40 results on '"Yamamoto, Tori N."'
Search Results
2. Evaluation of SARS-CoV-2 serology assays reveals a range of test performance
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Whitman, Jeffrey D, Hiatt, Joseph, Mowery, Cody T, Shy, Brian R, Yu, Ruby, Yamamoto, Tori N, Rathore, Ujjwal, Goldgof, Gregory M, Whitty, Caroline, Woo, Jonathan M, Gallman, Antonia E, Miller, Tyler E, Levine, Andrew G, Nguyen, David N, Bapat, Sagar P, Balcerek, Joanna, Bylsma, Sophia A, Lyons, Ana M, Li, Stacy, Wong, Allison Wai-yi, Gillis-Buck, Eva Mae, Steinhart, Zachary B, Lee, Youjin, Apathy, Ryan, Lipke, Mitchell J, Smith, Jennifer Anne, Zheng, Tina, Boothby, Ian C, Isaza, Erin, Chan, Jackie, Acenas, Dante D, Lee, Jinwoo, Macrae, Trisha A, Kyaw, Than S, Wu, David, Ng, Dianna L, Gu, Wei, York, Vanessa A, Eskandarian, Haig Alexander, Callaway, Perri C, Warrier, Lakshmi, Moreno, Mary E, Levan, Justine, Torres, Leonel, Farrington, Lila A, Loudermilk, Rita P, Koshal, Kanishka, Zorn, Kelsey C, Garcia-Beltran, Wilfredo F, Yang, Diane, Astudillo, Michael G, Bernstein, Bradley E, Gelfand, Jeffrey A, Ryan, Edward T, Charles, Richelle C, Iafrate, A John, Lennerz, Jochen K, Miller, Steve, Chiu, Charles Y, Stramer, Susan L, Wilson, Michael R, Manglik, Aashish, Ye, Chun Jimmie, Krogan, Nevan J, Anderson, Mark S, Cyster, Jason G, Ernst, Joel D, Wu, Alan HB, Lynch, Kara L, Bern, Caryn, Hsu, Patrick D, and Marson, Alexander
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Biological Sciences ,Biomedical and Clinical Sciences ,Clinical Sciences ,Biodefense ,Pneumonia & Influenza ,Prevention ,Clinical Research ,Infectious Diseases ,Lung ,Vaccine Related ,Pneumonia ,Emerging Infectious Diseases ,Detection ,screening and diagnosis ,4.1 Discovery and preclinical testing of markers and technologies ,4.2 Evaluation of markers and technologies ,Infection ,Good Health and Well Being ,Adult ,Aged ,Aged ,80 and over ,Antibodies ,Viral ,Betacoronavirus ,Biotechnology ,COVID-19 ,COVID-19 Testing ,Chromatography ,Affinity ,Clinical Laboratory Techniques ,Coronavirus Infections ,Enzyme-Linked Immunosorbent Assay ,Female ,Humans ,Immunoglobulin G ,Immunoglobulin M ,Male ,Middle Aged ,Pandemics ,Pneumonia ,Viral ,Point-of-Care Testing ,Reverse Transcriptase Polymerase Chain Reaction ,SARS-CoV-2 ,Sensitivity and Specificity ,Young Adult - Abstract
Appropriate use and interpretation of serological tests for assessments of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure, infection and potential immunity require accurate data on assay performance. We conducted a head-to-head evaluation of ten point-of-care-style lateral flow assays (LFAs) and two laboratory-based enzyme-linked immunosorbent assays to detect anti-SARS-CoV-2 IgM and IgG antibodies in 5-d time intervals from symptom onset and studied the specificity of each assay in pre-coronavirus disease 2019 specimens. The percent of seropositive individuals increased with time, peaking in the latest time interval tested (>20 d after symptom onset). Test specificity ranged from 84.3% to 100.0% and was predominantly affected by variability in IgM results. LFA specificity could be increased by considering weak bands as negative, but this decreased detection of antibodies (sensitivity) in a subset of SARS-CoV-2 real-time PCR-positive cases. Our results underline the importance of seropositivity threshold determination and reader training for reliable LFA deployment. Although there was no standout serological assay, four tests achieved more than 80% positivity at later time points tested and more than 95% specificity.
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- 2020
3. Test performance evaluation of SARS-CoV-2 serological assays
- Author
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Whitman, Jeffrey D, Hiatt, Joseph, Mowery, Cody T, Shy, Brian R, Yu, Ruby, Yamamoto, Tori N, Rathore, Ujjwal, Goldgof, Gregory M, Whitty, Caroline, Woo, Jonathan M, Gallman, Antonia E, Miller, Tyler E, Levine, Andrew G, Nguyen, David N, Bapat, Sagar P, Balcerek, Joanna, Bylsma, Sophia A, Lyons, Ana M, Li, Stacy, Wong, Allison Wai-yi, Gillis-Buck, Eva Mae, Steinhart, Zachary B, Lee, Youjin, Apathy, Ryan, Lipke, Mitchell J, Smith, Jennifer Anne, Zheng, Tina, Boothby, Ian C, Isaza, Erin, Chan, Jackie, Acenas, Dante D, Lee, Jinwoo, Macrae, Trisha A, Kyaw, Than S, Wu, David, Ng, Dianna L, Gu, Wei, York, Vanessa A, Eskandarian, Haig Alexander, Callaway, Perri C, Warrier, Lakshmi, Moreno, Mary E, Levan, Justine, Torres, Leonel, Farrington, Lila A, Loudermilk, Rita, Koshal, Kanishka, Zorn, Kelsey C, Garcia-Beltran, Wilfredo F, Yang, Diane, Astudillo, Michael G, Bernstein, Bradley E, Gelfand, Jeffrey A, Ryan, Edward T, Charles, Richelle C, Iafrate, A John, Lennerz, Jochen K, Miller, Steve, Chiu, Charles Y, Stramer, Susan L, Wilson, Michael R, Manglik, Aashish, Ye, Chun Jimmie, Krogan, Nevan J, Anderson, Mark S, Cyster, Jason G, Ernst, Joel D, Wu, Alan HB, Lynch, Kara L, Bern, Caryn, Hsu, Patrick D, and Marson, Alexander
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Infectious Diseases ,Vaccine Related ,Clinical Research ,Pneumonia ,Lung ,Pneumonia & Influenza ,Biodefense ,Prevention ,Emerging Infectious Diseases ,Detection ,screening and diagnosis ,4.2 Evaluation of markers and technologies ,Infection ,Good Health and Well Being - Abstract
Background:Serological tests are crucial tools for assessments of SARS-CoV-2 exposure, infection and potential immunity. Their appropriate use and interpretation require accurate assay performance data. Method:We conducted an evaluation of 10 lateral flow assays (LFAs) and two ELISAs to detect anti-SARS-CoV-2 antibodies. The specimen set comprised 128 plasma or serum samples from 79 symptomatic SARS-CoV-2 RT-PCR-positive individuals; 108 pre-COVID-19 negative controls; and 52 recent samples from individuals who underwent respiratory viral testing but were not diagnosed with Coronavirus Disease 2019 (COVID-19). Samples were blinded and LFA results were interpreted by two independent readers, using a standardized intensity scoring system. Results:Among specimens from SARS-CoV-2 RT-PCR-positive individuals, the percent seropositive increased with time interval, peaking at 81.8-100.0% in samples taken >20 days after symptom onset. Test specificity ranged from 84.3-100.0% in pre-COVID-19 specimens. Specificity was higher when weak LFA bands were considered negative, but this decreased sensitivity. IgM detection was more variable than IgG, and detection was highest when IgM and IgG results were combined. Agreement between ELISAs and LFAs ranged from 75.7-94.8%. No consistent cross-reactivity was observed. Conclusion:Our evaluation showed heterogeneous assay performance. Reader training is key to reliable LFA performance, and can be tailored for survey goals. Informed use of serology will require evaluations covering the full spectrum of SARS-CoV-2 infections, from asymptomatic and mild infection to severe disease, and later convalescence. Well-designed studies to elucidate the mechanisms and serological correlates of protective immunity will be crucial to guide rational clinical and public health policies.
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- 2020
4. An engineered IL-2 partial agonist promotes CD8.sup.+ T cell stemness
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Mo, Fei, Yu, Zhiya, Li, Peng, Oh, Jangsuk, Spolski, Rosanne, Zhao, Liang, Glassman, Caleb R., Yamamoto, Tori N., Chen, Yun, Golebiowski, Filip M., Hermans, Dalton, Majri-Morrison, Sonia, Picton, Lora K., Liao, Wei, Ren, Min, Zhuang, Xiaoxun, and Mitra, Suman
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Agonists (Biochemistry) -- Physiological aspects ,T cells -- Physiological aspects ,Stem cells -- Physiological aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients.sup.1. Both the number of transferred T cells and their differentiation state are critical determinants of effective responses.sup.2,3. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells.sup.4,5 and lower therapeutic efficacy.sup.6, whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial.sup.7. Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of CD8.sup.+ T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T treatment sustained the expression of T cell transcription factor 1 (TCF-1) and promoted mitochondrial fitness, thereby facilitating the maintenance of a stem-cell-like state. Moreover, TCR-transgenic and chimeric antigen receptor-modified CD8.sup.+ T cells that were expanded with H9T showed robust anti-tumour activity in vivo in mouse models of melanoma and acute lymphoblastic leukaemia. Thus, engineering cytokine variants with distinctive properties is a promising strategy for creating new molecules with translational potential. H9T, an engineered IL-2 partial agonist, promotes the expansion of T cells while maintaining a stem-cell-like state, leading to improved efficacy of adoptive cell therapy in mouse models of melanoma and acute lymphoblastic leukaemia., Author(s): Fei Mo [sup.1] , Zhiya Yu [sup.2] , Peng Li [sup.1] , Jangsuk Oh [sup.1] , Rosanne Spolski [sup.1] , Liang Zhao [sup.3] , Caleb R. Glassman [sup.4] , [...]
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- 2021
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5. Developing neoantigen-targeted T cell-based treatments for solid tumors
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Yamamoto, Tori N., Kishton, Rigel J., and Restifo, Nicholas P.
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T cells -- Research ,Immune response -- Health aspects ,Immunotherapy -- Usage ,Cancer -- Research -- Care and treatment ,Biological sciences ,Health - Abstract
Stimulating an immune response against cancer through adoptive transfer of tumor-targeting lymphocytes has shown great promise in hematological malignancies, but clinical efficacy against many common solid epithelial cancers remains low. Targeting 'neoantigens'--the somatic mutations expressed only by tumor cells--might enable tumor destruction without causing undue damage to vital healthy tissues. Major challenges to targeting neoantigens with T cells include heterogeneity and variability in antigen processing and presentation of targets by tumors, and an incomplete understanding of which T cell qualities are essential for clinically effective therapies. Finally, the prospect of targeting somatic tumor mutations to promote T cell destruction of cancer must contend with the biology that not all tumor-expressed 'neoepitopes' actually generate neoantigens that can be functionally recognized and provoke an effective immune response. In this Review, we discuss the promise, progress and challenges for improving neoantigen-targeted T cell-based immunotherapies for cancer. This Review examines the promise, progress and challenges for developing personal T cell-based immunotherapies for cancer., Author(s): Tori N. Yamamoto [sup.1] [sup.2] [sup.3] , Rigel J. Kishton [sup.1] [sup.2] , Nicholas P. Restifo [sup.1] [sup.2] [sup.4] Author Affiliations: (1) Center for Cancer Research, National Cancer Institute [...]
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- 2019
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6. T cells genetically engineered to overcome death signaling enhance adoptive cancer immunotherapy
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Yamamoto, Tori N., Lee, Ping-Hsien, Vodnala, Suman K., Gurusamy, Devikala, Kishton, Rigel J., Yu, Zhiya, Eidizadeh, Arash, Eil, Robert, Fioravanti, Jessica, Gattinoni, Luca, Kochenderfer, James N., Fry, Terry J., Aksoy, Bulent Arman, Hammerbacher, Jeffrey E., Cruz, Anthony C., Siegel, Richard M., Restifo, Nicholas P., and Klebanoff, Christopher A.
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Acute lymphocytic leukemia -- Care and treatment ,Genetic engineering -- Research ,Immunotherapy -- Usage ,T cells -- Research ,Cancer treatment ,Medical law ,Cancer ,Antigens ,Apoptosis ,Tumors ,Genetically modified organisms ,Genes ,Autoimmunity ,Clinical trials ,Health care industry - Abstract
Across clinical trials, T cell expansion and persistence following adoptive cell transfer (ACT) have correlated with superior patient outcomes. Herein, we undertook a pan-cancer analysis to identify actionable ligand-receptor pairs capable of compromising T cell durability following ACT. We discovered that FASLG, the gene encoding the apoptosis-inducing ligand FasL, is overexpressed within the majority of human tumor microenvironments (TMEs). Further, we uncovered that Fas, the receptor for FasL, is highly expressed on patient-derived T cells used for clinical ACT. We hypothesized that a cognate Fas-FasL interaction within the TME might limit both T cell persistence and antitumor efficacy. We discovered that genetic engineering of Fas variants impaired in the ability to bind FADD functioned as dominant negative receptors (DNRs), preventing FasL-induced apoptosis in Fas-competent T cells. T cells coengineered with a Fas DNR and either a T cell receptor or chimeric antigen receptor exhibited enhanced persistence following ACT, resulting in superior antitumor efficacy against established solid and hematologic cancers. Despite increased longevity, Fas DNR-engineered T cells did not undergo aberrant expansion or mediate autoimmunity. Thus, T cell-intrinsic disruption of Fas signaling through genetic engineering represents a potentially universal strategy to enhance ACT efficacy across a broad range of human malignancies., Introduction Adoptive cell transfer (ACT) using genetically engineered T cells has entered the standard of care for patients with refractory B cell malignancies, including pediatric acute lymphoblastic leukemia (ALL) (1) [...]
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- 2019
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7. Cancer genes disfavoring T cell immunity identified via integrated systems approach
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Kishton, Rigel J., primary, Patel, Shashank J., additional, Decker, Amy E., additional, Vodnala, Suman K., additional, Cam, Maggie, additional, Yamamoto, Tori N., additional, Patel, Yogin, additional, Sukumar, Madhusudhanan, additional, Yu, Zhiya, additional, Ji, Michelle, additional, Henning, Amanda N., additional, Gurusamy, Devikala, additional, Palmer, Douglas C., additional, Stefanescu, Roxana A., additional, Girvin, Andrew T., additional, Lo, Winifred, additional, Pasetto, Anna, additional, Malekzadeh, Parisa, additional, Deniger, Drew C., additional, Wood, Kris C., additional, Sanjana, Neville E., additional, and Restifo, Nicholas P., additional
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- 2022
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8. Memory T cell-driven differentiation of naive cells impairs adoptive immunotherapy
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Klebanoff, Christopher A., Scott, Christopher D., Leonardi, Anthony J., Yamamoto, Tori N., Cruz, Anthony C., Ouyang, Claudia, Ramaswamy, Madhu, Roychoudhuri, Rahul, Ji, Yun, Eil, Robert L., Sukumar, Madhusudhanan, Crompton, Joseph G., Palmer, Douglas C., Borman, Zachary A., Clever, David, Thomas, Stacy K., Patel, Shashankkumar, Yu, Zhiya, Muranski, Pawel, Wang, Ena, Marincola, Francesco M., Gros, Alena, Gattinoni, Luca, Rosenberg, Steven A., Siegel, Richard M., and Restifo, Nicholas P.
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Immunotherapy -- Health aspects -- Research ,Cell differentiation -- Health aspects -- Research -- Genetic aspects ,Cells -- Health aspects -- Research ,Health care industry - Abstract
Adoptive cell transfer (ACT) of purified naive, stem cell memory, and central memory T cell subsets results in superior persistence and antitumor immunity compared with ACT of populations containing more-differentiated effector memory and effector T cells. Despite a clear advantage of the less-differentiated populations, the majority of ACT trials utilize unfractionated T cell subsets. Here, we have challenged the notion that the mere presence of less- differentiated T cells in starting populations used to generate therapeutic T cells is sufficient to convey their desirable attributes. Using both mouse and human cells, we identified a T cell-T cell interaction whereby antigen- experienced subsets directly promote the phenotypic, functional, and metabolic differentiation of naive T cells. This process led to the loss of less- differentiated T cell subsets and resulted in impaired cellular persistence and tumor regression in mouse models following ACT. The T memory-induced conversion of naive T cells was mediated by a nonapoptotic Fas signal, resulting in Akt- driven cellular differentiation. Thus, induction of Fas signaling enhanced T cell differentiation and impaired antitumor immunity, while Fas signaling blockade preserved the antitumor efficacy of naive cells within mixed populations. These findings reveal that T cell subsets can synchronize their differentiation state in a process similar to quorum sensing in unicellular organisms and suggest that disruption of this quorum-like behavior among T cells has potential to enhance T cell-based immunotherapies., Introduction Adoptive cell transfer (ACT), the ex vivo expansion and reinfusion of antigen-specific (Ag-specific) T cells, represents a potentially curative treatment for patients with advanced cancer (1-4) and viral-reactivation syndromes [...]
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- 2016
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9. Ionic immune suppression within the tumour microenvironment limits T cell effector function
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Eil, Robert, Vodnala, Suman K., Clever, David, Klebanoff, Christopher A., Sukumar, Madhusudhanan, Pan, Jenny H., Palmer, Douglas C., Gros, Alena, Yamamoto, Tori N., Patel, Shashank J., Guittard, Geoffrey C., Yu, Zhiya, Carbonaro, Valentina, Okkenhaug, Klaus, Schrump, David S., Linehan, W. Marston, Roychoudhuri, Rahul, and Restifo, Nicholas P.
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- 2016
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10. Cytomegalovirus-specific T cells are primed early after cord blood transplant but fail to control virus in vivo
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McGoldrick, Suzanne M., Bleakley, Marie E., Guerrero, Abraham, Turtle, Cameron J., Yamamoto, Tori N., Pereira, Shalini E., Delaney, Colleen S., and Riddell, Stanley R.
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- 2013
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11. Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells
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Terakura, Seitaro, Yamamoto, Tori N., Gardner, Rebecca A., Turtle, Cameron J., Jensen, Michael C., and Riddell, Stanley R.
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- 2012
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12. The B-cell tumor–associated antigen ROR1 can be targeted with T cells modified to express a ROR1-specific chimeric antigen receptor
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Hudecek, Michael, Schmitt, Thomas M., Baskar, Sivasubramanian, Lupo-Stanghellini, Maria Teresa, Nishida, Tetsuya, Yamamoto, Tori N., Bleakley, Marie, Turtle, Cameron J., Chang, Wen-Chung, Greisman, Harvey A., Wood, Brent, Maloney, David G., Jensen, Michael C., Rader, Christoph, and Riddell, Stanley R.
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- 2010
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13. IMMUNOTHERAPY: Treatment of aggressive lymphomas with anti-CD19 CAR T cells
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Klebanoff, Christopher A., Yamamoto, Tori N., and Restifo, Nicholas P.
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- 2014
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14. Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine
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Jing, Lichen, Haas, Jurgen, Chong, Tiana M., Bruckner, Joseph J., Dann, Greg C., Dong, Lichun, Marshak, Joshua O., McClurkan, Christopher L., Yamamoto, Tori N., Bailer, Susanne M., Laing, Kerry J., Wald, Anna, Verjans, Georges M.G.M., and Koelle, David M.
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T cells -- Health aspects -- Genetic aspects -- Research ,Herpes simplex -- Health aspects -- Causes of -- Genetic aspects -- Prevention -- Research ,Herpesvirus vaccines -- Health aspects -- Research ,Health care industry - Abstract
Herpes simplex virus type 1 (HSV-1) not only causes painful recurrent oral-labial infections, it can also cause permanent brain damage and blindness. There is currently no HSV-1 vaccine. An effective vaccine must stimu-late coordinated T cell responses, but the large size of the genome and the low frequency of HSV-1-specific T cells have hampered the search for the most effective T cell antigens for inclusion in a candidate vaccine. We have now developed what we believe to be novel methods to efficiently generate a genome-wide map of the responsiveness of HSV-1-specific T cells, and demonstrate the applicability of these methods to a second complex microbe, vaccinia virus. We used cross-presentation and CD137 activation-based FACS to enrich for polyclonal CD[8..sup.+] T effector T cells. The HSV-1 proteome was prepared in a flexible format for analyzing both CD[8.sup.+] and CD[4.sup.+] T cells from study participants. Scans with participant-specific panels of artificial APCs identi-fied an oligospecific response in each individual. Parallel CD137-based CD[4.sup.+] T cell research showed discrete oligospecific recognition of HSV-1 antigens. Unexpectedly, the two HSV-1 proteins not previously considered as vaccine candidates elicited both CD[8.sup.+] and CD[4.sup.+] T cell responses in most HSV-1-infected individuals. In this era of microbial genomics, our methods - also demonstrated in principle for vaccinia virus for both CD[8.sup.+] and CD[4.sup.+] T cells - should be broadly applicable to the selection of T cell antigens for inclusion in candidate vaccines for many pathogens., Introduction Herpes simplex virus type 1 (HSV-1) infects 60% of the US population and has a significant cumulative health care burden in addition to causing painful recurrent oral-labial infections. For [...]
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- 2012
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15. Identification of MAGE-C1 (CT-7) epitopes for T-cell therapy of multiple myeloma
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Anderson, Jr., Larry D., Cook, Danielle R., Yamamoto, Tori N., Berger, Carolina, Maloney, David G., and Riddell, Stanley R.
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- 2011
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16. Identification of essential genes for cancer immunotherapy
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Patel, Shashank J., Sanjana, Neville E., Kishton, Rigel J., Eidizadeh, Arash, Vodnala, Suman K., Cam, Maggie, Gartner, Jared J., Jia, Li, Steinberg, Seth M., Yamamoto, Tori N., Merchant, Anand S., Mehta, Gautam U., Chichura, Anna, Shalem, Ophir, Tran, Eric, Eil, Robert, Sukumar, Madhusudhanan, Guijarro, Eva Perez, Day, Chi-Ping, Robbins, Paul, Feldman, Steve, Merlino, Glenn, Zhang, Feng, and Restifo, Nicholas P.
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Cancer treatment -- Genetic aspects ,DNA sequencing -- Methods ,Immunotherapy -- Genetic aspects ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies. Here we perturbed genes in human melanoma cells to mimic loss-of-function mutations involved in resistance to these therapies, by using a genome-scale CRISPRCas9 library that consisted of around 123,000 single-guide RNAs, and profiled genes whose loss in tumour cells impaired the effector function of CD8[sup.+] T cells. The genes that were most enriched in the screen have key roles in antigen presentation and interferon- signalling, and correlate with cytolytic activity in patient tumours from The Cancer Genome Atlas. Among the genes validated using different cancer cell lines and antigens, we identified multiple loss-of-function mutations in APLNR, encoding the apelin receptor, in patient tumours that were refractory to immunotherapy. We show that APLNR interacts with JAK1, modulating interferon- responses in tumours, and that its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in mouse models. Our results link the loss of essential genes for the effector function of CD8[sup.+] T cells with the resistance or non-responsiveness of cancer to immunotherapies., Author(s): Shashank J. Patel (corresponding author) [1, 2]; Neville E. Sanjana (corresponding author) [3, 4]; Rigel J. Kishton [1]; Arash Eidizadeh [1]; Suman K. Vodnala [1]; Maggie Cam [1]; Jared [...]
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- 2017
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17. Multi-phenotype CRISPR-Cas9 Screen Identifies p38 Kinase as a Target for Adoptive Immunotherapies
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Gurusamy, Devikala, primary, Henning, Amanda N., additional, Yamamoto, Tori N., additional, Yu, Zhiya, additional, Zacharakis, Nikolaos, additional, Krishna, Sri, additional, Kishton, Rigel J., additional, Vodnala, Suman K., additional, Eidizadeh, Arash, additional, Jia, Li, additional, Kariya, Christine M., additional, Black, Mary A., additional, Eil, Robert, additional, Palmer, Douglas C., additional, Pan, Jenny H., additional, Sukumar, Madhusudhanan, additional, Patel, Shashank J., additional, and Restifo, Nicholas P., additional
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- 2020
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18. An engineered IL-2 partial agonist promotes CD8+ T cell stemness and anti-tumor efficacy
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Mo, Fei, primary, Yu, Zhiya, additional, Li, Peng, additional, Oh, Jangsuk, additional, Spolski, Rosanne, additional, Zhao, Liang, additional, Glassman, Caleb R., additional, Yamamoto, Tori N., additional, Chen, Yun, additional, Golebiowski, Filip M., additional, Hermans, Dalton, additional, Marjri, Sonia S., additional, Picton, Lora, additional, Liao, Wei, additional, Ren, Min, additional, Zhuang, Xiaoxuan, additional, Mitra, Suman, additional, Lin, Jian-Xin, additional, Gattinoni, Luca, additional, Powell, Jonathan D., additional, Restifo, Nicholas P., additional, Garcia, K. Christopher, additional, and Leonard, Warren J, additional
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- 2020
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19. Test performance evaluation of SARS-CoV-2 serological assays
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Whitman, Jeffrey D., primary, Hiatt, Joseph, additional, Mowery, Cody T., additional, Shy, Brian R., additional, Yu, Ruby, additional, Yamamoto, Tori N., additional, Rathore, Ujjwal, additional, Goldgof, Gregory M., additional, Whitty, Caroline, additional, Woo, Jonathan M., additional, Gallman, Antonia E., additional, Miller, Tyler E., additional, Levine, Andrew G., additional, Nguyen, David N., additional, Bapat, Sagar P., additional, Balcerek, Joanna, additional, Bylsma, Sophia A., additional, Lyons, Ana M., additional, Li, Stacy, additional, Wong, Allison Wai-yi, additional, Gillis-Buck, Eva Mae, additional, Steinhart, Zachary B., additional, Lee, Youjin, additional, Apathy, Ryan, additional, Lipke, Mitchell J., additional, Smith, Jennifer Anne, additional, Zheng, Tina, additional, Boothby, Ian C., additional, Isaza, Erin, additional, Chan, Jackie, additional, Acenas, Dante D., additional, Lee, Jinwoo, additional, Macrae, Trisha A., additional, Kyaw, Than S., additional, Wu, David, additional, Ng, Dianna L., additional, Gu, Wei, additional, York, Vanessa A., additional, Eskandarian, Haig Alexander, additional, Callaway, Perri C., additional, Warrier, Lakshmi, additional, Moreno, Mary E., additional, Levan, Justine, additional, Torres, Leonel, additional, Farrington, Lila A., additional, Loudermilk, Rita, additional, Koshal, Kanishka, additional, Zorn, Kelsey C., additional, Garcia-Beltran, Wilfredo F., additional, Yang, Diane, additional, Astudillo, Michael G., additional, Bernstein, Bradley E., additional, Gelfand, Jeffrey A., additional, Ryan, Edward T., additional, Charles, Richelle C., additional, Iafrate, A. John, additional, Lennerz, Jochen K., additional, Miller, Steve, additional, Chiu, Charles Y., additional, Stramer, Susan L., additional, Wilson, Michael R., additional, Manglik, Aashish, additional, Ye, Chun Jimmie, additional, Krogan, Nevan J., additional, Anderson, Mark S., additional, Cyster, Jason G., additional, Ernst, Joel D., additional, Wu, Alan H. B., additional, Lynch, Kara L., additional, Bern, Caryn, additional, Hsu, Patrick D., additional, and Marson, Alexander, additional
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- 2020
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20. Genome-wide profiling of druggable active tumor defense mechanisms to enhance cancer immunotherapy
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Kishton, Rigel J., primary, Patel, Shashank J., additional, Vodnala, Suman K., additional, Decker, Amy E., additional, Patel, Yogin, additional, Sukumar, Madhusudhanan, additional, Yamamoto, Tori N., additional, Yu, Zhiya, additional, Ji, Michelle, additional, Henning, Amanda N., additional, Gurusamy, Devikala, additional, Palmer, Douglas C., additional, Lo, Winifred, additional, Pasetto, Anna, additional, Malekzadeh, Parisa, additional, Deniger, Drew C., additional, Wood, Kris C., additional, Sanjana, Neville E., additional, and Restifo, Nicholas P., additional
- Published
- 2019
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21. An engineered IL-2 partial agonist promotes CD8+ T cell stemness.
- Author
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Mo, Fei, Yu, Zhiya, Li, Peng, Oh, Jangsuk, Spolski, Rosanne, Zhao, Liang, Glassman, Caleb R., Yamamoto, Tori N., Chen, Yun, Golebiowski, Filip M., Hermans, Dalton, Majri-Morrison, Sonia, Picton, Lora K., Liao, Wei, Ren, Min, Zhuang, Xiaoxuan, Mitra, Suman, Lin, Jian-Xin, Gattinoni, Luca, and Powell, Jonathan D.
- Abstract
Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients1. Both the number of transferred T cells and their differentiation state are critical determinants of effective responses2,3. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells4,5 and lower therapeutic efficacy6, whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial7. Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of CD8
+ T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T treatment sustained the expression of T cell transcription factor 1 (TCF-1) and promoted mitochondrial fitness, thereby facilitating the maintenance of a stem-cell-like state. Moreover, TCR-transgenic and chimeric antigen receptor-modified CD8+ T cells that were expanded with H9T showed robust anti-tumour activity in vivo in mouse models of melanoma and acute lymphoblastic leukaemia. Thus, engineering cytokine variants with distinctive properties is a promising strategy for creating new molecules with translational potential.H9T, an engineered IL-2 partial agonist, promotes the expansion of T cells while maintaining a stem-cell-like state, leading to improved efficacy of adoptive cell therapy in mouse models of melanoma and acute lymphoblastic leukaemia. [ABSTRACT FROM AUTHOR]- Published
- 2021
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22. Host conditioning with IL-1β improves the antitumor function of adoptively transferred T cells
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Lee, Ping-Hsien, primary, Yamamoto, Tori N., additional, Gurusamy, Devikala, additional, Sukumar, Madhusudhanan, additional, Yu, Zhiya, additional, Hu-Li, Jane, additional, Kawabe, Takeshi, additional, Gangaplara, Arunakumar, additional, Kishton, Rigel J., additional, Henning, Amanda N., additional, Vodnala, Suman K., additional, Germain, Ronald N., additional, Paul, William E., additional, and Restifo, Nicholas P., additional
- Published
- 2019
- Full Text
- View/download PDF
23. Mg2+ regulation of kinase signaling and immune function
- Author
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Kanellopoulou, Chryssa, primary, George, Alex B., additional, Masutani, Evan, additional, Cannons, Jennifer L., additional, Ravell, Juan C., additional, Yamamoto, Tori N., additional, Smelkinson, Margery G., additional, Jiang, Ping Du, additional, Matsuda-Lennikov, Mami, additional, Reilley, Julie, additional, Handon, Robin, additional, Lee, Ping-Hsien, additional, Miller, J. Richard, additional, Restifo, Nicholas P., additional, Zheng, Lixin, additional, Schwartzberg, Pamela L., additional, Young, Matthew, additional, and Lenardo, Michael J., additional
- Published
- 2019
- Full Text
- View/download PDF
24. T cell stemness and dysfunction in tumors are triggered by a common mechanism
- Author
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Vodnala, Suman Kumar, primary, Eil, Robert, additional, Kishton, Rigel J., additional, Sukumar, Madhusudhanan, additional, Yamamoto, Tori N., additional, Ha, Ngoc-Han, additional, Lee, Ping-Hsien, additional, Shin, MinHwa, additional, Patel, Shashank J., additional, Yu, Zhiya, additional, Palmer, Douglas C., additional, Kruhlak, Michael J., additional, Liu, Xiaojing, additional, Locasale, Jason W., additional, Huang, Jing, additional, Roychoudhuri, Rahul, additional, Finkel, Toren, additional, Klebanoff, Christopher A., additional, and Restifo, Nicholas P., additional
- Published
- 2019
- Full Text
- View/download PDF
25. Identification of essential genes for cancer immunotherapy
- Author
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Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research at MIT, Zhang, Feng, Patel, Shashank J., Sanjana, Neville E., Kishton, Rigel J., Eidizadeh, Arash, Vodnala, Suman K., Cam, Maggie, Gartner, Jared J., Jia, Li, Steinberg, Seth M., Yamamoto, Tori N., Merchant, Anand S., Mehta, Gautam U., Chichura, Anna, Shalem, Ophir, Tran, Eric, Eil, Robert, Sukumar, Madhusudhanan, Guijarro, Eva Perez, Day, Chi-Ping, Robbins, Paul, Feldman, Steve, Merlino, Glenn, Restifo, Nicholas P., Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences, McGovern Institute for Brain Research at MIT, Zhang, Feng, Patel, Shashank J., Sanjana, Neville E., Kishton, Rigel J., Eidizadeh, Arash, Vodnala, Suman K., Cam, Maggie, Gartner, Jared J., Jia, Li, Steinberg, Seth M., Yamamoto, Tori N., Merchant, Anand S., Mehta, Gautam U., Chichura, Anna, Shalem, Ophir, Tran, Eric, Eil, Robert, Sukumar, Madhusudhanan, Guijarro, Eva Perez, Day, Chi-Ping, Robbins, Paul, Feldman, Steve, Merlino, Glenn, and Restifo, Nicholas P.
- Abstract
Somatic gene mutations can alter the vulnerability of cancer cells to T-cell-based immunotherapies. Here we perturbed genes in human melanoma cells to mimic loss-of-function mutations involved in resistance to these therapies, by using a genome-scale CRISPR–Cas9 library that consisted of around 123,000 single-guide RNAs, and profiled genes whose loss in tumour cells impaired the effector function of CD8+ T cells. The genes that were most enriched in the screen have key roles in antigen presentation and interferon-γ signalling, and correlate with cytolytic activity in patient tumours from The Cancer Genome Atlas. Among the genes validated using different cancer cell lines and antigens, we identified multiple loss-of-function mutations in APLNR, encoding the apelin receptor, in patient tumours that were refractory to immunotherapy. We show that APLNR interacts with JAK1, modulating interferon-γ responses in tumours, and that its functional loss reduces the efficacy of adoptive cell transfer and checkpoint blockade immunotherapies in mouse models. Our results link the loss of essential genes for the effector function of CD8⁺ T cells with the resistance or non-responsiveness of cancer to immunotherapies.
- Published
- 2018
26. Inhibition of AKT signaling uncouples T cell differentiation from expansion for receptor-engineered adoptive immunotherapy
- Author
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Klebanoff, Christopher A., primary, Crompton, Joseph G., additional, Leonardi, Anthony J., additional, Yamamoto, Tori N., additional, Chandran, Smita S., additional, Eil, Robert L., additional, Sukumar, Madhusudhanan, additional, Vodnala, Suman K., additional, Hu, Jinhui, additional, Ji, Yun, additional, Clever, David, additional, Black, Mary A., additional, Gurusamy, Devikala, additional, Kruhlak, Michael J., additional, Jin, Ping, additional, Stroncek, David F., additional, Gattinoni, Luca, additional, Feldman, Steven A., additional, and Restifo, Nicholas P., additional
- Published
- 2017
- Full Text
- View/download PDF
27. An engineered IL-2 partial agonist promotes CD8+T cell stemness
- Author
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Mo, Fei, Yu, Zhiya, Li, Peng, Oh, Jangsuk, Spolski, Rosanne, Zhao, Liang, Glassman, Caleb R., Yamamoto, Tori N., Chen, Yun, Golebiowski, Filip M., Hermans, Dalton, Majri-Morrison, Sonia, Picton, Lora K., Liao, Wei, Ren, Min, Zhuang, Xiaoxuan, Mitra, Suman, Lin, Jian-Xin, Gattinoni, Luca, Powell, Jonathan D., Restifo, Nicholas P., Garcia, K. Christopher, and Leonard, Warren J.
- Abstract
Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients1. Both the number of transferred T cells and their differentiation state are critical determinants of effective responses2,3. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells4,5and lower therapeutic efficacy6, whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial7. Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of CD8+T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T treatment sustained the expression of T cell transcription factor 1 (TCF-1) and promoted mitochondrial fitness, thereby facilitating the maintenance of a stem-cell-like state. Moreover, TCR-transgenic and chimeric antigen receptor-modified CD8+T cells that were expanded with H9T showed robust anti-tumour activity in vivo in mouse models of melanoma and acute lymphoblastic leukaemia. Thus, engineering cytokine variants with distinctive properties is a promising strategy for creating new molecules with translational potential.
- Published
- 2021
- Full Text
- View/download PDF
28. Fas/CD95 prevents autoimmunity independently of lipid raft localization and efficient apoptosis induction
- Author
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Cruz, Anthony C., primary, Ramaswamy, Madhu, additional, Ouyang, Claudia, additional, Klebanoff, Christopher A., additional, Sengupta, Prabuddha, additional, Yamamoto, Tori N., additional, Meylan, Françoise, additional, Thomas, Stacy K., additional, Richoz, Nathan, additional, Eil, Robert, additional, Price, Susan, additional, Casellas, Rafael, additional, Rao, V. Koneti, additional, Lippincott-Schwartz, Jennifer, additional, Restifo, Nicholas P., additional, and Siegel, Richard M., additional
- Published
- 2016
- Full Text
- View/download PDF
29. Identifying Fas/CD95 non-apoptotic signaling pathways associated with T cell differentiation
- Author
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Thomas, Stacy K, primary, Ouyang, Claudia, additional, Cruz, Anthony C, additional, Klebanoff, Christopher A, additional, Yamamoto, Tori N, additional, Chan, Francis K, additional, Mocarski, Edward S, additional, Roback, Linda, additional, Restifo, Nicholas P, additional, and Siegel, Richard M, additional
- Published
- 2016
- Full Text
- View/download PDF
30. Memory T cell–driven differentiation of naive cells impairs adoptive immunotherapy
- Author
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Klebanoff, Christopher A., primary, Scott, Christopher D., additional, Leonardi, Anthony J., additional, Yamamoto, Tori N., additional, Cruz, Anthony C., additional, Ouyang, Claudia, additional, Ramaswamy, Madhu, additional, Roychoudhuri, Rahul, additional, Ji, Yun, additional, Eil, Robert L., additional, Sukumar, Madhusudhanan, additional, Crompton, Joseph G., additional, Palmer, Douglas C., additional, Borman, Zachary A., additional, Clever, David, additional, Thomas, Stacy K., additional, Patel, Shashankkumar, additional, Yu, Zhiya, additional, Muranski, Pawel, additional, Liu, Hui, additional, Wang, Ena, additional, Marincola, Francesco M., additional, Gros, Alena, additional, Gattinoni, Luca, additional, Rosenberg, Steven A., additional, Siegel, Richard M., additional, and Restifo, Nicholas P., additional
- Published
- 2015
- Full Text
- View/download PDF
31. Treatment of aggressive lymphomas with anti-CD19 CAR T cells
- Author
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Klebanoff, Christopher A., primary, Yamamoto, Tori N., additional, and Restifo, Nicholas P., additional
- Published
- 2014
- Full Text
- View/download PDF
32. Novel Serial Positive Enrichment Technology Enables Clinical Multiparameter Cell Sorting
- Author
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Stemberger, Christian, primary, Dreher, Stefan, additional, Tschulik, Claudia, additional, Piossek, Christine, additional, Bet, Jeannette, additional, Yamamoto, Tori N., additional, Schiemann, Matthias, additional, Neuenhahn, Michael, additional, Martin, Klaus, additional, Schlapschy, Martin, additional, Skerra, Arne, additional, Schmidt, Thomas, additional, Edinger, Matthias, additional, Riddell, Stanley R., additional, Germeroth, Lothar, additional, and Busch, Dirk H., additional
- Published
- 2012
- Full Text
- View/download PDF
33. Generation and Signaling Function of CD19 Chimeric Antigen Receptor Modified CD8+ T Cells Derived From Virus-Specific Central Memory Cells for Adoptive Therapy After Allogeneic Hematopoietic Stem Cell Transplant
- Author
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Terakura, Seitaro, primary, Yamamoto, Tori N., additional, Gardner, Rebecca A., additional, Turtle, Cameron J., additional, Jensen, Michael C., additional, and Riddell, Stanley R., additional
- Published
- 2011
- Full Text
- View/download PDF
34. Cytomegalovirus-Specific T Cells Are Elicited Early After Umbilical Cord Blood Transplant but Fail to Expand In Vivo and Control Virus Replication
- Author
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McGoldrick, Suzanne M., primary, Guerrero, Abraham, additional, Yamamoto, Tori N., additional, Delaney, Colleen, additional, and Riddell, Stanley R., additional
- Published
- 2011
- Full Text
- View/download PDF
35. Generation of CD19-chimeric antigen receptor modified CD8+ T cells derived from virus-specific central memory T cells.
- Author
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Terakura, Seitaro, Yamamoto, Tori N., Gardner, Rebecca A., Turtle, Cameron J., Jensen, Michael C., and Riddell, Stanley R.
- Subjects
- *
T cells , *ANTIGENS , *CELL receptors , *LEUKEMIA , *THERAPEUTICS - Abstract
The adoptive transfer of donor T cells that have been genetically modified to recognize leukemia could prevent or treat leukemia relapse after allogeneic HSCT (allo-HSCT). However, adoptive therapy after allo-HSCT should be performed with T cells that have a defined endogenous TCR specificity to avoid GVHD. Ideally, T cells selected for genetic modification would also have the capacity to persist in vivo to ensure leukemia eradication. Here, we provide a strategy for deriving virus-specific T cells from CD45RA-CD62L+CD8+ central memory T (TCM) cells purified from donor blood with clinical grade reagents, and redirect their specificity to the B-cell lineage marker CD19 through lentiviral transfer of a gene encoding a CD19-chimeric Ag receptor (CAR). Virus-specific TCM were selectively transduced by exposure to the CD19 CAR lentivirus after peptide stimulation, and bi-specific cells were subsequently enriched to high purity using MHC streptamers. Activation of bi-specific T cells through the CAR or the virus-specific TCR elicited phosphorylation of downstream signaling molecules with similar kinetics, and induced comparable cytokine secretion, proliferation, and lytic activity. These studies identify a strategy for tumor-specific therapy with CAR-modified T cells after allo-HSCT, and for comparative studies of CAR and TCR signaling. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
36. Generation of CD19-chimeric antigen receptor modified CD8+T cells derived from virus-specific central memory T cells
- Author
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Terakura, Seitaro, Yamamoto, Tori N., Gardner, Rebecca A., Turtle, Cameron J., Jensen, Michael C., and Riddell, Stanley R.
- Abstract
The adoptive transfer of donor T cells that have been genetically modified to recognize leukemia could prevent or treat leukemia relapse after allogeneic HSCT (allo-HSCT). However, adoptive therapy after allo-HSCT should be performed with T cells that have a defined endogenous TCR specificity to avoid GVHD. Ideally, T cells selected for genetic modification would also have the capacity to persist in vivo to ensure leukemia eradication. Here, we provide a strategy for deriving virus-specific T cells from CD45RA−CD62L+CD8+central memory T (TCM) cells purified from donor blood with clinical grade reagents, and redirect their specificity to the B-cell lineage marker CD19 through lentiviral transfer of a gene encoding a CD19-chimeric Ag receptor (CAR). Virus-specific TCMwere selectively transduced by exposure to the CD19 CAR lentivirus after peptide stimulation, and bi-specific cells were subsequently enriched to high purity using MHC streptamers. Activation of bi-specific T cells through the CAR or the virus-specific TCR elicited phosphorylation of downstream signaling molecules with similar kinetics, and induced comparable cytokine secretion, proliferation, and lytic activity. These studies identify a strategy for tumor-specific therapy with CAR-modified T cells after allo-HSCT, and for comparative studies of CAR and TCR signaling.
- Published
- 2012
- Full Text
- View/download PDF
37. Ionic immune suppression within the tumour microenvironment limits T cell effector function
- Author
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Eil, Robert, Vodnala, Suman K, Clever, David, Klebanoff, Christopher A, Sukumar, Madhusudhanan, Pan, Jenny H, Palmer, Douglas C, Gros, Alena, Yamamoto, Tori N, Patel, Shashank J, Guittard, Geoffrey C, Yu, Zhiya, Carbonaro, Valentina, Okkenhaug, Klaus, Schrump, David S, Linehan, W Marston, Roychoudhuri, Rahul, and Restifo, Nicholas P
- Subjects
Male ,Kv1.3 Potassium Channel ,T-Lymphocytes ,TOR Serine-Threonine Kinases ,Receptors, Antigen, T-Cell ,Cations, Monovalent ,Survival Analysis ,3. Good health ,Membrane Potentials ,Mice ,Necrosis ,Immune Tolerance ,Potassium ,Tumor Microenvironment ,Animals ,Humans ,Tumor Escape ,Immunotherapy ,Melanoma ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Tumours progress despite being infiltrated by tumour-specific effector T cells. Tumours contain areas of cellular necrosis, which are associated with poor survival in a variety of cancers. Here, we show that necrosis releases intracellular potassium ions into the extracellular fluid of mouse and human tumours, causing profound suppression of T cell effector function. Elevation of the extracellular potassium concentration ([K+]e) impairs T cell receptor (TCR)-driven Akt-mTOR phosphorylation and effector programmes. Potassium-mediated suppression of Akt-mTOR signalling and T cell function is dependent upon the activity of the serine/threonine phosphatase PP2A. Although the suppressive effect mediated by elevated [K+]e is independent of changes in plasma membrane potential (Vm), it requires an increase in intracellular potassium ([K+]i). Accordingly, augmenting potassium efflux in tumour-specific T cells by overexpressing the potassium channel Kv1.3 lowers [K+]i and improves effector functions in vitro and in vivo and enhances tumour clearance and survival in melanoma-bearing mice. These results uncover an ionic checkpoint that blocks T cell function in tumours and identify potential new strategies for cancer immunotherapy.
38. Generation and Signaling Function of CD19 Chimeric Antigen Receptor Modified CD8+T Cells Derived From Virus-Specific Central Memory Cells for Adoptive Therapy After Allogeneic Hematopoietic Stem Cell Transplant
- Author
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Terakura, Seitaro, Yamamoto, Tori N., Gardner, Rebecca A., Turtle, Cameron J., Jensen, Michael C., and Riddell, Stanley R.
- Abstract
Abstract 2978
- Published
- 2011
- Full Text
- View/download PDF
39. Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine.
- Author
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Lichen Jing, Haas, Jürgen, Chong, Tiana M., Bruckner, Joseph J., Dann, Greg C., Lichun Dong, Marshak, Joshua O., McClurkan, Christopher L., Yamamoto, Tori N., Bailer, Susanne M., Laing, Kerry J., Wald, Anna, Verjans, Georges M. G. M., and Koelle, David M.
- Subjects
- *
HERPES simplex virus , *VIRAL vaccines , *T cells , *ANTIGENS , *MICROBIAL genomes , *PATHOGENIC microorganisms - Abstract
Herpes simplex virus type 1 (HSV-1) not only causes painful recurrent oral-labial infections, it can also cause permanent brain damage and blindness. There is currently no HSV-1 vaccine. An effective vaccine must stimulate coordinated T cell responses, but the large size of the genome and the low frequency of HSV-1-specific T cells have hampered the search for the most effective T cell antigens for inclusion in a candidate vaccine. We have now developed what we believe to be novel methods to efficiently generate a genome-wide map of the responsiveness of HSV-1-specific T cells, and demonstrate the applicability of these methods to a second complex microbe, vaccinia virus. We used cross-presentation and CD137 activation-based FACS to enrich for polyclonal CD8+ T effector T cells. The HSV-1 proteome was prepared in a flexible format for analyzing both CD8+ and CD4+ T cells from study participants. Scans with participant-specific panels of artificial APCs identified an oligospecific response in each individual. Parallel CD137-based CD4+ T cell research showed discrete oligospecific recognition of HSV-1 antigens. Unexpectedly, the two HSV-1 proteins not previously considered as vaccine candidates elicited both CD8+ and CD4+ T cell responses in most HSV-1-infected individuals. In this era of microbial genomics, our methods - also demonstrated in principle for vaccinia virus for both CD8+ and CD4+ T cells - should be broadly applicable to the selection of T cell antigens for inclusion in candidate vaccines for many pathogens. [ABSTRACT FROM AUTHOR]
- Published
- 2012
- Full Text
- View/download PDF
40. Mg 2+ regulation of kinase signaling and immune function.
- Author
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Kanellopoulou C, George AB, Masutani E, Cannons JL, Ravell JC, Yamamoto TN, Smelkinson MG, Jiang PD, Matsuda-Lennikov M, Reilley J, Handon R, Lee PH, Miller JR, Restifo NP, Zheng L, Schwartzberg PL, Young M, and Lenardo MJ
- Subjects
- Animals, Biocatalysis drug effects, Blood Donors, CD4-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes drug effects, Calcium metabolism, Catalytic Domain drug effects, Cells, Cultured, Humans, Lymphocyte Activation drug effects, Magnesium blood, Magnesium chemistry, Male, Mice, Mice, Inbred C57BL, Orthomyxoviridae Infections blood, Orthomyxoviridae Infections virology, Osmolar Concentration, Protein Serine-Threonine Kinases metabolism, Protein-Tyrosine Kinases chemistry, Receptors, Antigen, T-Cell metabolism, Signal Transduction drug effects, Signal Transduction immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Influenza A Virus, H1N1 Subtype immunology, Magnesium pharmacology, Orthomyxoviridae Infections immunology, Protein-Tyrosine Kinases metabolism
- Abstract
Mg
2+ is required at micromolar concentrations as a cofactor for ATP, enzymatic reactions, and other biological processes. We show that decreased extracellular Mg2+ reduced intracellular Mg2+ levels and impaired the Ca2+ flux, activation marker up-regulation, and proliferation after T cell receptor (TCR) stimulation. Reduced Mg2+ specifically impairs TCR signal transduction by IL-2-inducible T cell kinase (ITK) due to a requirement for a regulatory Mg2+ in the catalytic pocket of ITK. We also show that altered catalytic efficiency by millimolar changes in free basal Mg2+ is an unrecognized but conserved feature of other serine/threonine and tyrosine kinases, suggesting a Mg2+ regulatory paradigm of kinase function. Finally, a reduced serum Mg2+ concentration in mice causes an impaired CD8+ T cell response to influenza A virus infection, reduces T cell activation, and exacerbates morbidity. Thus, Mg2+ directly regulates the active site of specific kinases during T cell responses, and maintaining a high serum Mg2+ concentration is important for antiviral immunity in otherwise healthy animals., (This is a work of the U.S. Government and is not subject to copyright protection in the United States. Foreign copyrights may apply.)- Published
- 2019
- Full Text
- View/download PDF
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