scholarly journals Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients

2019 ◽  
Vol 11 (513) ◽  
pp. eaay2574 ◽  
Author(s):  
Salo N. Ooft ◽  
Fleur Weeber ◽  
Krijn K. Dijkstra ◽  
Chelsea M. McLean ◽  
Sovann Kaing ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Standard Of Care ◽  
Prospective Clinical Study ◽  
In Vitro Test ◽  
Metastatic Lesions ◽  
Response To Chemotherapy ◽  
Vitro Test ◽  
Colorectal Cancer Patients

There is a clear and unmet clinical need for biomarkers to predict responsiveness to chemotherapy for cancer. We developed an in vitro test based on patient-derived tumor organoids (PDOs) from metastatic lesions to identify nonresponders to standard-of-care chemotherapy in colorectal cancer (CRC). In a prospective clinical study, we show the feasibility of generating and testing PDOs for evaluation of sensitivity to chemotherapy. Our PDO test predicted response of the biopsied lesion in more than 80% of patients treated with irinotecan-based therapies without misclassifying patients who would have benefited from treatment. This correlation was specific to irinotecan-based chemotherapy, however, and the PDOs failed to predict outcome for treatment with 5-fluorouracil plus oxaliplatin. Our data suggest that PDOs could be used to prevent cancer patients from undergoing ineffective irinotecan-based chemotherapy.

Interleukin 8 as predictive factor for response to chemotherapy in colorectal cancer patients

2019 ◽  
pp. 1-6
Author(s):  
Claudia Burz ◽  
Anca Bojan ◽  
Loredana Balacescu ◽  
Vlad-Vasile Pop ◽  
Ciprian Silaghi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cancer Patients ◽  
Predictive Factor ◽  
Interleukin 8 ◽  
Response To Chemotherapy ◽  
Colorectal Cancer Patients

scholarly journals Stage IV Colorectal Cancer Patients with High Risk Mutation Profiles Survived 16 Months Longer with Individualized Therapies

Cancers ◽  
2020 ◽  
Vol 12 (2) ◽  
pp. 393
Author(s):  
Alexander Hendricks ◽  
Anu Amallraja ◽  
Tobias Meißner ◽  
Peter Forster ◽  
Philip Rosenstiel ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Practice ◽  
High Risk ◽  
Metastatic Colorectal Cancer ◽  
Cancer Patients ◽  
Standard Of Care ◽  
High Risk Patients ◽  
Risk Patients ◽  
Individualized Treatments ◽  
Colorectal Cancer Patients

Personalized treatment vs. standard of care is much debated, especially in clinical practice. Here we investigated whether overall survival differences in metastatic colorectal cancer patients are explained by tumor mutation profiles or by treatment differences in real clinical practice. Our retrospective study of metastatic colorectal cancer patients of confirmed European ancestry comprised 54 Americans and 54 gender-matched Germans. The Americans received standard of care, and on treatment failure, 35 patients received individualized treatments. The German patients received standard of care only. Tumor mutations, tumor mutation burden and microsatellite status were identified by using the FoundationOne assay or the IDT Pan-Cancer assay. High-risk patients were identified according to the mutational classification by Schell and colleagues. Results: Kaplan–Meier estimates show the high-risk patients to survive 16 months longer under individualized treatments than those under only standard of care, in the median (p < 0.001). Tumor mutation profiles stratify patients by risk groups but not by country. Conclusions: High-risk patients appear to survive significantly longer (p < 0.001) if they receive individualized treatments after the exhaustion of standard of care treatments. Secondly, the tumor mutation landscape in Americans and Germans is congruent and thus warrants the transatlantic exchange of successful treatment protocols and the harmonization of guidelines.

scholarly journals Single-Cell Sequencing Reveals the Transcriptome and TCR Characteristics of pTregs and in vitro Expanded iTregs

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhenzhen Hui ◽  
Jiali Zhang ◽  
Yu Zheng ◽  
Lili Yang ◽  
Wenwen Yu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Single Cell ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
Critical Role ◽  
Interleukin 2 ◽  
Treg Cells ◽  
Single Cell Sequencing ◽  
Colorectal Cancer Patients

Regulatory T cells (Tregs) play a critical role in the maintenance of immune tolerance and tumor evasion. However, the relative low proportion of these cells in peripheral blood and tissues has hindered many studies. We sought to establish a rapamycin-based in vitro Treg expansion procedure in patients diagnosed with colorectal cancer and perform single-cell sequencing to explore the characteristics of Treg cells. CD25+ cells enriched from peripheral blood mononuclear cells (PBMC) of colorectal tumor patients were cultured in X-VIVO15 medium, supplemented with 5% human AB serum, L-glutamine, rapamycin, interleukin-2 (IL-2), and Dynabeads human Treg expander for 21 days to expand Tregs. Treg cells with satisfactory phenotype and function were successfully expanded from CD4+CD25+ cells in patients with colorectal cancer. The median expansion fold was 75 (range, 20–105-fold), and &gt;90.0% of the harvest cells were CD4+CD25+CD127dim/− cells. The ratio of CD4+CD25+Foxp3+ cells exceeded 60%. Functional assays showed that iTregs significantly inhibited CD8+T cell proliferation in vitro. Single-cell sequencing showed that the transcriptome of pTreg (CD4+CD25+CD127dim/− cells isolated from PBMC of colorectal cancer patients) and iTreg (CD4+CD25+CD127dim/− cells expanded in vitro according to the above regimen) cells were interlaced. pTregs exhibited enhanced suppressive function, whereas iTregs exhibited increased proliferative capacity. TCR repertoire analysis indicated minimal overlap between pTregs and iTregs. Pseudo-time trajectory analysis of Tregs revealed that pTregs were a continuum composed of three main branches: activated/effector, resting and proliferative Tregs. In contrast, in vitro expanded iTregs were a mixture of proliferating and activated/effector cells. The expression of trafficking receptors was also different in pTregs and iTregs. Various chemokine receptors were upregulated in pTregs. Activated effector pTregs overexpressed the chemokine receptor CCR10, which was not expressed in iTregs. The chemokine CCL28 was overexpressed in colorectal cancer and associated with poor prognosis. CCR10 interacted with CCL28 to mediate the recruitment of Treg into tumors and accelerated tumor progression. Depletion of CCR10+Treg cells from tumor microenvironment (TME) could be used as an effective treatment strategy for colorectal cancer patients. Our data distinguished the transcriptomic characteristics of different subsets of Treg cells and revealed the context-dependent functions of different populations of Treg cells, which was crucial to the development of alternative therapeutic strategies for Treg cells in autoimmune disease and cancer.

Pharmacodynamic analysis of receptor tyrosine kinase (RTK) activity reveals differential target inhibition in skin and tumor in a phase I study of advanced colorectal cancer patients treated with AEE788

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3601-3601
Author(s):  
D. W. Davis ◽  
J. Huang ◽  
W. Liu ◽  
L. Xiao ◽  
A. Thomas ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Endothelial Cell ◽  
Cancer Patients ◽  
Advanced Colorectal Cancer ◽  
Post Treatment ◽  
Dependent Manner ◽  
Colorectal Cancer Patients ◽  
Dose Dependent ◽  
Ht 29

3601 Background: AEE788 (AEE) is an oral inhibitor against tyrosine kinases and has an IC50 of < 100 nM against EGFR and VEGFR-2. This PD study investigated the effects of AEE on its targets in vitro and in biopsies from advanced colorectal cancer patients. Methods: HUVECs and HT-29 cells were incubated with AEE for 4h at 0–1 mM. 22 pts were treated at doses of 25 (n=4), 50 (n=3), 100 (n=4), 250 (n=1), 300 (n=4), and 400 mg (n=6) mg/day in 28-day cycles. No major clinical respones were observed. Wound-induced paired skin biopsies were performed on days -8, -1, 22, 29. Tumor biopsies were obtained before and 28 days post-treatment. Evaluable paired skin and tumor samples were available in 18 and 14 patients respectively. The effects of AEE on pKDR, pEGFR, AKT, Ki67, and apoptosis were analyzed by laser scanning cytometry (LSC). Wilcoxon signed rank test and Spearman correlation were used to compare biomarker changes post-treatment and correlation with dose, respectively. Results: In vitro, AEE treatment resulted in a dose-dependent inhibition of pKDR and pEGFR with inhibition of 65% and 63% at 1 mM in HUVECs and HT-29 cells, respectively. pKDR levels increased in response to AEE treatment in HT-29 cells. In skin, AEE increased basal levels of pKDR (p=0.03) post-treatment. AEE increased AKT (p=0.02) and EGFR (p=0.01) in a dose-dependent manner. In wound-induced skin pairs, AEE significantly inhibited endothelial cell pKDR/KDR (ratio) in a dose-dependent manner (p=0.02). In tumors, AEE increased pKDR expression (p=0.05) and was dose-dependent (p=0.06). Tumor endothelial cell pKDR levels decreased (avg. 47%) after AEE treatment (p=0.08). Furthermore, levels of Ki67 increased (p=0.08) and no significant effects were observed on pEGFR or apoptosis at any dose level in post-treatment samples. Conclusions: LSC quantitative analysis confirmed the target inhibition of AEE in vitro and in wound-induced skin pairs. The lack of significant target inhibition in tumors is consistent with the lack of clinical activity of AEE in this cohort of patients. Quantifying pKDR/KDR in wound-induced skin pairs may serve as a surrogate for assessing the activity of an angiogenesis inhibitor such as AEE. [Table: see text]

scholarly journals Cancer-Initiating Cells from Colorectal Cancer Patients Escape from T Cell–Mediated Immunosurveillance In Vitro through Membrane-Bound IL-4

2013 ◽  
Vol 192 (1) ◽  
pp. 523-532 ◽  
Author(s):  
Andrea Volonté ◽  
Tiziano Di Tomaso ◽  
Michela Spinelli ◽  
Matilde Todaro ◽  
Francesca Sanvito ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
T Cell ◽  
Cancer Patients ◽  
Membrane Bound ◽  
Colorectal Cancer Patients
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