ACTR-09. TARGETING MYELOID DERIVED SUPPRESSOR CELLS: PHASE 0/1 TRIAL OF LOW DOSE CAPECITABINE + BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA

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

Biomaterials ◽

10.1016/j.biomaterials.2016.04.010 ◽

2016 ◽

Vol 96 ◽

pp. 47-62 ◽

Cited By ~ 65

Author(s):

Maria Stella Sasso ◽

Giovanna Lollo ◽

Marion Pitorre ◽

Samantha Solito ◽

Laura Pinton ◽

...

Keyword(s):

Cancer Immunotherapy ◽

Low Dose ◽

Suppressor Cells ◽

Myeloid Derived Suppressor Cells ◽

Lipid Nanocapsules

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Targeting Myeloid-Derived Suppressor Cells for Premetastatic Niche Disruption After Tumor Resection

Annals of Surgical Oncology ◽

10.1245/s10434-020-09371-z ◽

2020 ◽

Cited By ~ 1

Author(s):

Fan Tang ◽

Yan Tie ◽

Weiqi Hong ◽

Yuquan Wei ◽

Chongqi Tu ◽

...

Keyword(s):

Extracellular Matrix ◽

Low Dose ◽

Surgical Stress ◽

Suppressor Cells ◽

Extracellular Matrix Remodeling ◽

Matrix Remodeling ◽

Myeloid Derived Suppressor Cells ◽

Term Survival ◽

Premetastatic Niche

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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Reduction of immune inhibitory myeloid derived suppressor cells by low dose sunitinib combined with a cancer vaccine to provide therapeutic benefit to tumor-bearing mice.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e23084 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e23084-e23084

Author(s):

Helen Kim Cho ◽

Paul Cockle ◽

Cindy Wei Li ◽

Steve Burgess ◽

Terrence Coleman ◽

...

Keyword(s):

Cancer Vaccine ◽

Side Effect ◽

Low Dose ◽

Suppressor Cells ◽

Cytokine Profile ◽

Vegf Receptor ◽

Side Effect Profile ◽

Myeloid Derived Suppressor Cells ◽

Tumor Bearing ◽

Immunomodulatory Properties

e23084 Background: Sunitinib is a receptor tyrosine kinase inhibitor (RTK) approved as a monotherapy for the treatment of advanced RCC, gastrointestinal stromal tumors and advanced pancreatic neuroendocrine tumors. At the approved doses, it inhibits angiogenesis in tumors and targets RTKs (PDGF receptor, VEGF receptor, KIT, FLT-3, and RET) involved in tumor cell growth. Sunitinib also has been shown in murine studies and patients, to exhibit immunomodulatory properties that reduce a heterogeneous population of cells termed myeloid derived suppressor cells (MDSCs) and restore the immune stimulatory Th1 cytokine profile of T cells. The approved anti-angiogenic sunitinib dosing regimens in RCC have a safety profile that is overall manageable with the most commonly reported sunitinib-related grade 3 adverse events including hypertension, fatigue, diarrhea and hand-foot syndrome. Although the tolerability of sunitinib as monotherapy was acceptable in advanced stage diseases, the drug’s side effect profile could potentially pose challenges for use in combination with other oncology therapies. Thus, if the dose of sunitinib could be lowered to improve the side effect profile without impacting its immune modulatory properties, it could be combined with cancer vaccine regimens, offering a better tolerated and highly potent immunotherapy for patients with cancer of all stages. Methods: To evaluate the relationship of dose of sunitinib on its immunomodulatory properties, the pharmacokinetic profile, the frequency of MDSCs, cytokine profile, vaccine induced immune responses and anti-tumor efficacy were monitored in a subcutaneous tumor bearing BALB-neuT mice in the presence or absence of a cancer vaccine. Results: The data suggested that sunitinib doses below the approved daily dose of 50 mg may maintain the drug’s immune modulatory properties and improve overall survival when given concurrently with a cancer vaccine. Conclusions: The data suggested that low dose sunitinib can be administered as an immunomodulator to reduce MDSCs safely in combination with potent, multi-component cancer vaccine regimens.

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Metronomic capecitabine as an immune modulator in glioblastoma patients reduces myeloid-derived suppressor cells

10.1101/655688 ◽

2019 ◽

Author(s):

David M. Peereboom ◽

Tyler J. Alban ◽

Matthew M. Grabowski ◽

Alvaro G. Alvarado ◽

Balint Otvos ◽

...

Keyword(s):

Overall Survival ◽

Low Dose ◽

Tumor Tissue ◽

Cleveland Clinic ◽

Suppressor Cells ◽

Comprehensive Cancer Center ◽

Cancer Center ◽

Myeloid Derived Suppressor Cells ◽

Immune Infiltration ◽

Low Dose Chemotherapy

AbstractBackgroundMyeloid-derived suppressor cells (MDSCs) are elevated in glioblastoma (GBM) patient circulation, present in tumor tissue, and associated with poor prognosis. While low-dose chemotherapy reduces MDSCs in preclinical models, the use of this strategy to reduce MDSCs in GBM patients has yet to be evaluated.MethodsA phase 0/1 dose-escalation clinical trial was conducted in recurrent glioblastoma patients treated 5-7 days prior to surgery with low-dose chemotherapy via capecitabine followed by concomitant low-dose capecitabine and bevacizumab. Clinical outcomes, including progression-free and overall survival, were measured, along with safety and toxicity profiles. Over the treatment time course, circulating MDSC levels were measured by multi-parameter flow cytometry, and tumor tissue immune profiles were assessed via mass cytometry time-of-flight.ResultsA total of 11 patients were enrolled across escalating dose cohorts of 150, 300, and 450 mg bid, with a progression-free survival of 5.8 months (range of 1.8-27.8 months) and an overall survival of 11.5 months (range of 3->28.0 months) from trial enrollment. No serious adverse events related to the drug combination were observed. Compared to pre-treatment baseline, circulating MDSCs were found to be higher after surgery in the 150 mg treatment arm and lower in the 300 mg and 450 mg treatment arms. Increased cytotoxic immune infiltration was observed after low-dose capecitabine compared to untreated GBM patients in the 300 mg and 450 mg treatment arms.ConclusionsLow-dose, metronomic capecitabine in combination with bevacizumab is well tolerated in GBM patients and was associated with a reduction in circulating MDSC levels and an increase in cytotoxic immune infiltration into the tumor microenvironment.Trial registrationNCT02669173FundingThis research was funded by the Cleveland Clinic, Case Comprehensive Cancer Center, Musella Foundation, and B*CURED. Capecitabine was provided in kind by Mylan Pharmaceuticals.

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