Cytochrome P-450 and aryl hydroxylase activity in tumor cells during long-term transplantation

1983 ◽  
Vol 96 (1) ◽  
pp. 989-991
Author(s):  
M. G. Kiseleva ◽  
A. Z. Prikhod'ko ◽  
G. A. Belitskii
Keyword(s):  
Tumor Cells ◽  
Hydroxylase Activity ◽  
Cytochrome P 450 ◽  
Aryl Hydroxylase

108 MCY-M11, a CAR-PBMC cell product transiently expressing a mesothelin targeted mRNA CAR, exhibits desirable functional and immune phenotype attributed to sustained antitumor immunity in vitro

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A120-A120
Author(s):  
Sashi Kasimsetty ◽  
Himavanth Gatla ◽  
Dhana Chinnasamy
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Antitumor Immunity ◽  
Memory T Cells ◽  
Cell Populations ◽  
Epitope Spreading ◽  
Antitumor Response ◽  
Cell Product

BackgroundMCY-M11, an anti-mesothelin CAR (Meso-CAR) mRNA transfected PBMC cell product manufactured through <1 day-process is under clinical evaluation for the treatment of advanced ovarian cancer and peritoneal mesothelioma. In this in-vitro study, we characterized the phenotypic and functional status of immune cell populations in MCY-M11 and their possible role in antitumor immunity.MethodsMCY-M11 cell product were generated using unmanipulated healthy donor PBMCs (n=5) by transfection of Meso-CAR mRNA using MaxCyte’s proprietary Flow Electroporation® system. Frozen MCY-M11 cell product was thawed and cultured for 18 hours, then co-cultured with hMSLNneg or hMSLNpos human mesothelioma cell line, MSTO-211H, or stimulated with anti-CD3/anti-CD28 antibodies in vitro for 8 days. Distinct cell populations in MCY-M11 were evaluated for kinetics and duration of CAR expression, differentiation, activation, exhaustion, and their ability to secrete various immunomodulatory molecules during in vitro stimulation. Antigen-specific proliferation and cytotoxicity of MCY-M11 against hMSLNpos tumor cells as well as their ability to mount long-term antitumor immunity through epitope spreading mechanisms were studied.ResultsIndividual cell populations in MCY-M11 exhibited a consistent but transient Meso-CAR expression persisting for about 7 days. Cell subsets in MCY-M11 acquired early signs of activation and differentiation within 18–24 hours post-culture, but only attained full activation and lineage-specific differentiation upon specific response to hMSLNpos tumor cells. hMSLN antigen experienced MCY-M11 retained significant fractions of Naïve and Central Memory T cells and increased percentage of Effector Memory T cells along with increased expression of CD62L, CD27, and chemokine receptors (CCR5, CCR7, and CXCR3). MCY-M11 exhibited strong antigen-specific cytotoxicity against hMSLNpos tumor cells with corresponding increase in activation and proliferation of CD4+ and CD8+ T cell subsets and displayed low or no acquisition of known exhaustion markers. NK cells also exhibited a functionally superior molecular signature exhibiting increased levels of NKG2D, NKp44, NKp46, FAS, and TRAIL. The Monocytes and B cells in MCY-M11 also acquired an activated, differentiated, and mature phenotype, expressing molecules required for antigen presentation (HLA-DR, HLA-ABC, and CD205) and T cell co-stimulation (CD80 and CD86) to mount a strong antitumor response. These phenotypic changes in cell subsets of MCY-M11 transpired with simultaneous secretion of potent immunostimulatory molecules and chemokines facilitating an extended antitumor response through epitope spreading.ConclusionsWe demonstrated that MCY-M11 is a unique cell product possessing a complete built-in immune cellular machinery with favorable phenotype and enhanced functions specialized in mediating an effective and long-term antitumor response.Trial RegistrationNCT03608618

Tumor Regression Grading After Preoperative Chemoradiotherapy for Locally Advanced Rectal Carcinoma Revisited: Updated Results of the CAO/ARO/AIO-94 Trial

2014 ◽  
Vol 32 (15) ◽  
pp. 1554-1562 ◽  
Author(s):  
Emmanouil Fokas ◽  
Torsten Liersch ◽  
Rainer Fietkau ◽  
Werner Hohenberger ◽  
Tim Beissbarth ◽  
...  
Keyword(s):  
Local Recurrence ◽  
Tumor Cells ◽  
Rectal Carcinoma ◽  
Distant Metastasis ◽  
Cumulative Incidence ◽  
Tumor Regression ◽  
Preoperative Chemoradiotherapy ◽  
Regression Grading ◽  
Clinicopathologic Parameters

Purpose We previously described the prognostic impact of tumor regression grading (TRG) on the outcome of patients with rectal carcinoma treated with preoperative chemoradiotherapy (CRT) in the CAO/ARO/AIO-94 trial. Here we report long-term results after a median follow-up of 132 months. Patients and Methods TRG after preoperative CRT was determined in 386 surgical specimens by the amount of viable tumor cells versus fibrosis, ranging from TRG 4 (no viable tumor cells) to TRG 0 (no signs of regression). Clinicopathologic parameters and TRG were correlated to the cumulative incidence of local recurrence, distant metastasis, and disease-free survival (DFS). Results Ten-year cumulative incidence of distant metastasis and DFS were 10.5% and 89.5% for patients with TRG 4 (complete regression), 29.3% and 73.6% for TRG 2 and 3 (intermediate regression), and 39.6% and 63% for TRG 0 and 1 (poor regression), respectively (P = .005 and P = .008, respectively). On multivariable analysis, residual lymph node metastasis (ypN+) and TRG were the only independent prognostic factors for cumulative incidence of distant metastasis (P < .001 and P = .035, respectively) and DFS (P < .001 and P = .039, respectively), whereas local recurrence was significantly affected by ypN status (P < .001) and lymphatic invasion (P = .026). Conclusion Complete and intermediate tumor regressions were associated with improved long-term outcome in patients with rectal carcinoma after preoperative CRT independent of clinicopathologic parameters. This classification system needs to be prospectively tested in multiple data sets to validate its reproducibility in a wider setting.

scholarly journals Clinicopathological variables of sporadic schwannomas of peripheral nerve in 291 patients and expression of biologically relevant markers

2018 ◽  
Vol 129 (3) ◽  
pp. 805-814 ◽  
Author(s):  
Eric D. Young ◽  
Davis Ingram ◽  
William Metcalf-Doetsch ◽  
Dilshad Khan ◽  
Ghadah Al Sannaa ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Peripheral Nerve ◽  
Tumor Cells ◽  
Tissue Microarray ◽  
Growth Factor Receptor ◽  
Nerve Sheath ◽  
Epidermal Growth

OBJECTIVEWhile sporadic peripheral schwannomas (SPSs) are generally well treated with surgery, their biology is not well understood. Consequently, treatment options are limited. The aim of this study was to provide a comprehensive description of SPS. The authors describe clinicopathological features and treatment outcomes of patients harboring these tumors, and they assess expression of biomarkers using a clinically annotated tissue microarray. Together, these data give new insight into the biology and management of SPS.METHODSPatients presenting with a primary SPS between 1993 and 2011 (n = 291) were selected from an institutional registry to construct a clinical database. All patients underwent follow-up, and short- and long-term outcomes were assessed. Expression of relevant biomarkers was assessed using a new tissue microarray (n = 121).RESULTSSPSs were generally large (mean 5.5 cm) and frequently painful at presentation (55%). Most patients were treated with surgery (80%), the majority of whom experienced complete resolution (52%) or improvement (18%) of their symptoms. Tumors that were completely resected (85%) did not recur. Some patients experienced short-term (16%) and long-term (4%) complications postoperatively. Schwannomas expressed higher levels of platelet-derived growth factor receptor–β (2.1) than malignant peripheral nerve sheath tumors (MPNSTs) (1.5, p = 0.004) and neurofibromas (1.33, p = 0.007). Expression of human epidermal growth factor receptor–2 was greater in SPSs (0.91) than in MPNSTs (0.33, p = 0.002) and neurofibromas (0.33, p = 0.026). Epidermal growth factor receptor was expressed in far fewer SPS cells (10%) than in MPNSTs (58%, p < 0.0001) or neurofibromas (37%, p = 0.007). SPSs more frequently expressed cytoplasmic survivin (66% of tumor cells) than normal nerve (46% of cells), but SPS expressed nuclear survivin in fewer tumor cells than in MPNSTs (24% and 50%, respectively; p = 0.018).CONCLUSIONSComplete resection is curative for SPS. Left untreated, however, these tumors can cause significant morbidity, and not all patients are candidates for resection. SPSs express a pattern of biomarkers consistent with the dysregulation of the tumor suppressor merlin observed in neurofibromatosis Type 2–associated schwannomas, suggesting a shared etiology. This SPS pattern is distinct from that of other tumors of the peripheral nerve sheath.

Effects of acetylenic and olefinic pyrenes upon cytochrome P-450 dependent benzo[a]pyrene hydroxylase activity in liver microsomes

1985 ◽  
Vol 129 (2) ◽  
pp. 591-596 ◽  
Author(s):  
Liang-Shang L. Gan ◽  
Jui-Yun L. Lu ◽  
Douglas M. Hershkowitz ◽  
William L. Alworth
Keyword(s):  
Liver Microsomes ◽  
Hydroxylase Activity ◽  
Pyrene Hydroxylase ◽  
Cytochrome P 450

scholarly journals Pharmacologic marrow purging in murine T cell leukemia

Blood ◽  
1988 ◽  
Vol 71 (6) ◽  
pp. 1656-1661 ◽  
Author(s):  
EA Copelan ◽  
SC Johnson ◽  
MR Grever ◽  
JF Sheridan ◽  
PJ Tutschka
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
In Vitro Assays ◽  
Cell Leukemia ◽  
Term Survival ◽  
Adenosine Deaminase Activity ◽  
Marrow Purging ◽  
Malignant T Cells

Abstract Deoxycoformycin in combination with deoxyadenosine was used to purge 6C3HED malignant T cells from murine marrow in vitro. Adenosine deaminase activity of 6C3HED cells was ablated by incubation with 10(- 6) mol/L deoxycoformycin (dCF). During a 12-hour incubation with 10(-6) mol/L dCF and 10(-4) mol/L deoxyadenosine, tumor cells sequentially accumulated dATP, became depleted of NAD followed by ATP, then died. More than 5 logs of 6C3HED cells were killed as measured by survival of mice injected with treated tumor cells. Identical incubation of 5 x 10(6) marrow cells did not interfere with rescue of syngeneic lethally irradiated mice. Long-term survival was demonstrated in 12 of 14 mice that received marrow that had been contaminated with 5% 6C3HED cells, incubated with deoxycoformycin and deoxyadenosine, then used to rescue lethally irradiated mice. This murine model provides information not available from in vitro assays and may be useful in the development of strategies to purge malignant T cells from marrow.

scholarly journals Immunomodulatory Effects of Tryptophan Metabolism in the Glioma Tumor Microenvironment

2021 ◽  
Vol 12 ◽  
Author(s):  
Yang Xu ◽  
Huikai Zhang ◽  
Qian Sun ◽  
Rongxin Geng ◽  
Fanen Yuan ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Cells ◽  
Immune Regulation ◽  
Acid Metabolism ◽  
Regulatory Mechanism ◽  
Term Treatment ◽  
Tryptophan Metabolism ◽  
Long Term Treatment ◽  
Regulation Mechanisms

Gliomas are the most common primary malignant tumor in adults’ central nervous system. While current research on glioma treatment is advancing rapidly, there is still no breakthrough in long-term treatment. Abnormalities in the immune regulatory mechanism in the tumor microenvironment are essential to tumor cell survival. The alteration of amino acid metabolism is considered a sign of tumor cells, significantly impacting tumor cells and immune regulation mechanisms in the tumor microenvironment. Despite the fact that the metabolism of tryptophan in tumors is currently discussed in the literature, we herein focused on reviewing the immune regulation of tryptophan metabolism in the tumor microenvironment of gliomas and analyzed possible immune targets. The objective is to identify potential targets for the treatment of glioma and improve the efficiency of immunotherapy.

Efficient and sustained gene expression in primary T lymphocytes and primary and cultured tumor cells mediated by adeno-associated virus plasmid DNA complexed to cationic liposomes

1994 ◽  
Vol 14 (4) ◽  
pp. 2411-2418
Author(s):  
R Philip ◽  
E Brunette ◽  
L Kilinski ◽  
D Murugesh ◽  
M A McNally ◽  
...  
Keyword(s):  
Gene Expression ◽  
Tumor Cells ◽  
Plasmid Dna ◽  
Interleukin 2 ◽  
Cationic Liposomes ◽  
Lymphoid Cells ◽  
Chromosomal Dna ◽  
Adeno Associated Virus ◽  
Cultured Tumor Cells

We have used cationic liposomes to facilitate adeno-associated virus (AAV) plasmid transfections of primary and cultured cell types. AAV plasmid DNA complexed with liposomes showed levels of expression several fold higher than those of complexes with standard plasmids. In addition, long-term expression (> 30 days) of the gene, unlike the transient expression demonstrated by typical liposome-mediated transfection with standard plasmids, was observed. Southern analysis of chromosomal DNA further substantiated the hypothesis that the long-term expression was due to the presence of the transgene in the AAV plasmid-transfected group and not in the standard plasmid-transfected group. AAV plasmid-liposome complexes induced levels of transgene expression comparable to those obtained by recombinant AAV transduction. Primary breast, ovarian, and lung tumor cells were transfectable with the AAV plasmid DNA-liposome complexes. Transfected primary and cultured tumor cells were able to express transgene product even after lethal irradiation. High-level gene expression was also observed in freshly isolated CD3+, CD4+, and CD8+ T cells from normal human peripheral blood. Transfection efficiency ranged from 10 to 50% as assessed by intracellular interleukin-2 levels in interleukin-2-transfected cells. The ability to express transgenes in primary tumor and lymphoid cells may be applied toward tumor vaccine studies and protocols which may eventually permit highly specific modulation of the cellular immune response in cancer and AIDS.

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