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Engineered T Cell Therapies from a Drug Development Viewpoint

Engineering 2019年第1期5卷 140-149页

作者： Fang Chen joseph A. Fraietta Carl H. j.ne Zhongwei Xu j. joseph melenhorst Simon F. Lacey Department of Pathology and Laboratory Medicine University of Pennsylvania Philadelphia PA 19104 USA Center for Cellular Immunotherapies University of Pennsylvania Philadelphia PA 19104 USA Parker Institute for Cancer Immunotherapy University of Pennsylvania Philadelphia PA 19104 USA Abramson Cancer Center University of Pennsylvania Philadelphia PA 19104 USA Department of Immunology Peking University Beijing 100871 China

Cancer is one of the leading causes of death worldwide. Recent advances in cellular therapy have demonstrated that this platform has the potential to give patients with certain cancers a second chance at life. Unlike chemical compounds and proteins, cells are living, self-replicating drugs that can be engineered to possess exquisite specificity. For example, T cells can be genetically modified to express chimeric antigen receptors (CARs), endowing them with the capacity to recognize and kill tumor cells and form a memory pool that is ready to strike back against persisting malignant cells. Anti-CD19 chimeric antigen receptor T cells (CART19s) have demonstrated a remarkable degree of clinical efficacy for certain malignancies. The process of developing CART19 essentially follows the conventional “one gene, one drug, one disease” paradigm derived from Paul Ehrlich’s “magic bullet” concept. With maj.r players within the pharmaceutical industry j.ining forces to commercialize this new category of “living drugs,” it is useful to use CART19 as an example to examine the similarities and differences in its development, compared with that of a conventional drug. In this way, we can assimilate existing knowledge and identify the most effective approach for advancing similar strategies. This article reviews the use of biomarker-based assays to guide the optimization of CAR constructs, preclinical studies, and the evaluation of clinical efficacy;adverse effects (AEs);and CART19 cellular kinetics. Advanced technologies and computational tools that enable the discovery of optimal targets, novel CAR binding domains, and biomarkers predicting clinical response and AEs are also discussed. We believe that the success of CART19 will lead to the development of other engineered T cell therapies in the same manner that the discovery of arsphenamine initiated the era of synthetic pharmaceuticals.

关键词： Engineered T cell therapies Chimeric antigen receptor Drug development process Biomarkers CD19-specific chimeric antigen receptor Anti-CD19 chimeric antigen receptor T cells

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CAR T-cell immunotherapy: a powerful weapon for fighting hematological B-cell malignancies

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Frontiers of Medicine 2021年第6期15卷 783-804页

作者： j.an-Qing Mi j.e Xu j.anfeng Zhou Weili Zhao Zhu Chen j.joseph melenhorst Saij.an Chen State Key Laboratory of Medical Genomics Shanghai Institute of HaematologyNational Research Centre for Translational MedicineRuijin Hospital Affiliated to Shanghai Jiao Tong University School of MedicineShanghai200025China Department of Pathology&Laboratory Medicine University of PennsylvaniaPhiladelphiaPA19104USA Immunotherapy Research Centre for Hematologic Diseases of Hubei Province Department of HaematologyTongji HospitalTongji Medical CollegeHuazhong University of Science and TechnologyWuhan430030China

The current standard of care in hematological malignancies has brought considerable clinical benefits to ***,important bottlenecks still limit optimal achievements following a current medical *** genetic complexity of the diseases and the heterogeneity of tumor clones cause difficulty in ensuring long-term efficacy of conventional treatments for most hematological ***,new treatment strategies are necessary to improve clinical *** antigen receptor T-cell(CAR T)immunotherapy opens a new path for targeted therapy of hematological *** this review,through a representative case study,we summarize the current experience of CAR T-cell therapy,the management of common side effects,the causative mechanisms of therapy resistance,and new strategies to improve the efficacy of CAR T-cell therapy.

关键词： CAR T cells hematological malignancies review

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The model of cytokine release syndrome in CAR T-cell treatment for B-cell non-Hodgkin lymphoma

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Signal Transduction and Targeted Therapy 2020年第1期5卷 1295-1303页

作者： j.anshu Wei Yang Liu Chunmeng Wang Yaj.ng Zhang Chuan Tong Guanghai Dai Wei Wang j.hn E.j.Rasko j.joseph melenhorst Wenbin Qian Aibin Liang Weidong Han Department of Bio-therapeutic the First Medical CenterChinese PLA General Hospital100853 BeijingChina Department of Oncology the first Medical CenterChinese PLA General Hospital100853 BeijingChina State Key Laboratory of Biotherapy and Cancer Center West China HospitalSichuan UniversityChengdu 610041China Collaborative Innovation Center for Biotherapy Chengdu 610041China Department of Cell and Molecular Therapies Royal Prince Alfred HospitalSydneyNSW 2006Australia Gene and Stem Cell Therapy Program Centenary InstituteUniversity of SydneySydneyNSW 2006Australia Central Clinical School Faculty of Medicine and HealthThe University of SydneyCamperdownNSW 2050Australia Department of Pathology and Laboratory Medicine Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPA 19104-515USA Department of Hematology The Second Affiliated HospitalCollege of MedicineZhejiang UniversityHangzhou 310009China Department of Hematology Shanghai Tongji HospitalTongji University School of MedicineShanghai 200065China State Key Laboratory of Kidney Diseases National Clinical Research Center for Kidney Diseases100853 BeijingChina

Chimeric antigen receptor T(CAR T)cell therapy has demonstrated efficacy in the treatment of haematologic ***,the accompanying adverse events,the most common of which is cytokine release syndrome(CRS),substantially limit its wide *** to its unique physiological characteristics,CRS in CAR T-cell treatment for B-cell non-Hodgkin lymphoma(BNHL)may exhibit some special *** existing guidelines had greatly promoted the recognition and management of CRS,many recommendations are not fully applicable to ***,it is imperative to identify responses that are specific to CRS observed following CAR T treatment for *** on underlying biological processes and known pathophysiological mechanisms,we tentatively propose a new model to illustrate the occurrence and evolution of CAR T-cell-therapy-related CRS in *** this model,tumour burden and bone marrow suppression are considered determinants of *** phenomena after CAR T-cell infusion(such as local inflammatory response)are further *** proposed model will help us better understand the basic biology of CRS and recognize and manage it more rationally.

关键词： cytokine lymphoma treatment

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Compost Input Effect on Dryland Wheat and Forage Yields and Soil Quality

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Pedosphere 2018年第3期28卷 451-462页

作者： Francisco j. CALDERON Merle F. VIGIL joseph BENj.MIN United States Department of Agriculture-Agricultural Research Service (USDA-ARS) Central Great Plains Research Station Akron80720 CO( USA)

Organic agricultural systems rely on organic amendments to achieve crop fertility requirements, and weed control must be achieved without synthetic herbicides. Our obj.ctive was to determine the crop yield and soil quality as affected by a transition from grass to dryland organic agriculture in the Central Great Plains of North America. This study evaluated three beef feedlot compost(BFC)treatments in 2010–2015 following biennial application rates: 0(control), 22.9, and 108.7 t ha^(-1) on two dryland organic cropping systems: a wheat(Triticum aestivum)-fallow(WF) rotation harvested for grain and a triticale(Triticosecale)/pea(Pisum sativum)-fallow(T/P-F) rotation harvested for forage. The triticale + pea biomass responded positively to the 108.7-t ha^(-1) BFC treatment,but not the 22.9-t ha^(-1) BFC treatment. The wheat biomass was not affected by BFC addition, but biomass N content *** feedlot compost input did not increase wheat grain yields, but had a positive effect on wheat grain Zn content. Soil total C and N contents increased with the rate of 108.7 t ha^(-1) BFC after three applications, but not with 22.9 t ha^(-1) BFC. Soil enzyme activities associated with N and C cycling responded positively to the 108.7-t ha^(-1) BFC treatment. Saturated salts were high in the soil receiving 108.7 t ha^(-1) of BFC, but did not affect crop yields. These results showed that BFC was effective in enhancing forage yields, wheat grain quality, and soil C and N, as well as specific microbial enzymes important for nutrient cycling. However, the large rates of BFC necessary to elicit these positive responses did not increase grain yields, and resulted in an excessive buildup of soil P.

关键词： organic agriculture soil C soil enzyme activity soil N pea triticale

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Cyanobacterial photo-driven mixotrophic metabolism and its advantages for biosynthesis

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Frontiers of Chemical Science and Engineering 2015年第3期9卷 308-316页

作者： Ni Wan Mary Abernathy joseph Kuo-Hsiang Tang Yinj.e j. Tang Le You Department of Energy Environmental and Chemical Engineering Washington University St. Louis MO 63130 USA Biodesign Institute Arizona State University Tempe AZ 85281 USA

Cyanobacterium offers a promising chassis for phototrophic production of renewable chemicals. Although engineered cyanobacteria can achieve similar product carbon yields as heterotrophic microbial hosts, their production rate and titer under photoautotrophic conditions are 10 to 100 folds lower than those in fast growing E. colt. Cyanobacterial factories face three indomitable bottlenecks. First, photosynthesis has limited ATP and NADPH generation rates. Second, CO2 fixation by ribulose-l,5-bisphosphate carboxylase/oxygenase （RuBisCO） has poor efficiency. Third, CO2 mass transfer and light supply are deficient within large photobioreac- tors. On the other hand, cyanobacteria may employ organic substrates to promote phototrophic cell growth, Nz fixation, and metabolite synthesis. The photo-fermenta- tions show enhanced photosynthesis, while CO2 loss from organic substrate degradation can be reused by the Calvin cycle. In addition, the plasticity of cyanobacterial path- ways （e.g., oxidative pentose phosphate pathway and the TCA cycle） has been recently revealed to facilitate the catabolism. The use of cyanobacteria as ＂green E. colt＂ could be a promising route to develop robust photobiorefineries.

关键词： CO2 mass transfer N2 fixation photosystem RuBisCO the TCA cycle

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Chinese Secret Societies and Popular Religions Revisited： An Introduction

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Frontiers of History in China 2016年第4期11卷 503-509页

作者： Robert j. Antony joseph Tse-Hei Lee Canton's Thirteen Hongs Research Center Guangzhou University Guangzhou 510006 China Department of History and Confucius Institute Pace University New York NY 10038 USA

It has been over forty years since j.an Chesneaux published his edited volume Popular Movements and Secret Societies in China, and some twenty years since David Ownby and Mary Somers Heidhues published their edited volume Secret Societies Reconsidered On popular religions, both Daniel Overmyer＇s FoItc Buddhist Religion and Susan Naquin＇s Millenarian Rebellion in China were also published almost forty years ago.1 Although there have been a number of important studies published both inside and outside of China on secret societies and popular religions since the 1990s, in recent years there has been a surge in new research, much of it still unpublished, on this important subj.ct in Chinese history.

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CT103A, a forward step in multiple myeloma immunotherapies

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Blood Science 2021年第2期3卷 59-61页

作者： j.e Xu j.joseph melenhorst Center for Cellular Immunotherapies Perelman School of Medicine at the University of PennsylvaniaPhiladelphiaPA 19104USA Department of Hematology Shanghai Institute of HematologyRuijin Hospital affiliated to Shanghai Jiao Tong University School of MedicineShanghaiPR China

Even with the most potent,modern therapies,multiple myeloma(MM)remains a largely incurable *** reprogramming of a patient’s T-lymphocytes with a cancerassociated antigen-specific chimeric antigen receptor(CAR)has improved the outcome of patients with this debilitating disease.B cell maturation antigen(BCMA),a marker almost exclusively expressing by plasma cells,^(1) is the most attractive target for designing CAR-T cells against MM.

关键词： myeloma therapies attractive

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Age-dependent slowing of enteric axonal transport in insulin-resistant mice

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World j.urnal of Gastroenterology 2013年第4期19卷 482-491页

作者： Kathy j.LePard joseph Cellini Department of Physiology Chicago College of Osteopathic MedicineMidwestern UniversityDowners GroveIL 60515United States

AIM:To investigate retrograde tracer transport by gastric enteric neurons in insulin resistant mice with low or high glycosylated hemoglobin(Hb).METHODS:Under anesthesia,the retrograde tracer fluorogold was superficially inj.cted into the fundus or antrum using a microsyringe in KK Cg-Ay/j.mice prior to onset of type 2 diabetes mellitus(T2DM;4 wk of age),at onset of T2DM(8 wk of age),and after 8,16,or 24 wk of untreated T2DM and in age-matched KK/HIj.*** days later,mice were sacrificed by CO 2 narcosis followed by *** were removed and *** from fundus,corpus and antrum were excised and mounted on a glass ***-labeled neurons were viewed using a microscope and manually *** were expressed as the number of neurons in short and long descending and ascending pathways and in local fundus and antrum pathways,and the number of neurons in all regions labeled after inj.ction of tracer into either the fundus or the ***:By 8 wk of age,body weights of KKAy mice(n=12,34±1 g) were heavier than KK mice(n=17,29±1 g;F(4,120)=4.414,P=0.002] and glycosylated Hb was higher [KK:(n=7),4.97%±0.04%;KKAy:(n=6),6.57%±0.47%;F(1,26)=24.748,P<0.001].The number of tracer labeled enteric neurons was similar in KK and KKAy mice of all ages in the short descending pathway [F(1,57)=2.374,P=0.129],long descending pathway [F(1,57)=0.922,P=0.341],local fundus pathway [F(1,53)=2.464,P=0.122],local antrum pathway [F(1,57)=0.728,P=0.397],and short ascending pathway [F(1,53)=2.940,P=0.092].In the long ascending pathway,fewer tracer-labeled neurons were present in KKAy as compared to KK mice [KK:(n=34),302±17;KKAy:(n=29),230±15;F(1,53)=8.136,P=0.006].The number of tracer-labeled neurons was decreased in all mice by 16 wk as compared to 8 wk of age in the short descending pathway [8 wk:(n=15),305±26;16 wk:(n=13),210±30;F(4,57)=9.336,P<0.001],local antrum pathway [8 wk:(n=15),349±20;16 wk:(n=13),220±33;F(4,57)=8.920,P<0.001],short ascending pathway [

关键词： Autonomic neuropathy Retrograde transport KKAy mice Fluorogold Type 2 diabetes mellitus

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Sodium modification of zirconia catalysts for ethanol coupling to 1-butanol

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j.urnal of Energy Chemistry 2013年第1期22卷 58-64页

作者： joseph T. Kozlowski Robert j. Davis Department of Chemical Engineering University of Virginia

The influences of adding sodium to zirconia on the acid-base properties of the surface and on the catalytic conversion of ethanol and acetone were investigated. The rates of ethanol dehydration, dehydrogenation and coupling were evaluated in a fixed-bed flow reactor operating at temperatures from 613 to 673 K. The rate of acetone condensation was evaluated in the same reactor operating at 473-573 K. Addition of 1.0 wt% Na to ZrO2 decreased the rate of ethanol dehydration by more than an order of magnitude, which was consistent with a neutralization of acid sites evaluated by ammonia adsorption microcalorimetry. Addition of 1.0 wt% Na to ZrO2 also increased the base site density quantified by carbon dioxide adsorption microcalorimetry and the rate of acetone condensation. Although the rate of ethanol coupling was not increased by the addition of Na, the overall selectivity of ethanol to butanol was improved over the 1.0 wt% Na/ZrO2 sample because of the significant inhibition of ethanol dehydration.

关键词： Guerbet reaction alcohol condensation zirconia microcalorimetry acetone condensation

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Superior growth performance in broiler chicks fed chelated compared to inorganic zinc in presence of elevated dietary copper

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j.urnal of Animal Science and Biotechnology 2016年第4期7卷 561-569页

作者： j.nmei Zhao Robert B. Shirley j.lia j. Dibner Karen j. Wedekind Frances Yan Paula Fisher Thomas R. Hampton joseph L. Evans Mercedes Vazquez-Anon research and development novus international20 Research Park DriveSaint CharlesMO 63304USA current affiliation:poultry technical services adisseo usaAlpharettaGA 30022USA

Background： The goal of this study was to compare the antagonism of elevated dietary Cu （250 mg/kg） from CuS04 on three different Zn sources （ZnS04. H20; [Zn bis（-2-hydroxy-4-（methylthio）butanoic acid）], Zn（HMTBa）2 a chelated Zn methionine hydroxy analogue; and Zn-Methionine）, as measured using multiple indices of animal performance in ROSS 308 broilers. Methods： Three experiments were conducted in broiler chicks fed a semi-purified diet. All birds were fed a Zn-deficient diet （8.5 mg/kg diet） for 1 wk, and then provided with the experimental diets for 2 wks. Results： Experiment 1 was a 2 x 2 factorial design with two levels of Cu （8 vs. 250 mg/kg diet from CuSO4） and two Zn sources at 30 mg/kg [ZnSO4. H20 vs. Zn（HMTBa）2]. Elevated Cu impaired growth performance only in birds fed ZnSO4. Compared to ZnSO4. H20, Zn（HMTBa）2 improved feed intake （12 %; P 〈 0.001） and weight gain （12 %, P 〈 0.001） and the benefits were more pronounced in the presence of 250 mg/kg diet Cu. Experiment 2 was a dose titration of ZnSO4- H20 and Zn（HMTBa）2 at 30, 4,5, 60, and 75 mg/kg diet in the presence of 250 mg/kg CuSO4. Feed：gain was decreased and tibia Zn was increased with increasing Zn levels from 30 to 75 mg/kg. Birds fed Zn（HMTBa）2 consumed more food and gained more weight compared to birds fed ZnSO4, especially at lower supplementation levels （30 and 45 mg/kg; interaction P 〈 0,05）. Experiment 3 compared two organic Zn sources （Zn（HMTBa）2 vs. Zn-Methionine） at 30 mg/kg with or without 250 mg/kg CuSO4. No interactions were observed between Zn sources and Cu levels on performance or tissue mineral concentrations. High dietary Cu decreased weight gain （P 〈 0.01）. Tibia Cu and liver Cu were significantly increased with 250 mg/kg dietary Cu supplementation （P 〈 0.01）. No difference was observed between the two Zn sources. Conclusions： Dietary 250 mg/kg Cu significantly impaired feed intake and weight gain in birds fed ZnSO4. H20, but had less impact in birds fed Zn（HMTBa）2. No difference

关键词： Antagonism Broilers Chelates Growth MineraLs Organic Performance

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