.G. Pestell).

1.
Velasco-Velazquez
M
,
Xolalpa
W
,
Pestell
RG
. 
The potential to target CCL5/CCR5 in breast cancer
.
Expert Opin Ther Targets
2014
;
18
:
1265
75
.
2.
Gao
D
,
Fish
EN
. 
Chemokines in breast cancer: regulating metabolism
.
Cytokine
2018
;
109
:
57
64
.
3.
Olson
WC
,
Rabut
GE
,
Nagashima
KA
,
Tran
DN
,
Anselma
DJ
,
Monard
SP
, et al
Differential inhibition of human immunodeficiency virus type 1 fusion, gp120 binding, and CC-chemokine activity by monoclonal antibodies to CCR5
.
J Virol
1999
;
73
:
4145
55
.
4.
Velasco-Velazquez
M
,
Jiao
X
,
De La Fuente
M
,
Pestell
TG
,
Ertel
A
,
Lisanti
MP
, et al
CCR5 antagonist blocks metastasis of basal breast cancer cells
.
Cancer Res
2012
;
72
:
3839
50
.
5.
Jiao
X
,
Velasco-Velazquez
MA
,
Wang
M
,
Li
Z
,
Rui
H
,
Peck
AR
, et al
CCR5 governs DNA damage repair and breast cancer stem cell expansion
.
Cancer Res
2018
;
78
:
1657
71
.
6.
Dean
M
,
Carrington
M
,
Winkler
C
,
Huttley
GA
,
Smith
MW
,
Allikmets
R
, et al
Genetic restriction of HIV-1 infection and progression to AIDS by a deletion allele of the CKR5 structural gene. Hemophilia Growth and Development Study, Multicenter AIDS Cohort Study, Multicenter Hemophilia Cohort Study, San Francisco City Cohort, ALIVE Study
.
Science
1996
;
273
:
1856
62
.
7.
Samson
M
,
Libert
F
,
Doranz
BJ
,
Rucker
J
,
Liesnard
C
,
Farber
CM
, et al
Resistance to HIV-1 infection in Caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene
.
Nature
1996
;
382
:
722
5
.
8.
Lalani
AS
,
Masters
J
,
Zeng
W
,
Barrett
J
,
Pannu
R
,
Everett
H
, et al
Use of chemokine receptors by poxviruses
.
Science
1999
;
286
:
1968
71
.
9.
Alonzo
F
 III
,
Kozhaya
L
,
Rawlings
SA
,
Reyes-Robles
T
,
DuMont
AL
,
Myszka
DG
, et al
CCR5 is a receptor for Staphylococcus aureus leukotoxin ED
.
Nature
2013
;
493
:
51
5
.
10.
Fatkenheuer
G
,
Nelson
M
,
Lazzarin
A
,
Konourina
I
,
Hoepelman
AI
,
Lampiris
H
, et al
Subgroup analyses of maraviroc in previously treated R5 HIV-1 infection
.
N Engl J Med
2008
;
359
:
1442
55
.
11.
Kaplon
H
,
Reichert
JM
. 
Antibodies to watch in 2018
.
MAbs
2018
;
10
:
183
203
.
12.
Dhody
K
,
Kazempour
K
,
Pourhassan
N
,
Maddon
PJ
. 
Primary efficacy results of PRO 140 SC in a pivotal phase 2b/3 study in heavily treatment-experienced HIV-1 patients
. In:
Proceedings of the ASM Microbe
;
2018 Jun 7–11
;
Atlanta, Georgia. Washington, DC
:
ASM
; 
2018
.
13.
Kaplon
H
,
Reichert
JM
. 
Antibodies to watch in 2019
.
MAbs
2019
;
11
:
219
38
.
14.
Tan
MC
,
Goedegebuure
PS
,
Belt
BA
,
Flaherty
B
,
Sankpal
N
,
Gillanders
WE
, et al
Disruption of CCR5-dependent homing of regulatory T cells inhibits tumor growth in a murine model of pancreatic cancer
.
J Immunol
2009
;
182
:
1746
55
.
15.
Zhang
X
,
Haney
KM
,
Richardson
AC
,
Wilson
E
,
Gewirtz
DA
,
Ware
JL
, et al
Anibamine, a natural product CCR5 antagonist, as a novel lead for the development of anti-prostate cancer agents
.
Bioorg Med Chem Lett
2010
;
20
:
4627
30
.
16.
Robinson
SC
,
Scott
KA
,
Wilson
JL
,
Thompson
RG
,
Proudfoot
AE
,
Balkwill
FR
. 
A chemokine receptor antagonist inhibits experimental breast tumor growth
.
Cancer Res
2003
;
63
:
8360
5
.
17.
Nichols
WG
,
Steel
HM
,
Bonny
T
,
Adkison
K
,
Curtis
L
,
Millard
J
, et al
Hepatotoxicity observed in clinical trials of aplaviroc (GW873140)
.
Antimicrob Agents Chemother
2008
;
52
:
858
65
.
18.
Lin
SS
,
Fan
W
,
Sun
L
,
Li
FF
,
Zhao
RP
,
Zhang
LY
, et al
The saponin DT-13 inhibits gastric cancer cell migration through down-regulation of CCR5-CCL5 axis
.
Chin J Nat Med
2014
;
12
:
833
40
.
19.
Che
LF
,
Shao
SF
,
Wang
LX
. 
Downregulation of CCR5 inhibits the proliferation and invasion of cervical cancer cells and is regulated by microRNA-107
.
Exp Ther Med
2016
;
11
:
503
9
.
20.
Kim
HJ
,
Lee
HJ
,
Kim
H
,
Cho
SW
,
Kim
JS
. 
Targeted genome editing in human cells with zinc finger nucleases constructed via modular assembly
.
Genome Res
2009
;
19
:
1279
88
.
21.
Sutton
A
,
Friand
V
,
Papy-Garcia
D
,
Dagouassat
M
,
Martin
L
,
Vassy
R
, et al
Glycosaminoglycans and their synthetic mimetics inhibit RANTES-induced migration and invasion of human hepatoma cells
.
Mol Cancer Ther
2007
;
6
:
2948
58
.
22.
Shin
N
,
Solomon
K
,
Zhou
N
,
Wang
KH
,
Garlapati
V
,
Thomas
B
, et al
Identification and characterization of INCB9471, an allosteric noncompetitive small-molecule antagonist of C-C chemokine receptor 5 with potent inhibitory activity against monocyte migration and HIV-1 infection
.
J Pharmacol Exp Ther
2011
;
338
:
228
39
.
23.
Blattner
C
,
Fleming
V
,
Weber
R
,
Himmelhan
B
,
Altevogt
P
,
Gebhardt
C
, et al
CCR5+ myeloid-derived suppressor cells are enriched and activated in melanoma lesions
.
Cancer Res
2018
;
78
:
157
67
.
24.
Ryu
H
,
Baek
SW
,
Moon
JY
,
Jo
IS
,
Kim
N
,
Lee
HJ
. 
C-C motif chemokine receptors in gastric cancer
.
Mol Clin Oncol
2018
;
8
:
3
8
.
25.
Sicoli
D
,
Jiao
X
,
Ju
X
,
Velasco-Velazquez
M
,
Ertel
A
,
Addya
S
, et al
CCR5 receptor antagonists block metastasis to bone of v-Src oncogene-transformed metastatic prostate cancer cell lines
.
Cancer Res
2014
;
74
:
7103
14
.
26.
Halama
N
,
Zoernig
I
,
Berthel
A
,
Kahlert
C
,
Klupp
F
,
Suarez-Carmona
M
, et al
Tumoral immune cell exploitation in colorectal cancer metastases can be targeted effectively by anti-CCR5 therapy in cancer patients
.
Cancer Cell
2016
;
29
:
587
601
.
27.
Pervaiz
A
,
Ansari
S
,
Berger
MR
,
Adwan
H
. 
CCR5 blockage by maraviroc induces cytotoxic and apoptotic effects in colorectal cancer cells
.
Med Oncol
2015
;
32
:
158
.
28.
Liu
J
,
Wang
C
,
Ma
X
,
Tian
Y
,
Wang
C
,
Fu
Y
, et al
High expression of CCR5 in melanoma enhances epithelial-mesenchymal transition and metastasis via TGFbeta1
.
J Pathol
2018
;
247
:
481
93
.
29.
Casagrande
N
,
Borghese
C
,
Visser
L
,
Mongiat
M
,
Colombatti
A
,
Aldinucci
D
. 
CCR5 antagonism by maraviroc inhibits Hodgkin lymphoma microenvironment interactions and xenograft growth
.
Haematologica
2019
;
104
:
564
75
.
30.
Gonzalez-Arriagada
WA
,
Lozano-Burgos
C
,
Zuniga-Moreta
R
,
Gonzalez-Diaz
P
,
Coletta
RD
. 
Clinicopathological significance of chemokine receptor (CCR1, CCR3, CCR4, CCR5, CCR7 and CXCR4) expression in head and neck squamous cell carcinomas
.
J Oral Pathol Med
2018
;
47
:
755
63
.
31.
Aldinucci
D
,
Casagrande
N
. 
Inhibition of the CCL5/CCR5 axis against the progression of gastric cancer
.
Int J Mol Sci
2018
;
19
:
E1477
.
32.
Wu
YC
,
Shen
YC
,
Chang
JW
,
Hsieh
JJ
,
Chu
Y
,
Wang
CH
. 
Autocrine CCL5 promotes tumor progression in esophageal squamous cell carcinoma in vitro
.
Cytokine
2018
;
110
:
94
103
.
33.
Singh
SK
,
Mishra
MK
,
Eltoum
IA
,
Bae
S
,
Lillard
JW
 Jr
,
Singh
R
. 
CCR5/CCL5 axis interaction promotes migratory and invasiveness of pancreatic cancer cells
.
Sci Rep
2018
;
8
:
1323
.
34.
Zi
J
,
Yuan
S
,
Qiao
J
,
Zhao
K
,
Xu
L
,
Qi
K
, et al
Treatment with the C-C chemokine receptor type 5 (CCR5)-inhibitor maraviroc suppresses growth and induces apoptosis of acute lymphoblastic leukemia cells
.
Am J Cancer Res
2017
;
7
:
869
80
.
35.
Yaal-Hahoshen
N
,
Shina
S
,
Leider-Trejo
L
,
Barnea
I
,
Shabtai
EL
,
Azenshtein
E
, et al
The chemokine CCL5 as a potential prognostic factor predicting disease progression in stage II breast cancer patients
.
Clin Cancer Res
2006
;
12
:
4474
80
.
36.
Niwa
Y
,
Akamatsu
H
,
Niwa
H
,
Sumi
H
,
Ozaki
Y
,
Abe
A
. 
Correlation of tissue and plasma RANTES levels with disease course in patients with breast or cervical cancer
.
Clin Cancer Res
2001
;
7
:
285
9
.
37.
Vaday
GG
,
Peehl
DM
,
Kadam
PA
,
Lawrence
DM
. 
Expression of CCL5 (RANTES) and CCR5 in prostate cancer
.
Prostate
2006
;
66
:
124
34
.
38.
Tsukishiro
S
,
Suzumori
N
,
Nishikawa
H
,
Arakawa
A
,
Suzumori
K
. 
Elevated serum RANTES levels in patients with ovarian cancer correlate with the extent of the disorder
.
Gynecol Oncol
2006
;
102
:
542
5
.
39.
Sima
AR
,
Sima
HR
,
Rafatpanah
H
,
Hosseinnezhad
H
,
Ghaffarzadehgan
K
,
Valizadeh
N
, et al
Serum chemokine ligand 5 (CCL5/RANTES) level might be utilized as a predictive marker of tumor behavior and disease prognosis in patients with gastric adenocarcinoma
.
J Gastrointest Cancer
2014
;
45
:
476
80
.
40.
Suenaga
M
,
Mashima
T
,
Kawata
N
,
Wakatsuki
T
,
Horiike
Y
,
Matsusaka
S
, et al
Serum VEGF-A and CCL5 levels as candidate biomarkers for efficacy and toxicity of regorafenib in patients with metastatic colorectal cancer
.
Oncotarget
2016
;
7
:
34811
23
.
41.
Vangelista
L
,
Vento
S
. 
The expanding therapeutic perspective of CCR5 blockade
.
Front Immunol
2017
;
8
:
1981
.
42.
Cambien
B
,
Richard-Fiardo
P
,
Karimdjee
BF
,
Martini
V
,
Ferrua
B
,
Pitard
B
, et al
CCL5 neutralization restricts cancer growth and potentiates the targeting of PDGFRbeta in colorectal carcinoma
.
PLoS One
2011
;
6
:
e28842
.
43.
Sugasawa
H
,
Ichikura
T
,
Kinoshita
M
,
Ono
S
,
Majima
T
,
Tsujimoto
H
, et al
Gastric cancer cells exploit CD4+ cell-derived CCL5 for their growth and prevention of CD8+ cell-involved tumor elimination
.
Int J Cancer
2008
;
122
:
2535
41
.
44.
Hanahan
D
,
Weinberg
RA
. 
Hallmarks of cancer: the next generation
.
Cell
2011
;
144
:
646
74
.
45.
Massague
J
,
Obenauf
AC
. 
Metastatic colonization by circulating tumour cells
.
Nature
2016
;
529
:
298
306
.
46.
Liu
W
,
Vivian
CJ
,
Brinker
AE
,
Hampton
KR
,
Lianidou
E
,
Welch
DR
. 
Microenvironmental influences on metastasis suppressor expression and function during a metastatic cell's journey
.
Cancer Microenviron
2014
;
7
:
117
31
.
47.
Karnoub
AE
,
Dash
AB
,
Vo
AP
,
Sullivan
A
,
Brooks
MW
,
Bell
GW
, et al
Mesenchymal stem cells within tumour stroma promote breast cancer metastasis
.
Nature
2007
;
449
:
557
63
.
48.
Zhang
W
,
Xu
J
,
Fang
H
,
Tang
L
,
Chen
W
,
Sun
Q
, et al
Endothelial cells promote triple-negative breast cancer cell metastasis via PAI-1 and CCL5 signaling
.
FASEB J
2018
;
32
:
276
88
.
49.
Hawila
E
,
Razon
H
,
Wildbaum
G
,
Blattner
C
,
Sapir
Y
,
Shaked
Y
, et al
CCR5 directs the mobilization of CD11b+Gr1+Ly6Clow polymorphonuclear myeloid cells from the bone marrow to the blood to support tumor development
.
Cell Rep
2017
;
21
:
2212
22
.
50.
Blattner
C
,
Fleming
V
,
Weber
R
,
Himmelhan
B
,
Altevogt
P
,
Gebhardt
C
, et al
CCR5+ myeloid-derived suppressor cells are enriched and activated in melanoma lesions
.
Cancer Res
2018
;
78
:
157
67
.
51.
Schlecker
E
,
Stojanovic
A
,
Eisen
C
,
Quack
C
,
Falk
CS
,
Umansky
V
, et al
Tumor-infiltrating monocytic myeloid-derived suppressor cells mediate CCR5-dependent recruitment of regulatory T cells favoring tumor growth
.
J Immunol
2012
;
189
:
5602
11
.
52.
Sleeman
JP
. 
The lymph node pre-metastatic niche
.
J Mol Med
2015
;
93
:
1173
84
.
53.
Nishikawa
G
,
Kawada
K
,
Nakagawa
J
,
Toda
K
,
Ogawa
R
,
Inamoto
S
, et al
Bone marrow-derived mesenchymal stem cells promote colorectal cancer progression via CCR5
.
Cell Death Dis
2019
;
10
:
264
.
54.
Harlin
H
,
Meng
Y
,
Peterson
AC
,
Zha
Y
,
Tretiakova
M
,
Slingluff
C
, et al
Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment
.
Cancer Res
2009
;
69
:
3077
85
.
55.
Adler
EP
,
Lemken
CA
,
Katchen
NS
,
Kurt
RA
. 
A dual role for tumor-derived chemokine RANTES (CCL5)
.
Immunol Lett
2003
;
90
:
187
94
.
56.
Chang
LY
,
Lin
YC
,
Mahalingam
J
,
Huang
CT
,
Chen
TW
,
Kang
CW
, et al
Tumor-derived chemokine CCL5 enhances TGF-beta-mediated killing of CD8(+) T cells in colon cancer by T-regulatory cells
.
Cancer Res
2012
;
72
:
1092
102
.
57.
Castellino
F
,
Huang
AY
,
Altan-Bonnet
G
,
Stoll
S
,
Scheinecker
C
,
Germain
RN
. 
Chemokines enhance immunity by guiding naive CD8+ T cells to sites of CD4+ T cell-dendritic cell interaction
.
Nature
2006
;
440
:
890
5
.
58.
Halvorsen
EC
,
Hamilton
MJ
,
Young
A
,
Wadsworth
BJ
,
LePard
NE
,
Lee
HN
, et al
Maraviroc decreases CCL8-mediated migration of CCR5(+) regulatory T cells and reduces metastatic tumor growth in the lungs
.
Oncoimmunology
2016
;
5
:
e1150398
.
59.
Qian
BZ
,
Pollard
JW
. 
Macrophage diversity enhances tumor progression and metastasis
.
Cell
2010
;
141
:
39
51
.
60.
Azenshtein
E
,
Luboshits
G
,
Shina
S
,
Neumark
E
,
Shahbazian
D
,
Weil
M
, et al
The CC chemokine RANTES in breast carcinoma progression: regulation of expression and potential mechanisms of promalignant activity
.
Cancer Res
2002
;
62
:
1093
102
.
61.
Kitamura
T
,
Qian
BZ
,
Soong
D
,
Cassetta
L
,
Noy
R
,
Sugano
G
, et al
CCL2-induced chemokine cascade promotes breast cancer metastasis by enhancing retention of metastasis-associated macrophages
.
J Exp Med
2015
;
212
:
1043
59
.
62.
Arwert
EN
,
Harney
AS
,
Entenberg
D
,
Wang
Y
,
Sahai
E
,
Pollard
JW
, et al
A unidirectional transition from migratory to perivascular macrophage is required for tumor cell intravasation
.
Cell Rep
2018
;
23
:
1239
48
.
63.
Azizi
E
,
Carr
AJ
,
Plitas
G
,
Cornish
AE
,
Konopacki
C
,
Prabhakaran
S
, et al
Single-cell map of diverse immune phenotypes in the breast tumor microenvironment
.
Cell
2018
;
174
:
1293
308.e36
.
64.
Gajewski
TF
. 
The next hurdle in cancer immunotherapy: overcoming the non-T-cell-inflamed tumor microenvironment
.
Semin Oncol
2015
;
42
:
663
71
.
65.
Tumeh
PC
,
Harview
CL
,
Yearley
JH
,
Shintaku
IP
,
Taylor
EJ
,
Robert
L
, et al
PD-1 blockade induces responses by inhibiting adaptive immune resistance
.
Nature
2014
;
515
:
568
71
.
66.
Ji
RR
,
Chasalow
SD
,
Wang
L
,
Hamid
O
,
Schmidt
H
,
Cogswell
J
, et al
An immune-active tumor microenvironment favors clinical response to ipilimumab
.
Cancer Immunol Immunother
2012
;
61
:
1019
31
.
67.
Taube
JM
,
Young
GD
,
McMiller
TL
,
Chen
S
,
Salas
JT
,
Pritchard
TS
, et al
Differential expression of immune-regulatory genes associated with PD-L1 display in melanoma: implications for PD-1 pathway blockade
.
Clin Cancer Res
2015
;
21
:
3969
76
.
68.
Ayers
M
,
Lunceford
J
,
Nebozhyn
M
,
Murphy
E
,
Loboda
A
,
Kaufman
DR
, et al
IFN-gamma-related mRNA profile predicts clinical response to PD-1 blockade
.
J Clin Invest
2017
;
127
:
2930
40
.
69.
Cristescu
R
,
Mogg
R
,
Ayers
M
,
Albright
A
,
Murphy
E
,
Yearley
J
, et al
Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy
.
Science
2018
;
12
:
362
.
70.
Jamal
R
,
Lapointe
R
,
Cocolakis
E
,
Thebault
P
,
Kazemi
S
,
Friedmann
JE
, et al
Peripheral and local predictive immune signatures identified in a phase II trial of ipilimumab with carboplatin/paclitaxel in unresectable stage III or stage IV melanoma
.
J Immunother Cancer
2017
;
5
:
83
.
71.
Chang
LY
,
Lin
YC
,
Kang
CW
,
Hsu
CY
,
Chu
YY
,
Huang
CT
, et al
The indispensable role of CCR5 for in vivo suppressor function of tumor-derived CD103+ effector/memory regulatory T cells
.
J Immunol
2012
;
189
:
567
74
.
72.
Highfill
SL
,
Cui
Y
,
Giles
AJ
,
Smith
JP
,
Zhang
H
,
Morse
E
, et al
Disruption of CXCR2-mediated MDSC tumor trafficking enhances anti-PD1 efficacy
.
Sci Transl Med
2014
;
6
:
237ra67
.
73.
Seto
T
,
Sam
D
,
Pan
M
. 
Mechanisms of primary and secondary resistance to immune checkpoint inhibitors in cancer
.
Med Sci
2019
:
7
;
E14
.
74.
Soria
G
,
Ben-Baruch
A
. 
The inflammatory chemokines CCL2 and CCL5 in breast cancer
.
Cancer Lett
2008
;
267
:
271
85
.
75.
Ben-Baruch
A
. 
The tumor-promoting flow of cells into, within and out of the tumor site: regulation by the inflammatory axis of TNFα and chemokines
.
Cancer Microenviron
2012
;
5
:
151
64
.
76.
Gao
D
,
Cazares
LH
,
Fish
EN
. 
CCL5-CCR5 interactions modulate metabolic events during tumor onset to promote tumorigenesis
.
BMC Cancer
2017
;
17
:
834
.
77.
Frankenberger
C
,
Rabe
D
,
Bainer
R
,
Sankarasharma
D
,
Chada
K
,
Krausz
T
, et al
Metastasis suppressors regulate the tumor microenvironment by blocking recruitment of prometastatic tumor-associated macrophages
.
Cancer Res
2015
;
75
:
4063
73
.
78.
Wang
LH
,
Lin
CY
,
Liu
SC
,
Liu
GT
,
Chen
YL
,
Chen
JJ
, et al
CCL5 promotes VEGF-C production and induces lymphangiogenesis by suppressing miR-507 in human chondrosarcoma cells
.
Oncotarget
2016
;
7
:
36896
908
.
79.
Kang
S
,
Lee
SP
,
Kim
KE
,
Kim
HZ
,
Memet
S
,
Koh
GY
. 
Toll-like receptor 4 in lymphatic endothelial cells contributes to LPS-induced lymphangiogenesis by chemotactic recruitment of macrophages
.
Blood
2009
;
113
:
2605
13
.
80.
Martinez-Outschoorn
UE
,
Peiris-Pages
M
,
Pestell
RG
,
Sotgia
F
,
Lisanti
MP
. 
Cancer metabolism: a therapeutic perspective
.
Nat Rev Clin Oncol
2017
;
14
:
11
31
.
81.
Gao
D
,
Rahbar
R
,
Fish
EN
. 
CCL5 activation of CCR5 regulates cell metabolism to enhance proliferation of breast cancer cells
.
Open Biol
2016
;
6
:
pii:160122
.
82.
Jiao
X
,
Wang
M
,
Pestell
RG
. 
Leronlimab, a humanized monoclonal antibody to CCR5, blocks breast cancer cellular invasion and enhances cell death induced by DNA damaging chemotherapies
. In:
Proceedings of AACR Annual Meeting 2019
;
2019 March 29–April 3
;
Atlanta, GA
:
AACR
; 
2019
.
Abstract nr 2009
.
83.
Ban
Y
,
Mai
J
,
Li
X
,
Mitchell-Flack
M
,
Zhang
T
,
Zhang
L
, et al
Targeting autocrine CCL5-CCR5 axis reprograms immunosuppressive myeloid cells and reinvigorates antitumor immunity
.
Cancer Res
2017
;
77
:
2857
68
.
84.
Tanabe
Y
,
Sasaki
S
,
Mukaida
N
,
Baba
T
. 
Blockade of the chemokine receptor, CCR5, reduces the growth of orthotopically injected colon cancer cells via limiting cancer-associated fibroblast accumulation
.
Oncotarget
2016
;
7
:
48335
45
.
85.
Tang
Q
,
Jiang
J
,
Liu
J
. 
CCR5 blockade suppresses melanoma development through inhibition of IL-6-stat3 pathway via upregulation of SOCS3
.
Inflammation
2015
;
38
:
2049
56
.
86.
Kutlu
O
,
Kaleli
HN
,
Ozer
E
. 
Molecular pathogenesis of nonalcoholic steatohepatitis- (NASH-) related hepatocellular carcinoma
.
Can J Gastroenterol Hepatol
2018
;
2018
:
8543763
.
87.
Perez-Martinez
L
,
Ochoa-Callejero
L
,
Rubio-Mediavilla
S
,
Narro
J
,
Bernardo
I
,
Oteo
JA
, et al
Maraviroc improves hepatic triglyceride content but not inflammation in a murine nonalcoholic fatty liver disease model induced by a chronic exposure to high-fat diet
.
Transl Res
2018
;
196
:
17
30
.
88.
Ochoa-Callejero
L
,
Perez-Martinez
L
,
Rubio-Mediavilla
S
,
Oteo
JA
,
Martinez
A
,
Blanco
JR
. 
Maraviroc, a CCR5 antagonist, prevents development of hepatocellular carcinoma in a mouse model
.
PLoS One
2013
;
8
:
e53992
89.
Socie
G
,
Ritz
J
. 
Current issues in chronic graft-versus-host disease
.
Blood
2014
;
124
:
374
84
.
90.
Forcade
E
,
Paz
K
,
Flynn
R
,
Griesenauer
B
,
Amet
T
,
Li
W
, et al
An activated Th17-prone T cell subset involved in chronic graft-versus-host disease sensitive to pharmacological inhibition
.
JCI Insight
2017
;
2
:
pii92111
.
91.
Burger
DR
,
Parker
Y
,
Guinta
K
,
Lindner
D
. 
PRO 140 monoclonal antibody to CCR5 prevents acute xenogeneic graft-versus-host disease in NOD-scid IL-2Ry(null) mice
.
Biol Blood Marrow Transplant
2018
;
24
:
260
6
.
92.
Tacke
F
. 
Cenicriviroc for the treatment of non-alcoholic steatohepatitis and liver fibrosis
.
Expert Opin Investig Drugs
2018
;
27
:
301
11
.
93.
Moy
RH
,
Huffman
AP
,
Richman
LP
,
Crisalli
L
,
Wang
XK
,
Hoxie
JA
, et al
Clinical and immunologic impact of CCR5 blockade in graft-versus-host disease prophylaxis
.
Blood
2017
;
129
:
906
16
.