Low dose gemcitabine-loaded lipid nanocapsules target monocytic myeloid-derived suppressor cells and potentiate cancer immunotherapy

AbstractSurgical resection is a common therapeutic option for primary solid tumors. However, high cancer recurrence and metastatic rates after resection are the main cause of cancer related mortalities. This implies the existence of a “fertile soil” following surgery that facilitates colonization by circulating cancer cells. Myeloid-derived suppressor cells (MDSCs) are essential for premetastatic niche formation, and may persist in distant organs for up to 2 weeks after surgery. These postsurgical persistent lung MDSCs exhibit stronger immunosuppression compared with presurgical MDSCs, suggesting that surgery enhances MDSC function. Surgical stress and trauma trigger the secretion of systemic inflammatory cytokines, which enhance MDSC mobilization and proliferation. Additionally, damage associated molecular patterns (DAMPs) directly activate MDSCs through pattern recognition receptor-mediated signals. Surgery also increases vascular permeability, induces an increase in lysyl oxidase and extracellular matrix remodeling in lungs, that enhances MDSC mobilization. Postsurgical therapies that inhibit the induction of premetastatic niches by MDSCs promote the long-term survival of patients. Cyclooxygenase-2 inhibitors and β-blockade, or their combination, may minimize the impact of surgical stress on MDSCs. Anti-DAMPs and associated inflammatory signaling inhibitors also are potential therapies. Existing therapies under tumor-bearing conditions, such as MDSCs depletion with low-dose chemotherapy or tyrosine kinase inhibitors, MDSCs differentiation using all-trans retinoic acid, and STAT3 inhibition merit clinical evaluation during the perioperative period. In addition, combining low-dose epigenetic drugs with chemokine receptors, reversing immunosuppression through the Enhanced Recovery After Surgery protocol, repairing vascular leakage, or inhibiting extracellular matrix remodeling also may enhance the long-term survival of curative resection patients.

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Explicating the Pivotal Pathogenic, Diagnostic, and Therapeutic Biomarker Potentials of Myeloid-Derived Suppressor Cells in Glioblastoma

Disease Markers ◽

10.1155/2020/8844313 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13

Author(s):

Seidu A. Richard

Keyword(s):

Peripheral Blood ◽

Low Dose ◽

Suppressor Cells ◽

Good Prognosis ◽

Myeloid Derived Suppressor Cells ◽

Heterogeneous Cluster ◽

Multiple Tumor ◽

Glioma Growth ◽

Almost All ◽

The Brain

Glioblastoma (GBM) is a malignant and aggressive central nervous tumor that originates from astrocytes. These pathogenic astrocytes divide rapidly and are sustained by enormous network of blood vessels via which they receive requisite nutrients. It well proven that GBM microenvironment is extremely infiltrated by myeloid-derived suppressor cells (MDSCs). MDSCs are a heterogeneous cluster of immature myeloid progenitors. They are key mediates in immune suppression as well as sustenance glioma growth, invasion, vascularization, and upsurge of regulatory T cells via different molecules. MDSCs are often elevated in the peripheral blood of patients with GBM. MDSCs in the peripheral blood as well as those infiltrating the GBM microenvironment correlated with poor prognosis. Also, an upsurge in circulating MDSCs in the peripheral blood of patients with GBM was observed compared to benign and grade I/II glioma patients. GBM patients with good prognosis presented with reduced MDSCs as well as augmented dendritic cells. Almost all chemotherapeutic medication for GBM has shown no obvious improvement in overall survival in patients. Nevertheless, low-dose chemotherapies were capable of suppressing the levels of MDSCs in GBM as well as multiple tumor models with metastatic to the brain. Thus, MDSCs are potential diagnostic as well as therapeutic biomarkers for GBM patients.

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ATIM-24. TARGETING MYELOID DERIVED SUPPRESSOR CELLS: PHASE 0/1 TRIAL OF LOW DOSE CAPECITABINE + BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/nox168.119 ◽

2017 ◽

Vol 19 (suppl_6) ◽

pp. vi31-vi31

Author(s):

David M Peereboom ◽

Michael Vogelbaum ◽

Alireza Mohammadi ◽

Tyler Alban ◽

Cathy Brewer ◽

...

Keyword(s):

Low Dose ◽

Suppressor Cells ◽

Recurrent Glioblastoma ◽

Myeloid Derived Suppressor Cells ◽

Phase 0

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Nanoparticle Systems Modulating Myeloid-Derived Suppressor Cells for Cancer Immunotherapy

Current Topics in Medicinal Chemistry ◽

10.2174/1568026617666161122121412 ◽

2017 ◽

Vol 17 (16) ◽

pp. 1843-1857 ◽

Cited By ~ 10

Author(s):

Avia Wilkerson ◽

Julian Kim ◽

Alex Y. Huang ◽

Mei Zhang

Keyword(s):

Cancer Immunotherapy ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells

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Targeting myeloid derived suppressor cells: Phase 0/1 trial of low dose capecitabine + bevacizumab in patients with recurrent glioblastoma.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e13507 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e13507-e13507

Author(s):

David M. Peereboom ◽

Justin D. Lathia ◽

Tyler Alban ◽

Maksim Sinyuk ◽

Manmeet Singh Ahluwalia ◽

...

Keyword(s):

Low Dose ◽

Immune Cell ◽

Suppressor Cells ◽

Recurrent Glioblastoma ◽

Myeloid Derived Suppressor Cells ◽

T Regulatory Cell ◽

Grade 3 ◽

Novel Strategy ◽

Immunosuppressive Cells ◽

Tumor Types

e13507 Background: Glioblastoma (GBM) creates an immunosuppressive environment that allows tumor growth. Myeloid derived suppressor cells (MDSCs), a heterogeneous class of immunosuppressive cells, mediate immune suppression in GBMs. MDSCs are up-regulated in the blood of patients with GBM and multiple other tumor types. We have developed a novel strategy to target GBM immunosuppression using low dose 5-fluorouracil (5-FU) that, targets immune cells and does not depend on blood brain or blood tumor barrier penetration. Marked MDSC depletion occurs at 5-FU doses in mice equivalent to < 10% of the normal human dosing. Goal: proof of concept that MDSC suppression in feasible in GBM pts with low-dose capecitabine [cap], an oral 5-FU analogue). Methods: Eligibility: Recurrent GBM in need of surgical resection; no prior cap or bevacizumab (bev). Cohorts of 3-6 patients receive low-dose cap 150 mg/m2/d (dose level [DL] 1) for 7 days before surgery. After surgery, patients resume cap for one cycle after which bev is added. Blood MDSC, immune cell levels, and relevant secreted factors are measured at baseline; pre- and post-op; and after the addition of bev. Tumors are assayed for MDSCs and glioma stem-like cells (GSCs). Primary endpoint: MDSC and T-Regulatory cell reduction after cap. Secondary endpoints: Tumor concentrations of MDSCs, GSCs, and T-reg cells; safety; and PFS6. Results: Three of the 4 patients enrolled have data available. All patients received 5 days of pre-op cap at DL 1 with MDSC reductions of 20, 26, and 79% from baseline. The first patient reached a reduction of 93% (measured 2 days after pre-op course) whereas the other 2 experienced return to baseline. The regulatory T cells (T-reg) also fell approximately 15, 20, and 50%, respectively. CD8 concentrations appeared to rise at the time of MDSC and T-reg reduction. No patient experienced grade 3 or higher toxicity. Conclusions: Low dose capecitabine appears to reduce MDSC concentrations with minimal toxicity. During this course T-regs also fell and CD8 concentrations rose. Dose escalation continues. (NCT02669173) (Supported by Musella Foundation, Blast GBM, Sontag Foundation, Velosano, Mylan Pharmaceuticals) Clinical trial information: NCT02669173.

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