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Nature Communications Jul 2020Spinal cord injury (SCI) causes immune dysfunction, increasing the risk of infectious morbidity and mortality. Since bone marrow hematopoiesis is essential for proper...
Spinal cord injury (SCI) causes immune dysfunction, increasing the risk of infectious morbidity and mortality. Since bone marrow hematopoiesis is essential for proper immune function, we hypothesize that SCI disrupts bone marrow hematopoiesis. Indeed, SCI causes excessive proliferation of bone marrow hematopoietic stem and progenitor cells (HSPC), but these cells cannot leave the bone marrow, even after challenging the host with a potent inflammatory stimulus. Sequestration of HSPCs in bone marrow after SCI is linked to aberrant chemotactic signaling that can be reversed by post-injury injections of Plerixafor (AMD3100), a small molecule inhibitor of CXCR4. Even though Plerixafor liberates HSPCs and mature immune cells from bone marrow, competitive repopulation assays show that the intrinsic long-term functional capacity of HSPCs is still impaired in SCI mice. Together, our data suggest that SCI causes an acquired bone marrow failure syndrome that may contribute to chronic immune dysfunction.
Topics: Animals; Benzylamines; Bone Marrow; Bone Marrow Cells; Bone Marrow Failure Disorders; Cell Proliferation; Chemokine CXCL12; Cyclams; Disease Models, Animal; Female; Hematopoiesis; Hematopoietic Stem Cells; Heterocyclic Compounds; Male; Mice; Mice, Inbred C57BL; Mice, Inbred NOD; Mice, Transgenic; Receptors, CXCR4; Signal Transduction; Spinal Cord Injuries
PubMed: 32710081
DOI: 10.1038/s41467-020-17564-z -
American Journal of Hematology Nov 2020Stroma-leukemia interactions mediated by CXCR4, CD44, VLA4, and their respective ligands contribute to therapy resistance in FLT3-ITD-mutated acute myelogenous leukemia...
Stroma-leukemia interactions mediated by CXCR4, CD44, VLA4, and their respective ligands contribute to therapy resistance in FLT3-ITD-mutated acute myelogenous leukemia (AML). We conducted a phase 1 study with the combination of sorafenib (a FLT3-ITD inhibitor), plerixafor (a SDF-1/CXCR4 inhibitor), and G-CSF (that cleaves SDF-1, CD44, and VLA4). Twenty-eight patients with relapsed/refractory FLT3-ITD-mutated AML were enrolled from December 2010 to December 2013 at three dose levels of sorafenib (400, 600, and 800 mg twice daily) and G-CSF and plerixafor were administered every other day for seven doses starting on day one. Sorafenib 800 mg twice daily was selected for the expansion phase. While no dose-limiting toxicities (DLT) were encountered in the four-week DLT window, hand-foot syndrome and rash were seen beyond the DLT window, which required dose reductions in most patients. The response rate was 36% (complete response (CR) = 4, complete remission with incomplete platelet recovery (CRp) = 4, complete remission with incomplete hematologic recovery (CRi) = 1, and partial response (PR) = 1) for the intention to treat population. Treatment resulted in 58.4 and 47 mean fold mobilization of blasts and CD34 /38- stem/progenitor cells, respectively, to the circulation. Expression of the adhesion molecules CXCR4, CD44, and VLA4 on circulating leukemia cells correlated negatively with the mobilization of CD34+/38-, CD34+/38-/123+ "progenitor" cells (all P ≤ .002). Mass cytometry analysis of sequential samples from two patients demonstrated resistance emerging early on from sub-clones with persistent Akt and/or ERK signaling. In conclusion, the strategy of combined inhibition of FLT3 kinase and stromal adhesive interactions has promising activity in relapsed/refractory, FLT3-ITD-mutated AML, which warrants further evaluation in the front-line setting.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzylamines; Cyclams; Disease-Free Survival; Female; Granulocyte Colony-Stimulating Factor; Heterocyclic Compounds; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Sorafenib; Survival Rate; fms-Like Tyrosine Kinase 3
PubMed: 32697348
DOI: 10.1002/ajh.25943 -
The Oncologist Jun 2020On March 28, 2019, the Committee for Medicinal Products for Human Use adopted a positive opinion recommending the marketing authorization for the medicinal product... (Review)
Review
EMA Recommendation for the Pediatric Indications of Plerixafor (Mozobil) to Enhance Mobilization of Hematopoietic Stem Cells for Collection and Subsequent Autologous Transplantation in Children with Lymphoma or Malignant Solid Tumors.
On March 28, 2019, the Committee for Medicinal Products for Human Use adopted a positive opinion recommending the marketing authorization for the medicinal product plerixafor. The marketing authorization holder for this medicinal product is Genzyme Europe B.Th. The adoption was for an extension of the existing adult indication in combination with granulocyte colony-stimulating factor (G-CSF) to pediatric patients (aged 1 year to <18 years) to enhance mobilization of hematopoietic stem cells to the peripheral blood for collection and subsequent autologous transplantation in children with lymphoma or solid malignant tumors. This treatment is indicated either preemptively, when circulating stem cell count on the predicted day of collection after adequate mobilization with G-CSF (with or without chemotherapy) is expected to be insufficient with regard to desired hematopoietic stem cells yield, or in children who previously failed to collect sufficient hematopoietic stem cells. The efficacy and safety of plerixafor were evaluated in an open label, multicenter, phase I/II, dose-ranging, and randomized controlled study (DFI12860) in pediatric patients with solid tumors, including neuroblastoma, sarcoma, Ewing sarcoma, or lymphoma, who were eligible for autologous hematopoietic stem cell transplantation. Forty-five patients (aged 1 year to <18 years) were randomized, 2:1, using 0.24 mg/kg of plerixafor plus standard mobilization (G-CSF with or without chemotherapy) versus control (standard mobilization alone). The primary analysis showed that 80% of patients in the plerixafor arm experienced at least a doubling of the peripheral blood (PB) CD34+ count, observed from the morning of the day preceding the first planned apheresis to the morning prior to apheresis, versus 28.6% of patients in the control arm (p = .0019). The median increase in PB CD34+ cell counts from baseline to the day of apheresis was 3.2-fold in the plerixafor arm versus by 1.4-fold in the control arm. The observed safety profile in the pediatric population was consistent with that in adults, with adverse events mainly related to injection site reactions, hypokalemia, and increased blood bicarbonate. Importantly, plerixafor exposure did not seem to negatively affect transplant efficiency. This article summarizes the scientific review of the application leading to regulatory approval in the European Union. IMPLICATIONS FOR PRACTICE: This review of the marketing authorization of plerixafor will raise awareness of pediatric indication granted for this medicinal product.
Topics: Adult; Benzylamines; Child; Cyclams; Europe; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cells; Heterocyclic Compounds; Humans; Lymphoma; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Transplantation, Autologous
PubMed: 32154610
DOI: 10.1634/theoncologist.2019-0898 -
Leukemia & Lymphoma Apr 2018We investigated CD25 expression in older (≥60 years) patients with new acute myelogenous leukemia treated with decitabine and plerixafor. Patients resistant to therapy... (Comparative Study)
Comparative Study
We investigated CD25 expression in older (≥60 years) patients with new acute myelogenous leukemia treated with decitabine and plerixafor. Patients resistant to therapy or survival ≤1 year had significantly higher percentages of CD25 myeloid blasts in baseline bone marrow. CD25 patients had an increased odds of resistance compared to CD25 patients (p = .015). In univariate analysis, we found CD25 patients had inferior survival compared to CD25 (p = .002). In patients with intermediate risk cytogenetics, CD25 status stratified patients associating with inferior survival (p = .002). In multivariable analysis, CD25 and TP53 mutations trended towards predicting remission to therapy but were not predictive of survival. Only remission status, ASXL1 and TET2 mutations were found to independently predict overall survival (OS). We conclude CD25 expression identifies patients at risk for resistance to hypomethylating chemotherapy but does not independently predict OS in an older AML population treated with decitabine and plerixafor.
Topics: Age Factors; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Benzylamines; Bone Marrow; Cyclams; DNA Methylation; Decitabine; Drug Resistance, Neoplasm; Female; Heterocyclic Compounds; Humans; Interleukin-2 Receptor alpha Subunit; Leukemia, Myeloid, Acute; Male; Middle Aged; Mutation; Prognosis; Remission Induction; Retrospective Studies; Survival Analysis; Treatment Outcome; Tumor Suppressor Protein p53
PubMed: 28718760
DOI: 10.1080/10428194.2017.1352089 -
Biology of Blood and Marrow... May 2020Patients with multiple myeloma (MM) scheduled for autologous stem cell transplantation must undergo autologous stem cell mobilization; unfortunately, however, many do...
Patients with multiple myeloma (MM) scheduled for autologous stem cell transplantation must undergo autologous stem cell mobilization; unfortunately, however, many do not obtain an adequate collection yield. Despite the availability of plerixafor, its widespread and uniform use is limited by its cost, and consequently, many institutions have adopted various risk-adapted algorithms. We report our mobilization experience as we have modified our plerixafor algorithm to a more liberal one, with the expectation of greater collection efficiency and mobilization success with higher plerixafor use. A total of 344 mobilization attempts were analyzed over 3 time periods and using 3 different peripheral blood CD34 cell counts to guide plerixafor use: <15/µL (n = 66), <20/µL (n = 130), and <40/µL (n = 148). The primary endpoints were evaluation of changes in mean plerixafor utilization and apheresis days and assessment of the impact on overall mobilization costs. Secondary endpoints were a description of the impact of lenalidomide use on mobilization and evaluation of the rate of mobilization failure. We found that mean plerixafor use increased from 1.32 to 1.65 to 1.74 doses per mobilization (P = .026) and the mean days of apheresis decreased from 2.15 to 2.17 to 1.89 days per mobilization for the <15/µL, <20/µL, and <40/µL cohorts, respectively (P = .011). The combined cost of plerixafor and apheresis procedures at a threshold of 40/µL is close to that at a threshold of 15/µL, while saving 26 apheresis days per 100 patients. In general, there were low rates of mobilization failure across all thresholds. Patients who received more than 6 cycles of lenalidomide demonstrated impaired mobilization and required more apheresis sessions (P < .013) and greater plerixafor use (P < .001) to achieve target stem cell yields. Overall, using plerixafor in patients with MM, with a day 4 pCD34 count of <40/µL is a reasonable and cost-effective strategy to optimize apheresis utilization.
Topics: Benzylamines; Cyclams; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Heterocyclic Compounds; Humans; Multiple Myeloma; Transplantation, Autologous
PubMed: 31785375
DOI: 10.1016/j.bbmt.2019.11.024 -
Stem Cells Translational Medicine Sep 2020Bone marrow-derived cells contribute to tissue repair, but traffic of hematopoietic stem/progenitor cells (HSPCs) is impaired in diabetes. We therefore tested whether... (Randomized Controlled Trial)
Randomized Controlled Trial
Bone marrow-derived cells contribute to tissue repair, but traffic of hematopoietic stem/progenitor cells (HSPCs) is impaired in diabetes. We therefore tested whether HSPC mobilization with the CXCR4 antagonist plerixafor improved healing of ischemic diabetic wounds. This was a pilot, phase IIa, double-blind, randomized, placebo-controlled trial (NCT02790957). Patients with diabetes with ischemic wounds were randomized to receive a single subcutaneous injection of plerixafor or saline on top of standard medical and surgical therapy. The primary endpoint was complete healing at 6 months. Secondary endpoints were wound size, transcutaneous oxygen tension (TcO ), ankle-brachial index (ABI), amputations, and HSPC mobilization. Twenty-six patients were enrolled: 13 received plerixafor and 13 received placebo. Patients were 84.6% males, with a mean age of 69 years. HSPC mobilization was successful in all patients who received plerixafor. The trial was terminated after a preplanned interim analysis of 50% of the target population showed a significantly lower healing rate in the plerixafor vs the placebo group. In the final analysis data set, the rate of complete healing was 38.5% in the plerixafor group vs 69.2% in the placebo group (chi-square P = .115). Wound size tended to be larger in the plerixafor group for the entire duration of observation. No significant difference was noted for the change in TcO and ABI or in amputation rates. No other safety concern emerged. In conclusion, successful HSPC mobilization with plerixafor did not improve healing of ischemic diabetic wounds. Contrary to what was expected, outside the context of hematological disorders, mobilization of diabetic HSPCs might exert adverse effects on wound healing.
Topics: Aged; Benzylamines; Cyclams; Diabetes Mellitus; Double-Blind Method; Female; Hematopoietic Stem Cell Mobilization; Humans; Male; Placebos; Treatment Outcome; Wound Healing
PubMed: 32485785
DOI: 10.1002/sctm.20-0020 -
Bulletin Du Cancer Aug 2011Mobilization is the biological phenomenon by which hematopoietic stem and progenitor cells (HSPC) transiently egress the bone marrow compartment and circulates in... (Review)
Review
Mobilization is the biological phenomenon by which hematopoietic stem and progenitor cells (HSPC) transiently egress the bone marrow compartment and circulates in peripheral blood. The biological significance of this phenomenon is incompletely understood, although it is likely to be a component of physiological responses to various forms of stress, and needs for tissue repair. Some of the molecular actors that regulate HSPC mobilization have been unravelled. In addition, some of the inter-individual variability of this phenomenon can be ascribed to clinical as well as to biological parameters. The key role of the interaction between the chemokine SDF-1/CXCL12 and its receptor CXCR-4 has made it an attractive target for pharmacological agents. Recently, plerixafor, the first of its kind, obtained marketing authorization from the U.S. then the European health authorities, on the basis of its activity to increase the mobilization induced by rhG-CSF in patients treated for lymphoid malignancies and who are candidates for high-dose chemotherapy supported with autologous HSPC transplantation.
Topics: Benzylamines; Chemokine CXCL12; Cyclams; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Heterocyclic Compounds; Humans; Receptors, CXCR4; Recombinant Proteins
PubMed: 21835729
DOI: 10.1684/bdc.2011.1405 -
International Journal of Nanomedicine 2023Immune checkpoint inhibitors (ICI) have received the most attention for triple negative breast cancer (TNBC), while the response rate to ICI remains limited due to...
PURPOSE
Immune checkpoint inhibitors (ICI) have received the most attention for triple negative breast cancer (TNBC), while the response rate to ICI remains limited due to insufficient T cell infiltration. It is therefore essential that alternative strategies are developed to improve the therapeutic outcomes of ICI in non-responsive TNBC cases. The efficacy of pH-responsive nanomicelles (P/A/B@NM) co-loaded with paclitaxel (PTX), CXCR4 antagonist AMD3100, and PD-1/PD-L1 inhibitor BMS-1 activating the T cell-mediated antitumor immune response were evaluated using a 4T1 antiPD-1-resistance breast tumor model.
METHODS
In vitro, pH-responsive antitumor effect of P/A/B@NM was investigated by assessing cell viability, migration and invasion. In vivo, the distribution of P/A/B@NM was visualized in 4T1 orthotopic TNBC model using an IVIS spectrum imaging instrument. The efficacy of the co-delivery nanocarriers was evaluated by monitoring mouse survival, tumor growth and metastasis, cancer-associated fibroblasts (CAFs)-mediated tumor stroma and immunosuppressive microenvironment components, and the recruitment and infiltration of CD8 T cells.
RESULTS
The prepared P/A/B@NM in acid microenvironment demonstrates remarkable cytotoxicity against MDA-MB-231 cells, with an IC of 105 μg/mL. Additionally, it exhibits substantial inhibition of tumor cell migration and invasion. The P/A/B@NM based on co-delivery nanocarriers efficiently accumulate at the tumor site and release the drugs in a pH-responsive controlled manner. The nanomedicine-PTX, AMD3100, and BMS-1 formulation significantly inhibits tumor growth and lung/liver metastasis by inducing antitumor immune responses via CXCL12/CXCR4 axis blockade, and immunogenic cell death to reprogramme both tumor stroma and immunosuppressive microenvironment. As a result, CD8 T cell infiltration is triggered into the tumor site, boosting the efficacy of ICI therapy synergistically.
CONCLUSION
These results demonstrate that combination therapy using P/A/B@NM reshapes CAFs-mediated tumor stroma and immunosuppressive microenvironment, which can enhance the infiltration of CD8 T cells, thereby reactivating anti-tumor immunity for non-responsive TNBC cases.
Topics: Humans; Animals; Mice; Triple Negative Breast Neoplasms; Cancer-Associated Fibroblasts; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Paclitaxel; Immunosuppressive Agents; Immunotherapy; Tumor Microenvironment
PubMed: 37545872
DOI: 10.2147/IJN.S418100 -
Journal of Clinical Apheresis Feb 2022Germ cell tumors represent, among solid cancers, a potentially curable disease even if up to 20% to 30% of patients (pts) relapse after first-line treatment especially...
BACKGROUND
Germ cell tumors represent, among solid cancers, a potentially curable disease even if up to 20% to 30% of patients (pts) relapse after first-line treatment especially considering intermediate and poor prognosis groups. In this scenario, patients are candidates for high-dose chemotherapy and autologous stem-cells transplantation as second-line treatment even though stem-cells mobilization potential can be affected by several cycles and regimens of chemotherapy. To date, plerixafor is authorized in poor mobilizer adult pts diagnosed with lymphoma or multiple myeloma and in pediatric solid tumors or lymphoma. Therefore, the use of plerixafor in adult pts with relapsing/refractory GCT is still off label.
MATERIALS AND METHODS
In our study, we describe mobilization and collection of peripheral blood stem cells for 10 pts with germ cell tumors. Six patients underwent plerixafor administration since classified as poor mobilizers based on WBC count (>5.000/μL) and CD34+ cell count (<15/μL) the day before apheresis procedure.
RESULTS
On the first day of apheresis, plerixafor administration in poor mobilizers made possible a remarkable boost of CD34+ cells in such a way to overlap that of good mobilizers' (32/μL vs 35/μL, respectively, P > .05).
CONCLUSION
Therefore, in our experience, plerixafor made a good fraction of poor mobilizer patients eligible for mobilization and collection and able to undergo the predicted autologous stem-cells transplantation; thus, the lack of access to the use of plerixafor in this setting of patients risks jeopardizing an effective treatment, especially in case of poor prognosis.
Topics: Adolescent; Adult; Benzylamines; Blood Component Removal; Cyclams; Female; Hematopoietic Stem Cell Mobilization; Humans; Male; Middle Aged; Neoplasm Recurrence, Local; Neoplasms, Germ Cell and Embryonal; Peripheral Blood Stem Cell Transplantation; Peripheral Blood Stem Cells; Retrospective Studies; Transplantation, Autologous; Young Adult
PubMed: 34822725
DOI: 10.1002/jca.21952 -
Molecules (Basel, Switzerland) Feb 2019HIV entry in the host cell requires the interaction with the CD4 membrane receptor, and depends on the activation of one or both co-receptors CCR5 and CXCR4. Former... (Review)
Review
HIV entry in the host cell requires the interaction with the CD4 membrane receptor, and depends on the activation of one or both co-receptors CCR5 and CXCR4. Former selective co-receptor antagonists, acting at early stages of infection, are able to impair the receptor functions, preventing the viral spread toward AIDS. Due to the capability of HIV to develop resistance by switching from CCR5 to CXCR4, dual co-receptor antagonists could represent the next generation of AIDS prophylaxis drugs. We herein present a survey on relevant results published in the last few years on compounds acting simultaneously on both co-receptors, potentially useful as preventing agents or in combination with classical anti-retroviral drugs based therapy.
Topics: Anti-HIV Agents; Benzylamines; CCR5 Receptor Antagonists; Cyclams; HIV Infections; HIV-1; Heterocyclic Compounds; Humans; Maraviroc; Pyridines; Receptors, CCR5; Receptors, CXCR4
PubMed: 30717348
DOI: 10.3390/molecules24030550