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

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.

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

Biomaterials ◽  
2016 ◽  
Vol 96 ◽  
pp. 47-62 ◽  
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

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

2018 ◽  
Vol 20 (suppl_6) ◽  
pp. vi12-vi13
Author(s):  
David Peereboom ◽  
Justin Lathia ◽  
Tyler Alban ◽  
Alireza Mohammadi ◽  
Manmeet Ahluwalia ◽  
...  
Keyword(s):  
Low Dose ◽  
Suppressor Cells ◽  
Recurrent Glioblastoma ◽  
Myeloid Derived Suppressor Cells ◽  
Phase 0

Randomized Trial of Low-Dose Chemotherapy Added to Tamoxifen in Patients With Receptor-Positive and Lymph Node–Positive Breast Cancer

1999 ◽  
Vol 17 (6) ◽  
pp. 1701-1701 ◽  
Author(s):  
R. Jakesz ◽  
H. Hausmaninger ◽  
K. Haider ◽  
E. Kubista ◽  
H. Samonigg ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Hormone Receptor ◽  
Low Dose ◽  
Premenopausal Patients ◽  
Low Dose Chemotherapy ◽  
Disease Free ◽  
Positive Breast Cancer

PURPOSE: To evaluate the outcome in patients with stage II hormone receptor–positive breast cancer treated or not treated with low-dose, short-term chemotherapy in addition to tamoxifen in terms of disease-free and overall survival. PATIENTS AND METHODS: A total of 613 patients were randomized to receive either low-dose chemotherapy (doxorubicin 20 mg/m2 and vincristine 1 mg/m2 on day 1; cyclophosphamide 300 mg/m2; methotrexate 25 mg/m2; and fluorouracil 600 mg/m2 on days 29 and 36 intravenously) or no chemotherapy in addition to 20 mg of tamoxifen orally for 2 years. A third group without any treatment (postmenopausal patients only) was terminated after the accrual of 79 patients due to ethical reasons. RESULTS: After a median follow-up period of 7.5 years, the addition of chemotherapy did not improve the outcome in patients as compared with those treated with tamoxifen alone, neither with respect to disease-free nor overall survival. Multivariate analysis of prognostic factors for disease-free survival revealed menopausal status, in addition to nodal status, progesterone receptor, and histologic grade as significant. Both untreated postmenopausal and tamoxifen-treated premenopausal patients showed identical prognoses significantly inferior to the tamoxifen-treated postmenopausal cohort. Prognostic factors for overall survival in the multivariate analysis showed nodal and tumor stage, tumor grade, and hormone receptor level as significant. CONCLUSION: Low-dose chemotherapy in addition to tamoxifen does not improve the prognosis of stage II breast cancer patients with hormone-responsive tumors. Tamoxifen-treated postmenopausal patients show a significantly better prognosis than premenopausal patients, favoring the hypothesis of a more pronounced effect of tamoxifen in the older age groups.

A Maintenance Therapy with Differentiating Agents and Low-Dose Chemotherapy Increases Remission Duration and Survival in High Risk AML and MDS Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4614-4614
Author(s):  
Dario Ferrero ◽  
Chiara Dellacasa ◽  
Margherita Bonferroni ◽  
Mariella Grasso ◽  
Elisabetta Campa ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Maintenance Therapy ◽  
Maintenance Treatment ◽  
Low Dose ◽  
Normal Karyotype ◽  
Intensive Chemotherapy ◽  
Actuarial Survival ◽  
Maintenance Program ◽  
Low Dose Chemotherapy

Abstract Acute myeloid leukemia (AML) patients above the age of 60 or with secondary AML generally have an unfavourable outcome. The same is true for high risk myelodysplastic syndrome (MDS) patients ineligible to bone marrow transplantation. Indeed, in spite of an improved CR rate after intensive chemotherapy (about 60–65%), median CR duration and survival remain short (9–12 months in most studies), due to early relapses. (Sekeres MA et al.: Curr Opin Oncol2002;14:24–30. Verbeek W et al.: Ann Hematol2001;80:499–509). On the basis of our previous clinical trials with differentiative agents + low dose chemotherapy in MDS/AML patients unsuitable to intensive treatments, (Ferrero D et al.: Leuk Res1996;20:867–876; Haematologica2004;89:619–620), we adopted the same strategy as a post-remission maintenance therapy to patients with AML or MDS at high risk of relapse and ineligible to allogeneic transplant. Thirty-six patients (27 AML and 9 high risk MDS) who had obtained a CR after different schemes of intensive chemotherapy were scheduled to receive the maintenance treatment with 13-cis-retinoic acid (20–40 mg/day) + 1,25-di-hydroxy-vitamin D3 (1 microgram /day) in association to intermittent, low dose chemotherapy: 6-thioguanine 40 mg/day x 21 days every 5 weeks, alternated every 2–3 months, in 24 patients, to a 14 day course of ARA-C 8 mg/m2 s.c. x 2/day + 6-mercaptopurine 50 mg/day. Patients’ median age was 64 years (range 27–76), with only 9 below the age of 60. Cytogenetic analysis was performed successfully in 27 cases, and an unfavourable karyotype was found in 10. All patients presented at least one poor prognosis determinant, including age >60 (27), previous AML relapse after autologous BMT (1), therapy-related disease (5), AML secondary to MDS (7), resistance to 1st induction therapy (4), hyperleukocytosis (8), RAEB-2 (8), abnormal karyotype (10). Twenty six had received 1 - 4 courses of consolidation treatment, including autologous stem cell transplantation in 2 MDS patients, before starting the maintenance program. Three patients underwent a very early relapse before maintenance start and 1 patient refused to prosecute the therapy after the first 2 months. The other 32 patients received the treatment as outpatients, with good tolerance and no major toxicity, until relapse, death or 4 years of continuous CR. After a median follow up for alive patients of 23 months (6–76), median disease-free (dfs) and overall survival, based on "intention to treat analysis" are 22 (1–74+) and 23 (5–76+) months, respectively, with a 28% 4 year actuarial survival. Inclusion of ARA-C in the maintenance treatment did not significantly prolong CR duration. The 17 patients with a normal karyotype enjoyed better median dfs (43 months) and overall survival (50,5 months) compared to the 10 patients with abnormal cytogenetics (12,5 and 15,5 months respectively); however, the differences are not significant, probably due to sample exiguity. In conclusion, our patients evidenced quite longer dfs and overall survival than expected from literature data on AML/MDS patients with similar features. However some late relapses (after 3–4 years) occurred. Therefore, our maintenance program seems worthy to be evaluated on larger casistics in randomised trials.

Effect of age and ethnicity on the tumor location, nuclear accumulation of p53 and clinical outcome in colorectal adenocarcinoma.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 559-559
Author(s):  
Ravi Kumar Paluri ◽  
Michael Behring ◽  
James Posey ◽  
Upender Manne
Keyword(s):  
Overall Survival ◽  
Cox Regression ◽  
Prognostic Significance ◽  
Tumor Location ◽  
Genetic Alterations ◽  
Proximal Colon ◽  
Nuclear Accumulation ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Race Ethnicity

559 Background: The race/ethnicity based research in colorectal cancer (CRC) care continues to remain a high priority in developing personalized medicine, and to improve overall clinical outcomes. The role of p53 abnormalities in prognostication of CRC has been evaluated earlier. The incidence of nuclear accumulation of p53 (p53nac) and its prognostic relevance in African American (AA) and non-Hispanic white patients (pts) have been investigated, and it was suggested that the clinical consequences of p53nac in CRC varies with anatomic location of the tumor and the race of the patient. However, the clinical value of p53nac in relation to age, the tumor location, and race together is not assessed. Thus, we evaluated prognostic significance of p53nac by considering the tumor location, age, race/ethnicity and p53nacin CRCs in AA and white pts. Methods: Formalin fixed paraffin embedded CRC tissues from 242 AAs and 346 whites who underwent surgery were assessed for p53nac by routine immunohistochemistry (IHC). The routine (not antigen retrieval) IHC will identify the majority of genetic alterations ( > 95% missense point mutations) and have significant association with patient survival in CRC. The association between phenotypes, p53nac status, clinicopathologic features, and overall survival were evaluated using the x2 test and Cox regression analyses. Results: Approximately equivalent proportions of distal (52%) and proximal adenocarcinomas (48%) were positive for p53nac in AA pts. In contrast, distal CRC from whites more frequently were positive for p53nac than from the proximal colon (67% vs. 34%, x2 P = 0.006). p53nac was found to be a strong predictor of poor overall survival in young ( < 65 yr) white pts with proximal tumors [hazard ratio (HR) = 2.8, 95% Confidence Intervals (CI):1.2-6.4] but not in AAs (HR = 0.7, 95% CI: 0.41-1.21). Conclusions: The findings of this study suggest that p53nac is a strong prognostic marker for young white pts with proximal colon adenocarcinomas. Our findings are clinically relevant because several small-molecule inhibitors of mutant p53 are under investigation. These studies were supported by a pilot project grant by the UAB Comprehensive Cancer center.

Impact of care at Memorial Sloan Kettering Cancer Center (MSKCC): A comprehensive cancer center on overall survival (OS) in patients (pts) with AJCC stage IV pancreas adenocarcinoma (PDAC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18128-e18128
Author(s):  
Fiona Boland ◽  
Ahmad Cheema ◽  
Maeve Aine Lowery ◽  
Kenneth H. Yu ◽  
Anna M. Varghese ◽  
...  
Keyword(s):  
Overall Survival ◽  
Survival Rates ◽  
Stage Iv ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Contributing Factors ◽  
Term Survival ◽  
Entire Cohort ◽  
Line Therapy ◽  
Centralized Care

e18128 Background: PDAC has a rising incidence and relatively static mortality rates. Current cytotoxic regimens confer median survivals of 8.5- 11 months (Von Hoff, Conroy, et al. NEJM 2013, 2011). National Cancer Institute-designated Comprehensive Cancer Centers potentially allow greater access to multidisciplinary consultation for complex cancer care. Although the widespread benefits of NCICCCs are acknowledged, there is limited data demonstrating superior outcomes for patients treated at these centers. Methods: Patients with stage IV PDAC, diagnosed between 01/01/13 and 12/31/14, were identified and followed until death or 12/31/2016. These patients had care centralized to MSKCC and the analysis was conducted to evaluate key patient (pt) and disease characteristics, systemic therapies and outcomes.Survival times were calculated from the date of diagnosis. Results: N=391 pts identified, 210 males (54%), 181 females (46%). Median age 66 years (range 27-91). Table 1 outlines key points. For entire cohort, median overall survival (mOS): 11.4 + 9 months, 1-year (yr) and 2-yr survival rates (SR) of 48% and 15.1% respectively. N= 165 (42%) received mFOLFIRINOX-based regimen as 1st-line therapy with mOS 13.2 + 8.9 months, 1-yr and 2-yr SR of 59.4.% and 20% respectively. N= 118 (30.1%) received gemcitabine + nab-paclitaxel- based regimen as 1st line therapy had a mOS of 11.6 + 9 months with 1-yr and 2-yr SR of 49.1% and 16.2% respectively. Conclusions: At MSKCC, a major referral center for PDAC, outcomes for stage IV disease compare favorably to contemporary trial outcomes with notable 2-yr survivorship (long-term survival analysis of MPACT trial showed 1-yr and 2-yr SR of 35% and 10% respectively). Contributing factors likely reflect multidisciplinary expertize, patient selection and biases. Centralized care for complex illnesses may improve outcomes. [Table: see text]

Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, Wong YN, Hahn N, Kohli M, Cooney MM, Dreicer R, Vogelzang NJ, Picus J, Shevrin D, Hussain M, Garcia JA, DiPaola RS. Department of Medicine; Department of Biostatistics and Computational Biology; Dana-Farber Cancer Institute, Boston; Harvard Medical School, Boston; Johns Hopkins University, Baltimore; University of Wisconsin Carbone Cancer Center; School of Medicine and Public Health; Madison; Fox Chase Cancer Center, Temple University Health System, Philadelphia; Indiana University Melvin and Bren Simon Cancer Center, Indianapolis; Mayo Clinic, Rochester, MN; University Hospitals Case Medical Center, Seidman Cancer Center; Cleveland Clinic Taussig Cancer Institute; Both in Cleveland; University of Virginia Cancer Center, Charlottesville; Comprehensive Cancer Centers of Nevada, Las Vegas; Siteman Cancer Center, Washington University School of Medicine, St. Louis; NorthShore University Health System, Evanston, IL; University of Michigan Comprehensive Cancer Center, Ann Arbor; Rutgers Cancer Institute of New Jersey, New Brunswick.N Engl J Med. 2015 Aug 20;373(8):737-46. [Epub 2015 Aug 5]. doi: 10.1056/NEJMoa1503747.

2017 ◽  
Vol 35 (3) ◽  
pp. 123 ◽  
Author(s):  
Eggener Scott
Keyword(s):  
Health System ◽  
Medical Center ◽  
Cleveland Clinic ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
University Hospitals ◽  
University Of Wisconsin ◽  
School Of Medicine ◽  
Johns Hopkins University ◽  
Ann Arbor

scholarly journals Identification of Hyal2-expressing tumor-associated myeloid cells in cancer: implications for cancer-related inflammation through enhanced hyaluronan degradation

2020 ◽  
Author(s):  
Paul R. Dominguez Gutierrez ◽  
Elizabeth P. Kwenda ◽  
William Donelan ◽  
Padraic O’Malley ◽  
Paul L. Crispen ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Tumor Microenvironment ◽  
Tumor Tissue ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Major Constituent ◽  
Cancer Tissue ◽  
Myeloid Derived Suppressor Cells ◽  
Bladder Cancer Tissue ◽  
Tumor Infiltrate

AbstractIncreased presence of myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) in tumor tissue has been extensively reported. These cells represent a major constituent of tumor infiltrate and exhibit a distinct phenotype with immunosuppressive and tolerogenic functions. However, their role in the regulation of hyaluronan (HA) metabolism in the tumor microenvironment has not been established. Here we describe a novel function of tumor-associated myeloid cells related to the enhanced breakdown of extracellular HA in human bladder cancer tissue leading to accumulation of small HA fragments with MW <20 kDa. Increased fragmentation of extracellular HA and accumulation of low molecular weight HA (LMW-HA) in tumor tissue was associated with elevated production of multiple inflammatory cytokines, chemokines, and angiogenic factors. The fragmentation of HA by myeloid cells was mediated by the membrane-bound enzyme hyaluronidase 2 (Hyal2). The increased numbers of Hyal2+CD11b+ myeloid cells were detected in the tumor tissue as well as in the peripheral blood of bladder cancer patients. Co-expression of CD33 suggests that these cells belong to monocytic myeloid-derived suppressor cells. HA-degrading function of Hyal2-expressing MDSCs could be enhanced by exposure to tumor-conditioned medium, and IL-1β was identified as one of factors involved in the stimulation of Hyal2 activity. CD44-mediated signaling plays an important role in the regulation of HA-degrading activity of Hyal2-expressing myeloid cells, since engagement of CD44 receptor with specific monoclonal antibody triggered translocation of Hyal2 enzyme to the cellular surface and also stimulated secretion of IL-1β. Taken together, this work identifies the Hyal2-expressing tumor-associated myeloid cells, and links these cells to the accumulation of LMW-HA in the tumor microenvironment and cancer-related inflammation and angiogenesis.

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

2020 ◽  
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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