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Frontiers in Immunology 2019Immunotherapy is a clinically validated treatment for many cancers to boost the immune system against tumor growth and dissemination. Several strategies are used to... (Review)
Review
Immunotherapy is a clinically validated treatment for many cancers to boost the immune system against tumor growth and dissemination. Several strategies are used to harness immune cells: monoclonal antibodies against tumor antigens, immune checkpoint inhibitors, vaccination, adoptive cell therapies (e.g., CAR-T cells) and cytokine administration. In the last decades, it is emerging that the chemokine system represents a potential target for immunotherapy. Chemokines, a large family of cytokines with chemotactic activity, and their cognate receptors are expressed by both cancer and stromal cells. Their altered expression in malignancies dictates leukocyte recruitment and activation, angiogenesis, cancer cell proliferation, and metastasis in all the stages of the disease. Here, we review first attempts to inhibit the chemokine system in cancer as a monotherapy or in combination with canonical or immuno-mediated therapies. We also provide recent findings about the role in cancer of atypical chemokine receptors that could become future targets for immunotherapy.
Topics: Antibodies, Monoclonal, Humanized; Benzylamines; Chemokines, CC; Chemokines, CXC; Cyclams; Heterocyclic Compounds; Humans; Immunotherapy; Molecular Targeted Therapy; Neoplasms; Receptors, CCR; Receptors, CXCR
PubMed: 30894861
DOI: 10.3389/fimmu.2019.00379 -
Proceedings of the National Academy of... Nov 2020Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in...
Inhibition of the chemokine receptor CXCR4 in combination with blockade of the PD-1/PD-L1 T cell checkpoint induces T cell infiltration and anticancer responses in murine and human pancreatic cancer. Here we elucidate the mechanism by which CXCR4 inhibition affects the tumor immune microenvironment. In human immune cell-based chemotaxis assays, we find that CXCL12-stimulated CXCR4 inhibits the directed migration mediated by CXCR1, CXCR3, CXCR5, CXCR6, and CCR2, respectively, chemokine receptors expressed by all of the immune cell types that participate in an integrated immune response. Inhibiting CXCR4 in an experimental cancer medicine study by 1-wk continuous infusion of the small-molecule inhibitor AMD3100 (plerixafor) induces an integrated immune response that is detected by transcriptional analysis of paired biopsies of metastases from patients with microsatellite stable colorectal and pancreatic cancer. This integrated immune response occurs in three other examples of immune-mediated damage to noninfected tissues: Rejecting renal allografts, melanomas clinically responding to anti-PD1 antibody therapy, and microsatellite instable colorectal cancers. Thus, signaling by CXCR4 causes immune suppression in human pancreatic ductal adenocarcinoma and colorectal cancer by impairing the function of the chemokine receptors that mediate the intratumoral accumulation of immune cells.
Topics: Aged; Benzylamines; Carcinoma, Pancreatic Ductal; Chemokine CXCL12; Colorectal Neoplasms; Cyclams; Female; Heterocyclic Compounds; Humans; Immunity; Immunotherapy; Male; Middle Aged; Pancreas; Pancreatic Neoplasms; Receptors, CCR2; Receptors, CXCR3; Receptors, CXCR4; Receptors, CXCR5; Receptors, CXCR6; Receptors, Interleukin-8A; Signal Transduction; Tumor Microenvironment
PubMed: 33127761
DOI: 10.1073/pnas.2013644117 -
British Journal of Haematology Jan 2014We initially described the WHIM syndrome based on the combination of Warts, Hypogammaglobulinaemia, Infections and Myelokathexis (neutrophil retention in the bone... (Review)
Review
We initially described the WHIM syndrome based on the combination of Warts, Hypogammaglobulinaemia, Infections and Myelokathexis (neutrophil retention in the bone marrow). Translational research led to the discovery that this rare immunodeficiency disease is caused by a heterozygous mutation in the CXCR4 gene. Recently, Plerixafor has been suggested as a treatment for WHIM syndrome due to its efficacy as a CXCR4 antagonist, closing the translational research loop. In this review, we will focus on the clinical manifestations, pathophysiology, diagnosis and possible therapies for this rare entity.
Topics: Animals; Benzylamines; Cyclams; Heterocyclic Compounds; Humans; Immunologic Deficiency Syndromes; Primary Immunodeficiency Diseases; Receptors, CXCR4; Warts
PubMed: 24111611
DOI: 10.1111/bjh.12574 -
Nature Communications Mar 2021Advanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that...
Advanced prostate cancer (PCa) often develops bone metastasis, for which therapies are very limited and the underlying mechanisms are poorly understood. We report that bone-borne TGF-β induces the acetylation of transcription factor KLF5 in PCa bone metastases, and acetylated KLF5 (Ac-KLF5) causes osteoclastogenesis and bone metastatic lesions by activating CXCR4, which leads to IL-11 secretion, and stimulating SHH/IL-6 paracrine signaling. While essential for maintaining the mesenchymal phenotype and tumorigenicity, Ac-KLF5 also causes resistance to docetaxel in tumors and bone metastases, which is overcome by targeting CXCR4 with FDA-approved plerixafor. Establishing a mechanism for bone metastasis and chemoresistance in PCa, these findings provide a rationale for treating chemoresistant bone metastasis of PCa with inhibitors of Ac-KLF5/CXCR4 signaling.
Topics: Acetylation; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzylamines; Bone Neoplasms; Carcinogenesis; Cell Line, Tumor; Cyclams; Docetaxel; Epithelial-Mesenchymal Transition; Humans; Interleukin-11; Kruppel-Like Transcription Factors; Male; Mice; Mutation; Osteogenesis; Prostatic Neoplasms, Castration-Resistant; Receptors, CXCR4; Signal Transduction; Transforming Growth Factor beta
PubMed: 33731701
DOI: 10.1038/s41467-021-21976-w -
Protein & Cell Jun 2010
Review
Topics: Aminoquinolines; Anti-HIV Agents; Benzimidazoles; Benzylamines; Butylamines; CCR5 Receptor Antagonists; CD4 Antigens; Cyclams; Cyclohexanes; HIV-1; Heterocyclic Compounds; Heterocyclic Compounds, 1-Ring; Humans; Maraviroc; Piperazines; Pyrimidines; Receptors, CCR5; Receptors, CXCR4; T-Lymphocytes; Triazoles; Viral Tropism
PubMed: 21204004
DOI: 10.1007/s13238-010-0066-2 -
Pediatrics International : Official... Jan 2022Plerixafor is approved in Japan for hematopoietic stem cell mobilization prior to autologous transplant, but limited data are available on the use in children. This...
BACKGROUND
Plerixafor is approved in Japan for hematopoietic stem cell mobilization prior to autologous transplant, but limited data are available on the use in children. This study evaluates the safety and effectiveness of plerixafor in Japanese children aged <15 years.
METHODS
A multicenter, post-marketing surveillance study was conducted in Japan to evaluate the safety and effectiveness of plerixafor in routine clinical practice. This subgroup analysis examined the safety and effectiveness of plerixafor administered as a once-daily, subcutaneous injection in children aged <15 years. The primary effectiveness outcome was the proportion of patients with 2 × 10 cells CD34+ cells/kg collected via apheresis within 4 days.
RESULTS
Eighteen patients with solid tumors were included in this analysis; (median age 6.0 years, range, 1-13 years). In addition to granulocyte colony-stimulating factor, all patients had received chemotherapy immediately prior to plerixafor administration. The mean (SD) daily dose of plerixafor was 0.24 (0.01) mg/kg. Seven of the 18 patients (38.9%) developed adverse drug reactions (ADRs), all occurring in patients aged ≥6 years and weighing ≥16 kg. The most common ADRs were pyrexia (n = 4), vomiting (n = 3), nausea (n = 2), and abdominal pain (n = 2). Twelve patients (66.7%) achieved a CD34+ cell count ≥2 × 10 cells/kg within 4 days after the start of plerixafor administration.
CONCLUSIONS
The results provide an encouraging sign that plerixafor 0.24 mg/kg may be safe and effective in pediatric patients in routine clinical practice in Japan, but further research in larger studies is needed.
Topics: Benzylamines; Child; Cyclams; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Humans; Japan; Marketing
PubMed: 35396889
DOI: 10.1111/ped.15106 -
Blood Jul 2009
Topics: Animals; Antineoplastic Agents; Benzylamines; Bone Marrow Transplantation; Cell Movement; Cyclams; Drug Administration Schedule; Granulocyte Colony-Stimulating Factor; Heterocyclic Compounds; Humans; Leukemia; Mice; Neoadjuvant Therapy; Neoplastic Stem Cells; Receptors, CXCR4; Transplantation Conditioning
PubMed: 19628718
DOI: 10.1182/blood-2009-04-217299 -
Cell Communication and Signaling : CCS Mar 2023Matrix metalloproteinases (MMPs) play important roles in remodeling the extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). MMP19, which...
BACKGROUND
Matrix metalloproteinases (MMPs) play important roles in remodeling the extracellular matrix and in the pathogenesis of idiopathic pulmonary fibrosis (IPF). MMP19, which is an MMP, was significantly upregulated in hyperplastic alveolar epithelial cells in IPF lung tissues and promoted epithelial-mesenchymal transition (EMT). Recent studies have demonstrated that endothelial-to-mesenchymal transition (E(nd)MT) contributes to pulmonary fibrosis. However, the role of MMP19 in pulmonary vascular injury and repair and E(nd)MT remains unclear.
METHODS
To determine the role of MMP19 in E(nd)MT and pulmonary fibrosis. MMP19 expressions were determined in the lung endothelial cells of IPF patients and bleomycin (BLM)-induced mice. The roles of MMP19 in E(nd)MT and endothelial barrier permeability were studied in the MMP19 cDNA-transfected primary human pulmonary microvascular endothelial cells (HPMECs) and MMP19 adenoassociated virus (MMP19-AAV)-infected mice. The regulatory mechanism of MMP19 in pulmonary fibrosis was elucidated by blocking its interacting proteins SDF1 and ET1 with AMD3100 and Bosentan, respectively.
RESULTS
In this study, we found that MMP19 expression was significantly increased in the lung endothelial cells of IPF patients and BLM-induced mice compared to the control groups. MMP19 promoted E(nd)MT and the migration and permeability of HPMECs in vitro, stimulated monocyte infiltration into the alveolus, and aggravated BLM-induced pulmonary fibrosis in vivo. SDF1 and Endothelin-1 (ET1) were physically associated with MMP19 in HPMECs and colocalized with MMP19 in endothelial cells in IPF patient lung tissues. AMD3100 and bosentan alleviated the fibrosis induced by MMP19 in the BLM mouse model.
CONCLUSION
MMP19 promoted E(nd)MT by interacting with ET1 and stimulated monocyte infiltration into lung tissues via the SDF1/CXCR4 axis, thus aggravating BLM-induced pulmonary fibrosis. Vascular integrity regulated by MMP19 could be a promising therapeutic target for suppressing pulmonary fibrosis. Video abstract.
Topics: Animals; Humans; Mice; Bleomycin; Bosentan; Endothelial Cells; Epithelial-Mesenchymal Transition; Idiopathic Pulmonary Fibrosis; Lung; Monocytes; Matrix Metalloproteinases, Secreted
PubMed: 36915092
DOI: 10.1186/s12964-023-01040-4 -
Blood Advances Mar 2021We have developed an in vivo hemopoietic stem cell (HSC) gene therapy approach without the need for myelosuppressive conditioning and autologous HSC transplantation. It...
We have developed an in vivo hemopoietic stem cell (HSC) gene therapy approach without the need for myelosuppressive conditioning and autologous HSC transplantation. It involves HSC mobilization and IV injection of a helper-dependent adenovirus HDAd5/35++ vector system. The current mobilization regimen consists of granulocyte colony-stimulating factor (G-CSF) injections over a 4-day period, followed by the administration of plerixafor/AMD3100. We tested a simpler, 2-hour, G-CSF-free mobilization regimen using truncated GRO-β (MGTA-145; a CXCR2 agonist) and plerixafor in the context of in vivo HSC transduction in mice. The MGTA-145+plerixafor combination resulted in robust mobilization of HSCs. Importantly, compared with G-CSF+plerixafor, MGTA-145+plerixafor led to significantly less leukocytosis and no elevation of serum interleukin-6 levels and was thus likely to be less toxic. With both mobilization regimens, after in vivo selection with O6-benzylguanine (O6BG)/BCNU, stable GFP marking was achieved in >90% of peripheral blood mononuclear cells. Genome-wide analysis showed random, multiclonal vector integration. In vivo HSC transduction after mobilization with MGTA-145+plerixafor in a mouse model for thalassemia resulted in >95% human γ-globin+ erythrocytes at a level of 36% of mouse β-globin. Phenotypic analyses showed a complete correction of thalassemia. The γ-globin marking percentage and level were maintained in secondary recipients, further demonstrating that MGTA145+plerixafor mobilizes long-term repopulating HSCs. Our study indicates that brief exposure to MGTA-145+plerixafor may be advantageous as a mobilization regimen for in vivo HSC gene therapy applications across diseases, including thalassemia and sickle cell disease.
Topics: Animals; Benzylamines; Cyclams; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Leukocytes, Mononuclear; Mice; Thalassemia
PubMed: 33646305
DOI: 10.1182/bloodadvances.2020003714 -
Blood Advances Mar 2019Plerixafor, a direct antagonist of CXCR4/stromal-derived factor 1, can safely and rapidly mobilize allografts without the use of granulocyte colony-stimulating factor...
Plerixafor, a direct antagonist of CXCR4/stromal-derived factor 1, can safely and rapidly mobilize allografts without the use of granulocyte colony-stimulating factor (G-CSF). We conducted a phase 2, multicenter, prospective study of plerixafor-mobilized HLA-identical sibling allografts for allogeneic hematopoietic cell transplantation in recipients with hematological malignancies. Donors (n = 64) were treated with subcutaneous plerixafor (240 µg/kg) and started leukapheresis (LP) 4 hours later. The primary objective was to determine the proportion of donors who were successfully mobilized: defined as collection of ≥2.0 × 10 CD34 cells per kilogram recipient weight in ≤2 LP sessions. Recipients subsequently received reduced intensity (RIC; n = 33) or myeloablative (MAC; n = 30) conditioning. Sixty-three of 64 (98%) donors achieved the primary objective. The median CD34 cell dose per kilogram recipient weight collected within 2 days was 4.7 (0.9-9.6). Plerixafor was well tolerated with only grade 1 or 2 drug-related adverse events noted. Bone pain was not observed. Plerixafor-mobilized grafts engrafted promptly. One-year progression-free and overall survivals were 53% (95% confidence interval [CI], 36% to 71%) and 63% (95% CI, 46% to 79%) for MAC and 64% (95% CI, 47% to 79%) and 70% (95% CI, 53% to 84%) for RIC recipients, respectively. Donor toxicity was reduced relative to G-CSF mobilized related donors. This is the first multicenter trial to demonstrate that, as an alternative to G-CSF, plerixafor rapidly and safely mobilizes sufficient numbers of CD34 cells from matched sibling donors for HCT. Engraftment was prompt, and outcomes in recipients were encouraging. This trial was registered at clinicaltrials.gov as #NCT01696461.
Topics: Adult; Aged; Antigens, CD34; Benzylamines; Cyclams; Hematologic Neoplasms; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Heterocyclic Compounds; Histocompatibility; Humans; Middle Aged; Siblings; Tissue Donors; Transplantation, Homologous; Treatment Outcome
PubMed: 30890544
DOI: 10.1182/bloodadvances.2018027599