Publications by authors named "Shicheng Yang"

39 Publications

The Preventive Effect of Alprostadil on the Contrast-Induced Nephropathy of Coronary Heart Disease Treated by Percutaneous Coronary Intervention in Moderate and High-Risk Population Stratified by Mehran Score.

Angiology 2021 Jun 8:33197211015540. Epub 2021 Jun 8.

Department of Cardiology, Tianjin Chest Hospital, Tianjin, China.

The Mehran risk score (MRS) was used to classify patients with coronary heart disease and evaluate the preventive effect of alprostadil on contrast-induced nephropathy (CIN) after percutaneous coronary intervention. The patients (n = 1146) were randomized into an alprostadil and control group and then divided into 3 groups on the basis of the MRS: low-risk, moderate-risk, and high-risk groups. The primary end point was the occurrence of CIN (alprostadil + hydration vs simple hydration treatment); secondary end points included serum creatinine, blood urea nitrogen, creatinine clearance rate, cystatin C, interleukin-6, C-reactive protein, proteinuria, and differences in the incidence of major adverse events. In the low-risk, moderate-risk, and high-risk groups, the incidence of CIN in the control and alprostadil group was 2.9 versus 2.6% ( = .832), 11.4 versus 4.9% ( = .030), 19.1 versus 7.7% ( = .041), respectively. Multivariate logistic regression analysis showed that alprostadil treatment was a favorable protective factor for moderate-risk and high-risk CIN patients (OR = 0.343, 95% CI: 0.124-0.951, = .040). Alprostadil can be used as a preventive treatment for moderate- and high-risk CIN patients classified by the MRS. The reduction of CIN by alprostadil may be related to an anti-inflammatory effect.
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http://dx.doi.org/10.1177/00033197211015540DOI Listing
June 2021

Recent Developments in Nanomedicine for Pediatric Cancer.

J Clin Med 2021 Apr 1;10(7). Epub 2021 Apr 1.

Department of Chemical Engineering, Northeastern University, Boston, MA 02115, USA.

Cancer is the second biggest cause of death in children in the US. With the development of chemotherapy, there has been a substantial increase in the overall survival rate in the last 30 years. However, the overall mortality rate in children with cancer remains 25%, and many survivors experience a decline in overall quality of life and long-term adverse effects caused by treatments. Although cancer cells share common characteristics, pediatric cancers are different from adult cancers in their prevalence, mutation load, and drug response. Therefore, there is an urgent unmet need to develop therapeutic approaches specifically designed for children with cancer. Nanotechnology can potentially overcome the deficiencies of conventional methods of administering chemotherapy and ultimately improve clinical outcomes. The nanoparticle-based drug delivery systems can decrease the toxicity of therapy, provide a sustained or controlled drug release, improve the pharmacokinetic properties of loading contents, and achieve a targeted drug delivery with achievable modifications. Furthermore, therapeutic approaches based on combining nanoformulated drugs with novel immunotherapeutic agents are emerging. In this review, we discussed the recently developed nanotechnology-based strategies for treating blood and solid pediatric cancers.
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http://dx.doi.org/10.3390/jcm10071437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8036287PMC
April 2021

Life cycle water footprint analysis for second-generation biobutanol.

Bioresour Technol 2021 Aug 21;333:125203. Epub 2021 Apr 21.

College of Chemistry and Chemical Engineering, Henan Polytechnic University, Jiaozuo, Henan 454003, People's Republic of China.

Water is essential in conversion of crop to bioenergy. Therefore, it is important to carefully evaluate the impact of bioenergy technology on water source. Life cycle water footprints of biobutanol from wheat straw, corn grain and corn stover are analyzed in this study according to the characteristics of crop growing and climate conditions. The results show that life cycle water footprints of biobutanol from wheat straw, corn grain and corn stover are 271, 108 and 240 L HO/MJ biobutanol, respectively. Life cycle water footprints of the crop production stage for wheat straw, corn grain and corn stover are 269.89, 107.84 and 238.95 L HO/MJ biobutanol, respectively. Owing to the use of fertilizer in the crop production stage, gray water footprint of wheat straw, corn grain and corn stover accounts for 91.08%, 86.65% and 86.40% of the life cycle water footprint, respectively.
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http://dx.doi.org/10.1016/j.biortech.2021.125203DOI Listing
August 2021

Nanoparticle Formulations of Poly (ADP-ribose) Polymerase Inhibitors for Cancer Therapy.

Front Chem 2020 23;8:594619. Epub 2020 Nov 23.

Nanomedicine Innovation Center, Northeastern University, Boston, MA, United States.

A number of poly(ADP-ribose) polymerase (PARP) inhibitors have been recently approved for clinical use in BRCA mutated and other cancers. However, off-target toxicity of PARP inhibitors and the emergence of drug resistance following prolonged administration of these inhibitors indicate the need for improved methods of drug delivery to the tumors. Nanomedicines based upon nanoparticle formulations of conventional small molecule drugs and inhibitors offer many advantages, such as increased solubility and bioavailability of drugs, reduced toxicity and drug resistance, and improved tissue selectivity and therapeutic efficacy. This review highlights the current trends in formulations of PARP inhibitors developed by nanotechnology approaches and provides an insight into the applications and limitations of these PARP inhibitor nanomedicines for cancer therapies.
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http://dx.doi.org/10.3389/fchem.2020.594619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7719718PMC
November 2020

Effect of Cu-based metal organic framework (Cu-MOF) loaded with TiO2 on the photocatalytic degradation of rhodamine B dye.

Environ Sci Pollut Res Int 2021 Apr 26;28(13):15883-15889. Epub 2020 Nov 26.

College of Chemistry and Chemical Engineering, Henan Polytechnic University, Jiaozuo, 454003, Henan, People's Republic of China.

Using copper nitrate trihydrate as the copper source, [email protected] nanocomposites were prepared by a one-step crystallization method, and the effect of the amount of TiO2 loaded on the adsorption of rhodamine B was studied. X-ray diffraction (XRD), scanning electron microscope (SEM), energy spectrometer (EDS), N adsorption-desorption (BET), and infrared spectroscopy (FTIR) were used to characterize the microstructure and surface properties of composite materials. The results show that the composite material not only has a good degradability for rhodamine B, the decolorization rate reaches 98.03% after 120 min, but it also maintains a good cycle performance. Fitting the first-order kinetic equation to the reaction process, under the optimal conditions, R = 0.98, indicating that the reaction process conforms to the first-order kinetic equation. Therefore, the catalyst has good catalytic degradation and cycle performance.
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http://dx.doi.org/10.1007/s11356-020-11805-wDOI Listing
April 2021

Trimetazidine can prevent the occurrence of contrast-induced nephropathy after percutaneous coronary intervention in elderly patients with renal insufficiency.

Perfusion 2020 Sep 10:267659120957856. Epub 2020 Sep 10.

Tianjin Chest Hospital, Tianjin, China.

Background: Contrast-induced nephropathy (CIN) has become a common cause of hospital-acquired acute kidney injury in elderly patients. Trimetazidine (TMZ) is a type of anti-ischemic drug developed in recent years, which can reduce the incidence of CIN. This study aimed to evaluate the efficacy of TMZ in the prevention of contrast-induced nephropathy in elderly patients with renal insufficiency undergoing percutaneous coronary intervention (PCI) and to explore the mechanism of action.

Methods: A total of 310 elderly patients with renal insufficiency undergoing elective PCI were enrolled and randomly assigned to a control group (n = 155, hydration only) and a TMZ group (n = 155, 20 mg thrice daily orally 24 hours before and 72 hours after PCI). The primary endpoint of the study was the incidence of CIN, which was defined as an increase of 25% or more, or an absolute increase of 0.5 mg/dL or more in serum creatinine from baseline value, at 48 to 72 hours following the exposure to contrast media (CM).

Results: The incidence of CIN was significantly lower in the TMZ group than that in the control group (3.2% vs. 9.7%, p = 0.021). There was no difference regarding the incidence of major adverse events during hospitalization between the TMZ group and control group (1.9% vs. 2.6%, p = 1.000). Binary logistic regression results showed that TMZ was protective factors of CIN (OR = 0.274; 95% CI: 0.089-0.847; p = 0.025).

Conclusion: Therefore, we came to the conclusion that prophylactic administration of TMZ can prevent the occurrence of CIN in elderly patients with renal insufficiency undergoing PCI and has a certain protective effect on the renal function of patients. According to the experimental results and the mechanism of TMZ on cardiomyocytes, we speculate that TMZ increases kidney glucose metabolism, reduces fatty acid oxidation, and also has a protective effect on kidney free radical damage and ischemia-reperfusion injury.
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http://dx.doi.org/10.1177/0267659120957856DOI Listing
September 2020

Preventive effect of trimetazidine on contrast-induced nephropathy undergoing percutaneous coronary intervention in elderly moderate and high risk diabetics stratified by mehran score.

Perfusion 2021 Jul 24;36(5):491-500. Epub 2020 Aug 24.

Department of Cardiology, Tianjin Chest Hospital, Tianjin, China.

Background: The aim of this research was to use the Mehran risk score to classify elderly diabetics with coronary heart disease to assess the preventive effect of trimetazidine on contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) in different risk population.

Methods: An uncompromised of 760 elderly diabetics that went through PCI were included in this research. The patients were first divided into three groups in the light of MRS: low-risk, moderate-risk, and high-risk group, then randomized into trimetazidine group and the control group respectively. The first endpoint was the amount of CIN, which is described as a rise in serum creatinine levels by ⩾44.2 μmol/L or ⩾25% ratio within 48 or 72 hours after medication. Second endpoint included differences in creatinine clearance rate (CrCl), blood urea nitrogen (BUN), serum creatinine (Scr), cystatin-C (Cys-C), and the incidence of major adverse events after administration.

Results: In the three groups, the incidence of CIN in trimetazidine and control group was 5.0% versus 4.9%(χ = 0.005, p > 0.05), 8.0% versus 18.0% (χ = 7.685, p < 0.05), 10.4% versus 27.1% (χ = 4.376, p < 0.05), respectively. The multivariable logistic regression result demonstrated that trimetazidine intervention was a profitable element of CIN in moderate and high-risk groups (OR = 0.294, 95% CI 0.094-0.920, p = 0.035).

Conclusion: Our study confirmed that trimetazidine can be considered for preventive treatment of CIN occurrence in elderly diabetics with moderate and high-risk population, while there is no obvious advantage compared with hydration therapy in low-risk patients.
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http://dx.doi.org/10.1177/0267659120952057DOI Listing
July 2021

Efficacy of nicorandil on the prevention of contrast-induced nephropathy in patients with coronary heart disease undergoing percutaneous coronary intervention.

Coron Artery Dis 2020 05;31(3):284-288

Department of Cardiology, Tianjin Chest Hospital, Tianjin, China.

Objectives: The purpose of this study was to explore the effect of nicorandil on the incidence of contrast-induced nephropathy in patients with coronary heart disease undergoing percutaneous coronary intervention.

Methods: This study randomized 300 patients undergoing percutaneous coronary intervention to receive conventional treatment in the control group (hydration only; n = 150) vs. nicorandil therapy (nicorandil 10 mg three times daily plus hydration; n = 150). The primary endpoint was the incidence of contrast-induced nephropathy, defined as rise in serum creatinine ≥44.2 μmol/L or >25% above baseline within 72 hours after exposure to contrast administered during percutaneous coronary intervention. Secondary endpoints included differences in post-percutaneous coronary intervention serum creatinine, blood urea nitrogen, creatinine clearance rate, cystatin-C, and occurrence of major adverse events.

Results: Contrast-induced nephropathy incidence was 3.3% (5/150) in the nicorandil group vs. 10.7% (16/150) in the control group (P < 0.05). At 48 and 72 hours after contrast administration, cystatin-C levels were significantly lower and creatinine clearance rate were significantly higher with nicroandil therapy compared to conventional treatment (all P values <0.05). No statistical difference was observed in the incidence of major post-procedure side effect events in hospital and fourteen days of follow-up period between the nicorandil group and control group (3.3% vs. 4.0%, P > 0.05).

Conclusion: Compared to conventional treatment, oral nicorandil therapy was associated with less contrast-induced nephropathy and improved renal function following contrast administration during percutaneous coronary intervention.
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http://dx.doi.org/10.1097/MCA.0000000000000826DOI Listing
May 2020

Anion Specificity Effects on the Interfacial Aggregation Behavior of Poly(lauryl acrylate)--poly(-isopropylacrylamide).

Langmuir 2019 Jul 17;35(30):9904-9911. Epub 2019 Jul 17.

Department of Polymer Materials and Engineering, College of Material Science and Engineering , Harbin University of Science and Technology , 4 Linyuan Road , Harbin 150040 , PR China.

Aggregation behavior of an amphiphilic diblock copolymer poly(lauryl acrylate)--poly(-isopropylacrylamide) (PLA--PNIPAM) on neutral aqueous subphases with different salt species and salt concentrations, as well as the structures of its Langmuir-Blodgett (LB) films, were systematically studied. The presence of NaCl or NaSO in subphases makes PNIPAM chains shrink on the water surface and reduce their solubility underwater. On the contrary, the presence of NaNO or NaSCN makes PNIPAM chains more stretched on water and increase their solubility underwater, whose stretch degree and solubility both increase with the increase of salt concentration. Solubility of PNIPAM chains in the above subphase solutions is ranked as NaSCN ≫ NaNO > pure HO > NaCl ≈ NaSO, which is almost consistent with the Hofmeister series except for the latter two close cases. All the initial LB films of PLA--PNIPAM exhibit tiny isolated circular micelles. Upon compression, the LB films in the case of pure HO exhibit the dense mixed structures of circular micelles and wormlike aggregates. The formation of wormlike aggregates is due to connection of some adjoining cores, which is less possible in other subphase cases because of the conformation difference of PNIPAM chains.
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http://dx.doi.org/10.1021/acs.langmuir.9b01561DOI Listing
July 2019

Effect of on the Prevention of Postoperative Peritoneal Adhesions in Abrasion-Induced Rat Model.

Evid Based Complement Alternat Med 2019 10;2019:9148754. Epub 2019 Jun 10.

Department of Laboratory Animal Center, Liaoning University of Traditional Chinese Medicine, 110032 Shenyang, China.

Postoperative peritoneal adhesions (PPAs) constitute a common complication of abdominal surgery with a high incidence. (BS) is an important hemostatic drug used in China for nearly 2000 years. The purpose of this study was to investigate the effect of on postoperative intestinal adhesion in rats. PPA was induced by cecal wall abrasion, and was injected to observe its effect on adhesion in rats. The adhesion and inflammation score were assessed through visual observation and histopathologic evaluation. The levels of interleukin-1 (IL-1), tumor necrosis factor (TNF-), and interleukin-17F (IL-17F) in abdominal cavity and interleukin-6 (IL-6) in plasma were measured by enzyme-linked immunosorbent assay (ELISA) at 6 hours, 12 hours, 24 hours, and 1 week after operation. The tissue level of transforming growth factor beta-1 (TGF-1) was also determined by ELISA on the seventh day after surgery. The expressions of collagen and TNF- were, respectively, detected by Masson trichrome staining and immunohistochemical staining. The expression of TGF-1 and alpha smooth muscle actin (-SMA) was detected by Western blot. The result showed that has obvious preventive effect on PPAs and celiac inflammation of PPAs. could significantly reduce the level of IL-17F abdominal cavity and IL-6 in plasma. Masson trichrome staining and immunohistochemical staining results showed that also decreased the expression of TNF- and collagen. Western blot results showed that decreased the expression of -SMA and TGF-1. Our results suggest that decreased the development of abdominal adhesion in abrasion-induced model of rats and reduced the expression of the important substance which increased in PPAs. can be further studied as a new and cheaper antiadhesive substance.
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http://dx.doi.org/10.1155/2019/9148754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6590513PMC
June 2019

High Loading Dose of Atorvastatin for the Prevention of Serum Creatinine and Cystatin C-Based Contrast-Induced Nephropathy Following Percutaneous Coronary Intervention.

Angiology 2018 Sep 17;69(8):692-699. Epub 2018 Jan 17.

1 Department of Cardiology, Tianjin Chest Hospital, Tianjin, China.

The aim of this study is to assess the efficacy of high-dose atorvastatin on the prevention of contrast-induced nephropathy (CIN) in patients with acute coronary syndrome (ACS) undergoing percutaneous intervention and observe the incidence of cystatin C (CyC)-based CIN. A total of 496 patients with ACS were randomly assigned to either the control group (247 patients receiving conventional dose atorvastatin 10 mg daily from 1 day before to 3 days after contrast administration) or the high-dose atorvastatin group (249 patients receiving atorvastatin 40 mg daily for the same perioperative period). The baseline characteristics of the 2 groups were similar. The primary end point of serum creatinine (SCr)-based CIN occurred in 31 patients in the control group and 16 patients in the high-dose atorvastatin group (12.6% vs 6.4%; P = .02). Cystatin C-based CIN developed in 90 patients in the control group and 46 patients in the high-dose atorvastatin group (36.4% vs 18.5%; P < .001). A multivariable analysis revealed that high-dose atorvastatin was independently associated with a decreased risk of CIN. Our study demonstrated that prophylactic treatment with high-dose atorvastatin reduced the risk of both SCr and CyC-based CIN and suggested that CyC was a more reliable marker for early diagnosis of CIN compared with SCr.
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http://dx.doi.org/10.1177/0003319717750903DOI Listing
September 2018

Effects of subphase pH, temperature and ionic strength on the aggregation behavior of PnBA-b-PAA at the air/water interface.

J Colloid Interface Sci 2018 Feb 8;512:862-870. Epub 2017 Nov 8.

Department of Polymer Materials and Engineering, College of Material Science and Engineering, Harbin University of Science and Technology, 4 Linyuan Road, Harbin 150040, PR China.

Aggregation behavior of an amphiphilic diblock polyelectrolyte poly(n-butylacrylate)-b-poly(acrylic acid) (PnBA-b-PAA) at the air/water interface and morphologies of its LB films were characterized by the Langmuir monolayer technique and atomic force microscopy (AFM), respectively. Effects of subphase pH, temperature and ionic strength on the isotherms and hysteresis curves of the PnBA-b-PAA monolayers and the morphologies of its LB films were systematically studied. With the increase of subphase pH, the isotherms shift negatively and the quasi-plateaus disappear under neutral and alkaline conditions. Hysteresis phenomena of the PnBA-b-PAA monolayers on acidic and neutral subphases are quite obvious and similar, while the compression and expansion isotherms under alkaline condition are almost overlapped. The LB films of PnBA-b-PAA transferred from acidic subphase exhibit isolated circular micelles with large size, while those from alkaline subphase exhibit condensed ones with small size. With the rise in subphase temperature, PnBA blocks on the water surface are more likely to aggregate into large cores due to the higher molecular mobility. Furthermore, the totally ringlike nanostructures prepared from alkaline subphase with medium ionic strength are observed for the first time in LB films of block copolymers.
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http://dx.doi.org/10.1016/j.jcis.2017.11.002DOI Listing
February 2018

The efficacy of probucol combined with hydration in preventing contrast-induced nephropathy in patients with coronary heart disease undergoing percutaneous coronary intervention: a multicenter, prospective, randomized controlled study.

Int Urol Nephrol 2018 Jan 25;50(1):105-112. Epub 2017 Oct 25.

Department of Cardiology, Tianjin First Central Hospital, Tianjin, China.

Purpose: To investigate the preventive effect of probucol combined with hydration on contrast-induced nephropathy (CIN) in patients with coronary heart disease undergoing percutaneous coronary intervention (PCI).

Methods: A total of 641 patients undergoing PCI were randomly assigned to either a probucol group (probucol 500 mg twice daily and hydration; n = 321) or a control group (hydration only; n = 320). The primary endpoint was the incidence of CIN, defined as an increase in serum creatinine (Scr) by ≥ 44.2 μmol/L or ≥ 25% within 72 h after the administration of contrast agent. Secondary endpoints were changes in Scr, cystatin-C (Cys-C), creatinine clearance rate (Ccr), C-reactive protein (CRP), superoxide dismutase (SOD), and glutathione (GSH) within 72 h, and major adverse events during hospitalization or the 14-day follow-up period.

Results: The incidence of CIN was 4.0% (13/321) in the probucol group and 10.9% (35/320) in the control group. The probucol group had lower Cys-C and higher Ccr at 48 and 72 h after PCI compared with the control group. At 48 and 72 h following the operation, Cys-C and CRP were lower in the probucol group compared with the control group, but Ccr, SOD, and GSH were higher. There were no differences in the incidence of major adverse events during hospitalization or the 14-day follow-up between the groups. Multivariate logistic regression analysis showed that probucol was an independent protective factor for CIN.

Conclusions: Probucol combined with hydration more effectively decreased the incidence of CIN in patients with coronary heart disease undergoing PCI compared with hydration alone.
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http://dx.doi.org/10.1007/s11255-017-1718-4DOI Listing
January 2018

Efficacy of alprostadil in preventing contrast-induced nephropathy in patients undergoing percutaneous coronary intervention: A multicenter prospective randomized controlled trial.

Catheter Cardiovasc Interv 2018 03 10;91(4):742-750. Epub 2017 Oct 10.

Department of Cardiology, Teda International Cardiovascular Hospital, Tianjin, China.

Background: The role of alprostadil on the prevention of contrast-induced nephropathy (CIN) still remains controversial. The purpose of this study was to examine the effects of short-term alprostadil on the incidence of CIN in patients undergoing elective percutaneous coronary intervention (PCI).

Methods: A total of 480 patients with coronary heart disease undergoing PCI were enrolled in our study and randomly assigned to two groups. The control group (n = 240) was given only hydration therapy and the alprostadil group (n = 240) received intravenous administration of 20 ug/day (diluted with 100 ml normal saline) from 0.5∼1 hr before to 3 days after operation on the basis of hydration. The primary endpoint of the study was the incidence of CIN, which was defined as an increase in SCr concentration ≥ 44.2 umol/l or ≥25% above baseline within 48 hr∼72 hr after exposure of contrast media.

Results: The incidence of CIN was significantly lower in the alprostadil group than that in the control group (6.25% vs 11.67%, P = 0.038). Multivariate logistic regression analysis showed that alprostadil was the protective factor of CIN (OR = 0.699, 95% CI 0.542-0.902, P = 0.006). The benefits against CIN were consistent in prespecified high-risk patients with diabetes mellitus (P = 0.003). In addition, we also found that hs-CRP and blood homocysteine values after PCI were significantly lower in the alprostadil group than those in the control group.

Conclusion: Prophylactic administration of alprostadil may prevent against CIN in coronary heart disease patients undergoing elective PCI, particularly in high-risk patients with diabetes mellitus.
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http://dx.doi.org/10.1002/ccd.27353DOI Listing
March 2018

Function of Novel Anti-CD19 Chimeric Antigen Receptors with Human Variable Regions Is Affected by Hinge and Transmembrane Domains.

Mol Ther 2017 11 27;25(11):2452-2465. Epub 2017 Jul 27.

Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD 20892, USA. Electronic address:

Anti-CD19 chimeric antigen receptor (CAR) T cells have caused remissions of B cell malignancies, but problems including cytokine-mediated toxicity and short persistence of CAR T cells in vivo might limit the effectiveness of anti-CD19 CAR T cells. Anti-CD19 CARs that have been tested clinically had single-chain variable fragments (scFvs) derived from murine antibodies. We have designed and constructed novel anti-CD19 CARs containing a scFv with fully human variable regions. T cells expressing these CARs specifically recognized CD19 target cells and carried out functions including degranulation, cytokine release, and proliferation. We compared CARs with CD28 costimulatory moieties along with hinge and transmembrane domains from either the human CD28 molecule or the human CD8α molecule. Compared with T cells expressing CARs with CD28 hinge and transmembrane domains, T cells expressing CARs with CD8α hinge and transmembrane domains produced lower levels of cytokines and exhibited lower levels of activation-induced cell death (AICD). Importantly, CARs with hinge and transmembrane regions from either CD8α or CD28 had similar abilities to eliminate established tumors in mice. In anti-CD19 CARs with CD28 costimulatory moieties, lower levels of inflammatory cytokine production and AICD are potential clinical advantages of CD8α hinge and transmembrane domains over CD28 hinge and transmembrane domains.
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http://dx.doi.org/10.1016/j.ymthe.2017.07.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5675490PMC
November 2017

Efficacy of short-term moderate or high-dose rosuvastatin in preventing contrast-induced nephropathy: A meta-analysis of 15 randomized controlled trials.

Medicine (Baltimore) 2017 Jul;96(27):e7384

Graduate School of Tianjin Medical University Department of Cardiology, Tianjin Chest Hospital, Tianjin, China.

Background: The prophylactic efficacy of statin pretreatment for the prevention of contrast-induced nephropathy (CIN) in patients undergoing coronary angiography (CAG) or percutaneous coronary intervention (PCI) remains controversial. The aim of the study was to perform a meta-analysis of randomized controlled trials (RCTs) to assess the effectiveness of short-term moderate or high-dose rosuvastatin pretreatment in preventing CIN.

Methods: We included RCTs comparing short-term moderate or high-dose rosuvastatin treatment versus low-dose rosuvastatin treatment or placebo for preventing CIN. The primary endpoint was the incidence of CIN within 2 to 5 days after contrast administration, and related-parameters including serum creatinine (SCr), cystatin C (CysC), hypersensitive C-reactive protein (hs-CRP), urine microalbumin (mALB) were also extracted.

Results: Fifteen RCTs with a total of 2673 patients were identified and analyzed. Patients who received moderate or high-dose rosuvastatin pretreatment had a 55% lower risk of CIN compared with low-dose rosuvastatin pretreatment or placebo group based on a fixed effect model (RR = 0.45, 95% CI 0.35-0.58, P < .0001). The benefit of moderate or high-dose rosuvastatin was consistent in both comparisons with low-dose rosuvastatin (RR = 0.40, 95% CI 0.27-0.59, P < .0001) or placebo (RR = 0.45, 95% CI 0.35-0.58, P < .0001). And moderate (20 mg) or high dose (≥40 mg) rosuvastatin significantly reduced the incidence of CIN compared with the control (RR = 0.39, 95% CI 0.29-0.54, P < .0001, RR = 0.56, 95% CI 0.37-0.85, P = .006, respectively). Subgroup analysis showed that moderate or high-dose rosuvastatin pretreatment could decrease the incidence of CIN in patients with chronic kidney disease (CKD) (RR = 0.53, 95% CI 0.30-0.93, P = .03) or diabetes mellitus (DM) (RR = 0.51, 95% CI 0.31-0.86, P = .01) or acute coronary syndrome (ACS) patients undergoing PCI (RR = 0.52, 95% CI 0.35-0.76, P = .0009) or in studies which received mean contrast volume ≥110 mL (RR = 0.43, 95% CI 0.32-0.58, P < .0001). The SCr, CysC, hs-CRP, and mALB after the operation in the moderate or high-dose rosuvastatin group were lower than those of low-dose rosuvastatin group.

Conclusion: This meta-analysis demonstrated that moderate or high-dose rosuvastatin treatment could reduce the incidence of CIN in patients undergoing CAG or PCI. Moreover, moderate or high-dose rosuvastatin would be beneficial in high-risk patients with CKD or DM or undergoing PCI.
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http://dx.doi.org/10.1097/MD.0000000000007384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5502163PMC
July 2017

Novel role of hematopoietic stem cells in immunologic rejection of malignant gliomas.

Oncoimmunology 2015 Mar 22;4(3):e994374. Epub 2015 Jan 22.

UF Brain Tumor Immunotherapy Program; Preston A. Wells, Jr. Center for Brain Tumor Therapy; Department of Neurosurgery; University of Florida ; Gainesville, FL, USA.

Adoptive cellular therapy (ACT) after lymphodepletive conditioning can induce dramatic clinical responses, but this approach has been largely limited to melanoma due to a lack of reliable methods for expanding tumor-specific lymphocytes from the majority of other solid cancers. We have employed tumor RNA-pulsed dendritic cells (DCs) to reliably expand CD4 and CD8 tumor-reactive T lymphocytes for curative ACT in a highly-invasive, chemotherapy- and radiation-resistant malignant glioma model. Curative treatment of established intracranial tumors involved a synergistic interaction between myeloablative (MA) conditioning, adoptively transferred tumor-specific T cells, and tumor RNA-pulsed DC vaccines. Hematopoietic stem cells (HSCs), administered for salvage from MA conditioning, rapidly migrated to areas of intracranial tumor growth and facilitated the recruitment of tumor-specific lymphocytes through HSC-elaborated chemokines and enhanced immunologic rejection of intracranial tumors during ACT. Furthermore, HSC transplant under non-myeloablative (NMA) conditions also enhanced immunologic tumor rejection, indicating a novel role for the use of HSCs in the immunologic treatment of malignant gliomas and possibly other solid tumors.
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http://dx.doi.org/10.4161/2162402X.2014.994374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4404923PMC
March 2015

EGFRvIII-specific chimeric antigen receptor T cells migrate to and kill tumor deposits infiltrating the brain parenchyma in an invasive xenograft model of glioblastoma.

PLoS One 2014 10;9(4):e94281. Epub 2014 Apr 10.

Duke Brain Tumor Immunotherapy Program, Division of Neurosurgery, Department of Surgery, Duke University Medical Center, Durham, North Carolina, United States of America; Department of Pathology, Duke University Medical Center, Durham, North Carolina, United States of America; The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina, United States of America.

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and is uniformly lethal. T-cell-based immunotherapy offers a promising platform for treatment given its potential to specifically target tumor tissue while sparing the normal brain. However, the diffuse and infiltrative nature of these tumors in the brain parenchyma may pose an exceptional hurdle to successful immunotherapy in patients. Areas of invasive tumor are thought to reside behind an intact blood brain barrier, isolating them from effective immunosurveillance and thereby predisposing the development of "immunologically silent" tumor peninsulas. Therefore, it remains unclear if adoptively transferred T cells can migrate to and mediate regression in areas of invasive GBM. One barrier has been the lack of a preclinical mouse model that accurately recapitulates the growth patterns of human GBM in vivo. Here, we demonstrate that D-270 MG xenografts exhibit the classical features of GBM and produce the diffuse and invasive tumors seen in patients. Using this model, we designed experiments to assess whether T cells expressing third-generation chimeric antigen receptors (CARs) targeting the tumor-specific mutation of the epidermal growth factor receptor, EGFRvIII, would localize to and treat invasive intracerebral GBM. EGFRvIII-targeted CAR (EGFRvIII+ CAR) T cells demonstrated in vitro EGFRvIII antigen-specific recognition and reactivity to the D-270 MG cell line, which naturally expresses EGFRvIII. Moreover, when administered systemically, EGFRvIII+ CAR T cells localized to areas of invasive tumor, suppressed tumor growth, and enhanced survival of mice with established intracranial D-270 MG tumors. Together, these data demonstrate that systemically administered T cells are capable of migrating to the invasive edges of GBM to mediate antitumor efficacy and tumor regression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094281PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983153PMC
January 2015

A cytokine cocktail directly modulates the phenotype of DC-enriched anti-tumor T cells to convey potent anti-tumor activities in a murine model.

Cancer Immunol Immunother 2013 Nov 27;62(11):1649-62. Epub 2013 Aug 27.

Division of Neurosurgery, Department of Surgery, Brain Tumor Immunotherapy Program, Duke University Medical Center, 303 Research Drive, 220 Sands Building, DUMC 3050, Durham, NC, 27710, USA.

Adoptive cell transfer (ACT) using ex vivo-expanded anti-tumor T cells such as tumor-infiltrated lymphocytes or genetically engineered T cells potently eradicates established tumors. However, these two approaches possess obvious limitations. Therefore, we established a novel methodology using total tumor RNA (ttRNA) to prime dendritic cells (DC) as a platform for the ex vivo generation of anti-tumor T cells. We evaluated the antigen-specific expansion and recognition of T cells generated by the ttRNA-DC-T platform, and directly modulated the differentiation status of these ex vivo-expanded T cells with a cytokine cocktail. Furthermore, we evaluated the persistence and in vivo anti-tumor efficacy of these T cells through murine xenograft and syngeneic tumor models. During ex vivo culture, IL-2 preferentially expanded CD4 subset, while IL-7 enabled homeostatic proliferation from the original precursors. T cells tended to lose CD62L during ex vivo culture using IL-2; however, IL-12 could maintain high levels of CD62L by increasing expression on effector T cells (Tem). In addition, we validated that OVA RNA-DC only selectively expanded T cells in an antigen-specific manner. A cytokine cocktail excluding the use of IL-2 greatly increased CD62Lhigh T cells which specifically recognized tumor cells, engrafted better in a xenograft model and exhibited superior anti-tumor activities in a syngeneic intracranial model. ACT using the ex vivo ttRNA-DC-T platform in conjunction with a cytokine cocktail generated potent CD62Lhigh anti-tumor T cells and imposes a novel T cell-based therapeutic with the potential to treat brain tumors and other cancers.
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http://dx.doi.org/10.1007/s00262-013-1464-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3850168PMC
November 2013

B-cell maturation antigen is a promising target for adoptive T-cell therapy of multiple myeloma.

Clin Cancer Res 2013 Apr 23;19(8):2048-60. Epub 2013 Jan 23.

Experimental Transplantation and Immunology Branch; Laboratory of Pathology, National Cancer Institute, Bethesda, Maryland 20892, USA.

Purpose: Multiple myeloma is a usually incurable malignancy of plasma cells. New therapies are urgently needed for multiple myeloma. Adoptive transfer of chimeric antigen receptor (CAR)-expressing T cells is a promising new therapy for hematologic malignancies, but an ideal target antigen for CAR-expressing T-cell therapies for multiple myeloma has not been identified. B-cell maturation antigen (BCMA) is a protein that has been reported to be selectively expressed by B-lineage cells including multiple myeloma cells. Our goal was to determine if BCMA is a suitable target for CAR-expressing T cells.

Experimental Design: We conducted an assessment of BCMA expression in normal human tissues and multiple myeloma cells by flow cytometry, quantitative PCR, and immunohistochemistry. We designed and tested novel anti-BCMA CARs.

Results: BCMA had a restricted RNA expression pattern. Except for expression in plasma cells, BCMA protein was not detected in normal human tissues. BCMA was not detected on primary human CD34(+) hematopoietic cells. We detected uniform BCMA cell-surface expression on primary multiple myeloma cells from five of five patients. We designed the first anti-BCMA CARs to be reported and we transduced T cells with lentiviral vectors encoding these CARs. The CARs gave T cells the ability to specifically recognize BCMA. The anti-BCMA-CAR-transduced T cells exhibited BCMA-specific functions including cytokine production, proliferation, cytotoxicity, and in vivo tumor eradication. Importantly, anti-BCMA-CAR-transduced T cells recognized and killed primary multiple myeloma cells.

Conclusions: BCMA is a suitable target for CAR-expressing T cells, and adoptive transfer of anti-BCMA-CAR-expressing T cells is a promising new strategy for treating multiple myeloma.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-2422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3630268PMC
April 2013

Modulating the differentiation status of ex vivo-cultured anti-tumor T cells using cytokine cocktails.

Cancer Immunol Immunother 2013 Apr 4;62(4):727-36. Epub 2012 Dec 4.

Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Building 10, CRC 3 W-3864, Bethesda, MD, 20892, USA.

The genetic modification of CD8+ T cells using anti-tumor T-cell receptors (TCR) or chimeric antigen receptors is a promising approach for the adoptive cell therapy of patients with cancer. We previously developed a simplified method for the clinical-scale generation of central memory-like (Tcm) CD8+ T cells following transduction with lentivirus encoding anti-tumor TCR and culture in the presence of IL-2. In this study, we compared different cytokines or combinations of IL-2, IL-7, IL-12, IL-15, and IL-21 to expand genetically engineered CD8+ T cells. We demonstrated that specific cytokine combinations IL-12 plus IL-7 or IL-21 for 3 days followed by withdrawal of IL-12 yielded the phenotype of CD62L(high)CD28(high) CD127(high)CD27(high)CCR7(high), which is associated with less-differentiated T cells. Genes associated with stem cells (SOX2, NANOG, OCT4, and LIN28A), were also up-regulated by this cytokine cocktail. Moreover, the use of IL-12 plus IL-7 or IL-21 yielded CD8 T cells showing enhanced persistence in the NOD/SCID/γc-/- mouse model. This defined cytokine combination could also alter highly differentiated TIL from melanoma patients into cells with a less-differentiated phenotype. The methodology that we developed for generating a less-differentiated anti-tumor CD8+ T cells ex vivo may be ideal for the adoptive immunotherapy of cancer.
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http://dx.doi.org/10.1007/s00262-012-1378-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354242PMC
April 2013

Risk score for the prediction of contrast-induced nephropathy in elderly patients undergoing percutaneous coronary intervention.

Angiology 2013 Apr 29;64(3):188-94. Epub 2012 Nov 29.

Department of Cardiology, Tianjin Chest Hospital, Tianjin Medical University, Tianjin, China.

We developed a risk score for contrast-induced nephropathy (CIN) in elderly patients (n = 668) before percutaneous coronary intervention (PCI). Another 277 elderly patients were studied for validation. Based on the odds ratio, risk factors were assigned a weighted integer; the sum of the integers was the risk score. Among the 668 elderly patients, 105 (15.7%) experienced CIN. There were 9 risk factors for CIN (with weighted integer): estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) (4), diabetes (3), left ventricular ejection fraction <45% (3), hypotension (2), age >70 years (2), myocardial infarction (2), emergency PCI (2), anemia (2), and contrast agent volume >200 mL (2). The incidence of CIN was 3.4%, 11.9%, 36.9%, and 69.8% in the low-risk (≤4), moderate risk (5-8), high-risk (9-12), and very-high-risk groups (≥13). The model demonstrated good discriminative power in the validation population (c statistic = 0.79). This score can be used to plan preventative measures.
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http://dx.doi.org/10.1177/0003319712467224DOI Listing
April 2013

A simple and effective method to generate lentiviral vectors for ex vivo gene delivery to mature human peripheral blood lymphocytes.

Hum Gene Ther Methods 2012 Apr 19;23(2):73-83. Epub 2012 Apr 19.

Surgery Branch, National Cancer Institute , National Institutes of Health, Bethesda, MD 20892, USA.

Human ex vivo gene therapy protocols have been used successfully to treat a variety of genetic disorders, infectious diseases, and cancer. Murine oncoretroviruses (specifically, gammaretroviruses) have served as the primary gene delivery vehicles for these trials. However, in some cases, such vectors have been associated with insertional mutagenesis. As a result, alternative vector platforms such as lentiviral vectors (LVVs) are being developed. LVVs may provide advantages compared with gammaretroviral vectors, including the ability to transduce large numbers of nondividing cells, resistance to gene silencing, and a potentially safer integration profile. The aim of this study was to develop a simplified process for the rapid production of clinical-grade LVVs. To that end, we used a self-inactivating bicistronic LVV encoding an MART (melanoma antigen recognized by T cells)-1-reactive T cell receptor containing oPRE, an optimized and truncated version of woodchuck hepatitis virus posttranslational regulatory element (wPRE). Using our simplified clinical production process, 293T cells were transiently transfected in roller bottles. The LVV supernatant was collected, treated with Benzonase, and clarified by modified step filtration. LVV produced in this manner exhibited titers and a biosafety profile similar to those of cGMP (current Good Manufacturing Practices) LVVs previously manufactured at the Indiana University Vector Production Facility in support of a phase I/II clinical trial. We describe a simple, efficient, and low-cost method for the production of clinical-grade LVV for ex vivo gene therapy protocols.
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http://dx.doi.org/10.1089/hgtb.2011.199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847989PMC
April 2012

The shedding of CD62L (L-selectin) regulates the acquisition of lytic activity in human tumor reactive T lymphocytes.

PLoS One 2011 28;6(7):e22560. Epub 2011 Jul 28.

Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.

CD62L/L-selectin is a marker found on naïve T cells and further distinguishes central memory (Tcm, CD62L+) from effector memory (Tem, CD62L-) T cells. The regulation of CD62L plays a pivotal role in controlling the traffic of T lymphocytes to and from peripheral lymph nodes. CD62L is shed from the cell membrane following T cell activation, however, the physiological significance of this event remains to be elucidated. In this study, we utilized in vitro generated anti-tumor antigen T cells and melanoma lines as a model to evaluate the dynamics of CD62L shedding and expression of CD107a as a marker of lytic activity. Upon encounter, with matched tumor lines, antigen reactive T cells rapidly lose CD62L expression and this was associated with the acquisition of CD107a. By CD62L ELISA, we confirmed that this transition was mediated by the shedding of CD62L when T cells encountered specific tumor antigen. The introduction of a shedding resistant mutant of CD62L into the tumor antigen-reactive T cell line JKF6 impaired CD107a acquisition following antigen recognition and this was correlated with decreased lytic activity as measured by (51)Cr release assays. The linkage of the shedding of CD62L from the surface of anti-tumor T cells and acquisition of lytic activity, suggests a new function for CD62L in T cell effector functions and anti-tumor activity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022560PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3145643PMC
December 2011

Irradiation enhances human T-cell function by upregulating CD70 expression on antigen-presenting cells in vitro.

J Immunother 2011 May;34(4):327-35

Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

In addition to the direct killing of tumor cells, radiation therapy can alter the balance of immune cells in vivo due to the differential radiosensitivity of different cell types. The addition of adjuvant radiation therapy before adoptive cell transfer therapy has been shown to enhance antitumor responses in both mouse models and clinical trials. This study examines the effects of in vitro irradiation on the phenotype and function of human antigen-presenting cells. The results indicated that irradiation upregulated CD70 expression on both B cells and mature dendritic cells (DCs). Expression of CD70 on mature DCs was enhanced in a dose-dependent manner, whereas under the same conditions, no significant upregulation of CD80, CD86, or CD40 was observed. The levels of expression of CD70 induced on mature DC by irradiation correlated highly with the ability of those cells to stimulate T-cell proliferation and interferon-γ production. Furthermore, significant reductions in T-cell proliferation and interferon-γ production were seen when CD70 expression on DCs was partially reduced using shRNA, as well as when DCs were incubated with a blocking anti-CD70 antibody. Radiation therapy may therefore enhance T-cell activation in vivo through the CD27 pathway by virtue of its ability to upregulate the expression of CD70 on antigen-presenting cells.
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http://dx.doi.org/10.1097/CJI.0b013e318216983dDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3094909PMC
May 2011

Genetic engineering of murine CD8+ and CD4+ T cells for preclinical adoptive immunotherapy studies.

J Immunother 2011 May;34(4):343-52

Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

T-cell receptor (TCR) gene therapy enables for the rapid creation of antigen-specific T cells from mice of any strain and represents a valuable tool for preclinical immunotherapy studies. Here, we describe the superiority of γ-retroviral vectors compared with lentiviral vectors for transduction of murine T cells and surprisingly illustrate robust gene-transfer into phenotypically naive/memory-stem cell like (TN/TSCM; CD62L(hi)/CD44(low)) and central memory (TCM; CD62L(hi)/CD44(hi)) CD8+ T cells using murine stem cell-based γ-retroviral vectors (MSGV1). We created MSGV1 vectors for a major histocompatibility complex-class I-restricted TCR specific for the melanocyte-differentiation antigen, glycoprotein 100 (MSGV1-pmel-1), and a major histocompatibility complex-class II-restricted TCR specific for tyrosinase-related protein-1 (MSGV1-TRP-1), and found that robust gene expression required codon optimization of TCR sequences for the pmel-1 TCR. To test for functionality, we adoptively transferred TCR-engineered T cells into mice bearing B16 melanomas and observed delayed growth of established tumors with pmel-1 TCR engineered CD8+ T cells and significant tumor regression with TRP-1 TCR transduced CD4 T cells. We simultaneously created lentiviral vectors encoding the pmel-1 TCR, but found that these vectors mediated low TCR expression in murine T cells, but robust gene expression in other murine and human cell lines. These results indicate that preclinical murine models of adoptive immunotherapies are more practical using γ-retroviral rather than lentiviral vectors.
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http://dx.doi.org/10.1097/CJI.0b013e3182187600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3100770PMC
May 2011

In vitro generated anti-tumor T lymphocytes exhibit distinct subsets mimicking in vivo antigen-experienced cells.

Cancer Immunol Immunother 2011 May 9;60(5):739-49. Epub 2011 Feb 9.

Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Bethesda, MD 20892, USA.

The T-lymphocyte pool can be subdivided into naïve (Tn), effector memory (Tem), and central memory (Tcm) T cells. In this study, we characterized in vitro short-term cultured anti-tumor human T lymphocytes generated by lentiviral transduction with an anti-tumor antigen TCR vector. Within 2 weeks of in vitro culture, the cultured T cells showed a Tcm-like phenotype illustrated by a high percentage of CD62L and CD45RO cells. When the cells were sorted into populations that were CD45RO+/CD62L-(Tem), CD45RO+/CD62L+(Tcm), or CD45RO(low)/CD62L+(Tn) and co-cultured with antigen-matched tumor lines, the magnitude of cytokine release from these populations for IFNγ (Tn < Tcm < Tem) and IL-2 (Tn > Tcm > Tem) mimicked the types of immune cell responses observed in vivo. In comparing cell-mediated effector function, Tn were found to be deficient (relative to Tcm and Tem) in the ability to form conjugates with tumor cells and subsequent lytic activity. Moreover, analysis of the gene expression profiles of the in vitro cultured and sorted T-cell populations also demonstrated patterns consistent with their in vivo counterparts. When Tcm and Tem were tested for the ability to survive in vivo, Tcm displayed significantly increased engraftment and persistence in NOD/SCID/γc(-/-) mice. In general, a large percentage of in vitro generated anti-tumor T lymphocytes mimic a Tcm-like phenotype (based on phenotype, effector function, and increased persistence in vivo), which suggests that these Tcm-like cultured T cells may be optimal for adoptive immunotherapy.
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http://dx.doi.org/10.1007/s00262-011-0977-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3080434PMC
May 2011

Improving adoptive T cell therapy by targeting and controlling IL-12 expression to the tumor environment.

Mol Ther 2011 Apr 1;19(4):751-9. Epub 2011 Feb 1.

Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

Interleukin-12 (IL-12) is an important immunostimulatory cytokine, yet its clinical application has been limited by the systemic toxicity associated with its administration. In this work, we developed a strategy to selectively deliver IL-12 to the tumor environment using genetically engineered lymphocytes. However, peripheral blood lymphocytes (PBLs) transduced with a γ-retroviral vector, which constitutively expressed IL-12, failed to expand in culture due to apoptosis. To circumvent this problem, a vector was designed where IL-12 expression was directed by a composite promoter-containing binding motifs for nuclear factor of activated T-cells (NFAT.hIL12.PA2). The NFAT-responsive promoter was activated to drive IL-12 expression upon the recognition of tumor-specific antigen mediated by a T cell receptor (TCR) that was engineered into the same lymphocytes. We tested the efficacy of the inducible IL-12 vector in vivo in a murine melanoma model. Adoptive transfer of pmel-1 T cells genetically engineered with NFAT-murineIL12 (NFAT.mIL12.PA2) significantly enhanced regression of large established B16 melanoma. Notably, this targeted and controlled IL-12 treatment was without toxicity. Taken together, our results suggest that using the NFAT.hIL12.PA2 vector might be a promising approach to enhance adoptive cancer immunotherapy.
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http://dx.doi.org/10.1038/mt.2010.313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3070103PMC
April 2011

Human effector CD8+ T cells derived from naive rather than memory subsets possess superior traits for adoptive immunotherapy.

Blood 2011 Jan 22;117(3):808-14. Epub 2010 Oct 22.

National Cancer Institute, Bethesda, MD, USA.

Cluster of differentiation (CD)8(+) T cells exist as naive, central memory, and effector memory subsets, and any of these populations can be genetically engineered into tumor-reactive effector cells for adoptive immunotherapy. However, the optimal subset from which to derive effector CD8(+) T cells for patient treatments is controversial and understudied. We investigated human CD8(+) T cells and found that naive cells were not only the most abundant subset but also the population most capable of in vitro expansion and T-cell receptor transgene expression. Despite increased expansion, naive-derived cells displayed minimal effector differentiation, a quality associated with greater efficacy after cell infusion. Similarly, the markers of terminal differentiation, killer cell lectin-like receptor G1 and CD57, were expressed at lower levels in cells of naive origin. Finally, naive-derived effector cells expressed higher CD27 and retained longer telomeres, characteristics that suggest greater proliferative potential and that have been linked to greater efficacy in clinical trials. Thus, these data suggest that naive cells resist terminal differentiation, or "exhaustion," maintain high replicative potential, and therefore may be the superior subset for use in adoptive immunotherapy.
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http://dx.doi.org/10.1182/blood-2010-05-286286DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3035075PMC
January 2011

A simplified method for the clinical-scale generation of central memory-like CD8+ T cells after transduction with lentiviral vectors encoding antitumor antigen T-cell receptors.

J Immunother 2010 Jul-Aug;33(6):648-58

Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.

Adoptive transfer of antigen-specific CD8+ T cells can effectively treat patients with metastatic melanoma. Recent efforts have emphasized the in vitro generation of antitumor T cells by transduction of genes encoding antitumor T-cell receptors. At present, lentiviral vector-mediated transduction of CD8+ T cells relies on anti-CD3/CD28 bead stimulation; however, this method fails to efficiently expand CD8+ T cells. Herein we sought to establish a methodology for lentiviral vector transduction using optimal activating agents for efficient gene delivery and robust expansion of CD8+ T cells. To overcome the inability of anti-CD3/CD28 beads to efficiently expand CD8+ T cells, we evaluated alternative activating agents including feeder cells from allogeneic peripheral blood mononuclear cells and plate-bound anti-CD3 antibody. Analyses of gene transfer, cell phenotype, fold expansion, and biologic activities were used to determine the optimal methodology. Plate-bound anti-CD3 provided an ideal activation platform that afforded optimal lentiviral vector-mediated gene transfer efficiency (up to 90%), and coupled with peripheral blood mononuclear cells feeder cells yielded up to 600-fold expansion of CD8+ T cells within 12 days. The T-cell antigen receptor (TCR) engineered CD8+ T cells conferred specific antitumor activity and many displayed a central memory-like phenotype. The methodology described here could be readily applied for engineering CD8+ T cells with antitumor specificity for human adoptive immunotherapy.
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http://dx.doi.org/10.1097/CJI.0b013e3181e311cbDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365020PMC
December 2010