scholarly journals Ex vivo expansion of bone marrow from breast cancer patients: reduction in tumor cell content through passive purging

1998 ◽  
Vol 22 (2) ◽  
pp. 153-159 ◽  
Author(s):  
BI Lundell ◽  
JJ Vredenburgh ◽  
C Tyer ◽  
K DeSombre ◽  
AK Smith
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Tumor Cell ◽  
Cancer Patients ◽  
Ex Vivo ◽  
Ex Vivo Expansion ◽  
Breast Cancer Patients ◽  
Cell Content

scholarly journals Tumor Cell Purging by Ex Vivo Expansion of Hemopoietic Stem Cells from Breast Cancer Patients Combined with Targeting ErbB Receptors

2006 ◽  
Vol 12 (1) ◽  
pp. 68-74 ◽  
Author(s):  
Francesco Leone ◽  
Giuliana Cavalloni ◽  
Monica Gunetti ◽  
Ymera Pignochino ◽  
Wanda Piacibello ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Stem Cells ◽  
Tumor Cell ◽  
Cancer Patients ◽  
Ex Vivo ◽  
Ex Vivo Expansion ◽  
Erbb Receptors ◽  
Hemopoietic Stem Cells ◽  
Breast Cancer Patients

scholarly journals Ex vivo expansion of CD34+ peripheral blood progenitor cells: implications for the expansion of contaminating epithelial tumor cells

Blood ◽  
1996 ◽  
Vol 88 (7) ◽  
pp. 2707-2713 ◽  
Author(s):  
W Vogel ◽  
D Behringer ◽  
S Scheding ◽  
L Kanz ◽  
W Brugger
Keyword(s):  
Breast Cancer ◽  
Tumor Cell ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Ex Vivo ◽  
Stage Iv ◽  
Ex Vivo Expansion ◽  
Stage Ii ◽  
Breast Cancer Patients ◽  
Cd34 Cells

Cytokine-supported ex vivo expansion of peripheral blood progenitor cells (PBPCs) offers new perspectives for autografting after high-dose chemotherapy. One of the potential advantages is the possibility to reduce the volume of blood processed from the patient, thus allowing reduction of the overall tumor cell number in the final autograft. However, ex vivo expansion will only be advantageous if contaminating tumor cells are not expanded concomitantly. This question has not previously been addressed. Therefore, we analyzed unseparated PBPC preparations, CD34(+)-selected cell fractions, and ex vivo-expanded cell preparations from stage IV (n = 16) and high-risk stage II/III (n = 8) breast cancer patients for the presence of human epithelial antigen-(HEA) or cytokeratin (CK)-positive tumor cells. We found that three of 16 (18.8%) of the unseparated PBPC products from stage IV patients were HEA- and/or CK-positive, whereas none of the stage II/III patients were found to be positive after two cycles of induction chemotherapy with etoposide (VP16), ifosfamide, cisplatin, and epirubicin (VIP-E). After CD34+ cell selection (Ceprate SC; CellPro, Bothell, WA) and stem-cell factor (SCF), interleukin (IL)-1, IL-3, IL-6, and erythropoietin (EPO)-mediated ex vivo expansion of the CD34+ cells for 14 to 21 days, no tumor cells could be detected in these primary breast cancer patients at a sensitivity of 1 tumor cell per 4 x 10(5) nucleated cells. Thus, to answer the question of whether tumor cells are expanded concomitantly on ex vivo expansion of normal CD34+ cells, we cocultured defined numbers of primary renal carcinoma cells (RS-85), xenograft-derived breast cancer cells, and small-cell lung cancer cells with CD34+ cells selected from normal donors or cancer patients, either in serum or serum-free culture media. We found that none of the three epithelial tumor cell types increased significantly in number during a 14-day coculture period when compared with normal CD34+ cells alone or tumor cells alone, which increased 110- +/- 77-fold and 45- +/- 26-fold, respectively. However, during coculture, the tumor cells did not undergo cell death and were able to regrow when maintained in serum for longer time periods. We conclude that cytokine-supported expansion cultures of positively selected CD34+ PBPCs from primary high-risk stage II/III or stage IV breast cancer patients do not contain detectable tumor cells, which suggests that there is no increased risk of concomitantly expanding tumor cells. Moreover, cocultures of exogenously mixed tumor cell lines with normal CD34+ cells showed a relative disadvantage of tumor cell growth compared with the growth of hematopoietic cells, again without an apparent risk of concomitantly expanding tumor cells. However, considering the pronounced heterogeneity of tumor cell kinetics, ex vivo-expanded PBPC from cancer patients should be monitored for minimal residual disease.

scholarly journals Integrin alpha5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions

Oncogene ◽  
2021 ◽  
Author(s):  
Francesco Pantano ◽  
Martine Croset ◽  
Keltouma Driouch ◽  
Natalia Bednarz-Knoll ◽  
Michele Iuliani ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Bone Metastasis ◽  
Tumor Cell ◽  
Cancer Patients ◽  
Breast Cancer Patients ◽  
Osteolytic Lesions ◽  
Cell Colonization

AbstractBone metastasis remains a major cause of mortality and morbidity in breast cancer. Therefore, there is an urgent need to better select high-risk patients in order to adapt patient’s treatment and prevent bone recurrence. Here, we found that integrin alpha5 (ITGA5) was highly expressed in bone metastases, compared to lung, liver, or brain metastases. High ITGA5 expression in primary tumors correlated with the presence of disseminated tumor cells in bone marrow aspirates from early stage breast cancer patients (n = 268; p = 0.039). ITGA5 was also predictive of poor bone metastasis-free survival in two separate clinical data sets (n = 855, HR = 1.36, p = 0.018 and n = 427, HR = 1.62, p = 0.024). This prognostic value remained significant in multivariate analysis (p = 0.028). Experimentally, ITGA5 silencing impaired tumor cell adhesion to fibronectin, migration, and survival. ITGA5 silencing also reduced tumor cell colonization of the bone marrow and formation of osteolytic lesions in vivo. Conversely, ITGA5 overexpression promoted bone metastasis. Pharmacological inhibition of ITGA5 with humanized monoclonal antibody M200 (volociximab) recapitulated inhibitory effects of ITGA5 silencing on tumor cell functions in vitro and tumor cell colonization of the bone marrow in vivo. M200 also markedly reduced tumor outgrowth in experimental models of bone metastasis or tumorigenesis, and blunted cancer-associated bone destruction. ITGA5 was not only expressed by tumor cells but also osteoclasts. In this respect, M200 decreased human osteoclast-mediated bone resorption in vitro. Overall, this study identifies ITGA5 as a mediator of breast-to-bone metastasis and raises the possibility that volociximab/M200 could be repurposed for the treatment of ITGA5-positive breast cancer patients with bone metastases.

scholarly journals Amifostine (WR-2721) shortens the engraftment period of 4- hydroperoxycyclophosphamide-purged bone marrow in breast cancer patients receiving high-dose chemotherapy with autologous bone marrow support

Blood ◽  
1994 ◽  
Vol 83 (11) ◽  
pp. 3132-3137 ◽  
Author(s):  
EJ Shpall ◽  
SM Stemmer ◽  
L Hami ◽  
WA Franklin ◽  
L Shaw ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Cancer Patients ◽  
Ex Vivo ◽  
Autologous Bone Marrow ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Breast Cancer Patients ◽  
Significant Difference ◽  
Autologous Bone

4-Hydroperoxycyclophosphamide (4-HC), a commonly used marrow-purging agent, is active against many tumors, but is also toxic to normal marrow progenitors. Amifostine (WR-2721) is a sulfhydryl compound with chemoprotectant activity. Preclinical studies using suspensions of bone marrow and breast cancer cells demonstrated that ex vivo treatment with amifostine followed by 4-HC resulted in protection of marrow progenitors, with no compromise in the antitumor effect of 4-HC. This fact stimulated the development of a clinical trial. Bone marrow was harvested from 15 poor-prognosis breast cancer patients and randomly assigned to ex vivo treatment with amifostine followed by 4-HC (amifostine + 4-HC), or treatment with 4-HC alone. High-dose chemotherapy was then administered followed by infusion of the purged autologous bone marrow support (ABMS). Leukocyte engraftment, defined as a white blood cell count > or = 1 x 10(9)/L, was achieved in an average of 26 days for patients whose marrow was purged with amifostine + 4-HC versus 36 days for patients whose marrow was purged with 4-HC alone (P = .032). The average number of platelet transfusions (12 v 29; P = .017) and days of antibiotic therapy (28 v 40; P = .012) were significantly less for patients whose marrow was exposed to amifostine + 4-HC, compared with 4-HC alone. Unpurged backup marrow fractions were infused into three patients whose marrow was purged with 4-HC alone, because of inadequate marrow recovery. None of the patients who received amifostine + 4-HC-purged marrow required a backup marrow fraction. Complete remissions were achieved in 83% of patients with measurable disease, with no difference between the two cohorts. Forty- three percent of patients remained alive and progression-free at a mean of 13 months posttransplant. There was no significant difference in the rate or pattern of relapse for patients whose marrow was purged with amifostine + 4-HC compared with those whose marrow was purged with 4-HC alone. Ex vivo treatment of marrow with amifostine significantly shortens the time to marrow recovery, thereby reducing the risk of myelosuppressive complications in breast cancer patients receiving high- dose chemotherapy and 4-HC-purged ABMS. Since supportive care requirements are also significantly decreased, amifostine may reduce the cost of such therapy.

scholarly journals Functional signaling test identifies HER2 negative breast cancer patients who may benefit from c-Met and pan-HER combination therapy

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Ian A. MacNeil ◽  
Salmaan A. Khan ◽  
Adrish Sen ◽  
Sajjad M. Soltani ◽  
David J. Burns ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cell ◽  
Cell Signaling ◽  
Cancer Patients ◽  
Targeted Therapies ◽  
Ex Vivo ◽  
Clinical Test ◽  
Targeted Drugs ◽  
Breast Cancer Patients ◽  
Her Family

Abstract Background Research is revealing the complex coordination between cell signaling systems as they adapt to genetic and epigenetic changes. Tools to uncover these highly complex functional linkages will play an important role in advancing more efficacious disease treatments. Current tumor cell signal transduction research is identifying coordination between receptor types, receptor families, and transduction pathways to maintain tumor cell viability despite challenging tumor microenvironment conditions. Methods In this report, coactivated abnormal levels of signaling activity for c-Met and HER family receptors in live tumor cells were measured by a new clinical test to identify a subpopulation of breast cancer patients that could be responsive to combined targeted therapies. The CELsignia Multi-Pathway Signaling Function (CELsignia) Test uses an impedance biosensor to quantify an individual patient’s ex vivo live tumor cell signaling response in real-time to specific HER family and c-Met co-stimulation and targeted therapies. Results The test identified breast tumors with hyperactive HER1, HER2, HER3/4, and c-Met coordinated signaling that express otherwise normal amounts of these receptors. The supporting data of the pre-clinical verification of this test included analyses of 79 breast cancer patients’ cell response to HER and c-Met agonists. The signaling results were confirmed using clinically approved matching targeted drugs, and combinations of targeted drugs in addition to correlative mouse xenograft tumor response to HER and c-Met targeted therapies. Conclusions The results of this study demonstrated the potential benefit of a functional test for identifying a subpopulation of breast cancer patients with coordinated abnormal HER and c-Met signaling for a clinical trial testing combination targeted therapy.

Immunological effects after an adoptive cellular immunotherapy with reactivated autologous memory T-Cells from bone marrow

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12502-12502
Author(s):  
F. Schuetz ◽  
J. Rom ◽  
K. Ehlert ◽  
V. Schirrmacher ◽  
A. Schneeweiss ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
T Cells ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Memory T Cells ◽  
Ex Vivo ◽  
Cellular Immunotherapy ◽  
Breast Cancer Patients ◽  
Adoptive Cellular Immunotherapy

12502 Tumor-reactive CD4 and CD8 memory T cells (MTC) can be found in bone marrow (BM) of the majority of primary and metastatic breast cancer patients. In xenotransplant mouse models these cells, upon specific re-activation ex vivo, mediated efficient rejection of autologous breast tumors suggesting that the polyclonal natural MTC repertoire possesses therapeutic potential. In order to clinically exploit these anti-tumor capacities we treated 11 advanced metastasized breast cancer patients with autologous, tumor-reactive, reactivated MTC of BM in a phase-1 trial. Activation of T cells was done by MCF-7 lysate pulsed dendritic cells (DC). After reactivation both, T cells and pulsed DC were injected once intravenously. Peripheral blood was drawn on day 0, 1, 7, 14, 28. BM-re-aspiration was done on day 28 and 84. While TAA-reactive memory T cells were absent in the peripheral blood (PB) before therapy, 5 from 11 patients (=responders) showed TAA-specific PB T cell reactivity 7 days after therapeutic cell application suggesting a massive proliferation and mobilization into the blood of TAA-reactive T cells in these patients. A comparison of responders to adoptive cellular immunotherapy with non-responders revealed differences in the numbers of therapeutic cells that could be generated ex vivo and in the decreased frequency of tumor-reactive MTC in responders’ BM on days 28 and 84 which could be expained by a mobilization due to in situ activation by co-transferred DCs or due to local or systemic cytokine signals by transferred, activated T lymphocytes. Such effect might have contributed to the high numbers of circulating TAA-reactive T cells observed 7 days after the transfer. Furthermore we observed different concentrations of IL-4, IL-10, TNF-α, and INF-γ in PB and BM between the two groups leading to the hypothesis of a polarization in T cell responses (T1 type in responders vs T2 type in non-responders). No significant financial relationships to disclose.

scholarly journals Amifostine (WR-2721) shortens the engraftment period of 4- hydroperoxycyclophosphamide-purged bone marrow in breast cancer patients receiving high-dose chemotherapy with autologous bone marrow support

Blood ◽  
1994 ◽  
Vol 83 (11) ◽  
pp. 3132-3137 ◽  
Author(s):  
EJ Shpall ◽  
SM Stemmer ◽  
L Hami ◽  
WA Franklin ◽  
L Shaw ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Marrow ◽  
Cancer Patients ◽  
Ex Vivo ◽  
Autologous Bone Marrow ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Breast Cancer Patients ◽  
Significant Difference ◽  
Autologous Bone

Abstract 4-Hydroperoxycyclophosphamide (4-HC), a commonly used marrow-purging agent, is active against many tumors, but is also toxic to normal marrow progenitors. Amifostine (WR-2721) is a sulfhydryl compound with chemoprotectant activity. Preclinical studies using suspensions of bone marrow and breast cancer cells demonstrated that ex vivo treatment with amifostine followed by 4-HC resulted in protection of marrow progenitors, with no compromise in the antitumor effect of 4-HC. This fact stimulated the development of a clinical trial. Bone marrow was harvested from 15 poor-prognosis breast cancer patients and randomly assigned to ex vivo treatment with amifostine followed by 4-HC (amifostine + 4-HC), or treatment with 4-HC alone. High-dose chemotherapy was then administered followed by infusion of the purged autologous bone marrow support (ABMS). Leukocyte engraftment, defined as a white blood cell count > or = 1 x 10(9)/L, was achieved in an average of 26 days for patients whose marrow was purged with amifostine + 4-HC versus 36 days for patients whose marrow was purged with 4-HC alone (P = .032). The average number of platelet transfusions (12 v 29; P = .017) and days of antibiotic therapy (28 v 40; P = .012) were significantly less for patients whose marrow was exposed to amifostine + 4-HC, compared with 4-HC alone. Unpurged backup marrow fractions were infused into three patients whose marrow was purged with 4-HC alone, because of inadequate marrow recovery. None of the patients who received amifostine + 4-HC-purged marrow required a backup marrow fraction. Complete remissions were achieved in 83% of patients with measurable disease, with no difference between the two cohorts. Forty- three percent of patients remained alive and progression-free at a mean of 13 months posttransplant. There was no significant difference in the rate or pattern of relapse for patients whose marrow was purged with amifostine + 4-HC compared with those whose marrow was purged with 4-HC alone. Ex vivo treatment of marrow with amifostine significantly shortens the time to marrow recovery, thereby reducing the risk of myelosuppressive complications in breast cancer patients receiving high- dose chemotherapy and 4-HC-purged ABMS. Since supportive care requirements are also significantly decreased, amifostine may reduce the cost of such therapy.

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