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Article ; Online: Tailoring T

Verma, Anil / Hawes, Chase E / Elizaldi, Sonny R / Smith, Justin C / Rajasundaram, Dhivyaa / Pedersen, Gabriel Kristian / Shen, Xiaoying / Williams, LaTonya D / Tomaras, Georgia D / Kozlowski, Pamela A / Amara, Rama R / Iyer, Smita S

eLife

2024 Volume 12

Abstract: CD4 T follicular helper cells (T ...

Abstract	CD4 T follicular helper cells (T
MeSH term(s)	Animals ; Macaca mulatta ; AIDS Vaccines ; HIV-1 ; Chemokine CXCL10 ; HIV Antibodies ; DNA
Chemical Substances	AIDS Vaccines ; Chemokine CXCL10 ; HIV Antibodies ; DNA (9007-49-2)
Language	English
Publishing date	2024-02-22
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.89395
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Article ; Online: Lung tumor-infiltrating T

Dykema, Arbor G / Zhang, Jiajia / Cheung, Laurene S / Connor, Sydney / Zhang, Boyang / Zeng, Zhen / Cherry, Christopher M / Li, Taibo / Caushi, Justina X / Nishimoto, Marni / Munoz, Andrew J / Ji, Zhicheng / Hou, Wenpin / Zhan, Wentao / Singh, Dipika / Zhang, Tianbei / Rashid, Rufiaat / Mitchell-Flack, Marisa / Bom, Sadhana /

Science immunology

2023 Volume 8, Issue 87, Page(s) eadg1487

Abstract: Regulatory T cells (T ...

Abstract	Regulatory T cells (T
MeSH term(s)	Humans ; Animals ; Mice ; Lung Neoplasms/genetics ; Carcinoma, Non-Small-Cell Lung ; Granzymes ; Signal Transduction ; Single-Cell Analysis
Chemical Substances	Granzymes (EC 3.4.21.-)
Language	English
Publishing date	2023-09-15
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ISSN	2470-9468
ISSN (online)	2470-9468
DOI	10.1126/sciimmunol.adg1487
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Article ; Online: T

Reilly, Emma C / Lambert Emo, Kris / Buckley, Patrick M / Reilly, Nicholas S / Smith, Ian / Chaves, Francisco A / Yang, Hongmei / Oakes, Patrick W / Topham, David J

Proceedings of the National Academy of Sciences of the United States of America

2020 Volume 117, Issue 22, Page(s) 12306–12314

Abstract: Tissue-resident memory CD8 T (T ...

Abstract	Tissue-resident memory CD8 T (T
MeSH term(s)	Animals ; Antigens, CD/genetics ; Antigens, CD/immunology ; CD8-Positive T-Lymphocytes/cytology ; CD8-Positive T-Lymphocytes/immunology ; Cell Adhesion ; Cell Movement ; Humans ; Immunologic Memory ; Influenza A Virus, H3N2 Subtype/genetics ; Influenza A Virus, H3N2 Subtype/physiology ; Influenza, Human/genetics ; Influenza, Human/immunology ; Influenza, Human/physiopathology ; Influenza, Human/virology ; Integrin alpha Chains/genetics ; Integrin alpha Chains/immunology ; Integrin alpha1/genetics ; Integrin alpha1/metabolism ; Mice, Inbred C57BL
Chemical Substances	Antigens, CD ; Integrin alpha Chains ; Integrin alpha1 ; alpha E integrins
Language	English
Publishing date	2020-05-21
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1915681117
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Article ; Online: Single-cell analysis implicates T

McCluskey, Daniel / Benzian-Olsson, Natashia / Mahil, Satveer K / Hassi, Niina Karoliina / Wohnhaas, Christian T / Burden, A David / Griffiths, Christopher E M / Ingram, John R / Levell, Nick J / Parslew, Richard / Pink, Andrew E / Reynolds, Nick J / Warren, Richard B / Visvanathan, Sudha / Baum, Patrick / Barker, Jonathan N / Smith, Catherine H / Capon, Francesca

The Journal of allergy and clinical immunology

2022 Volume 150, Issue 4, Page(s) 882–893

Abstract: ... RNA-Seq of patient skin detected an unexpected signature of T-cell activation, with a significant ... overexpression of several T: Conclusions: PPP is associated with complex T-cell activation patterns and ... may explain why biologic drugs that target individual T helper cell populations have shown limited therapeutic ...

Abstract	Background: Palmoplantar pustulosis (PPP) is a severe inflammatory skin disorder characterized by eruptions of painful, neutrophil-filled pustules on the palms and soles. Although PPP has a profound effect on quality of life, it remains poorly understood and notoriously difficult to treat. Objective: We sought to investigate the immune pathways that underlie the pathogenesis of PPP. Methods: We applied bulk and single-cell RNA sequencing (RNA-Seq) methods to the analysis of skin biopsy samples and peripheral blood mononuclear cells. We validated our results by flow cytometry and immune fluorescence microscopy RESULTS: Bulk RNA-Seq of patient skin detected an unexpected signature of T-cell activation, with a significant overexpression of several T Conclusions: PPP is associated with complex T-cell activation patterns and may explain why biologic drugs that target individual T helper cell populations have shown limited therapeutic efficacy.
MeSH term(s)	Biological Products ; Cell Plasticity ; Chronic Disease ; Humans ; Leukocytes, Mononuclear/pathology ; Psoriasis ; Quality of Life ; Single-Cell Analysis ; Skin Diseases, Vesiculobullous
Chemical Substances	Biological Products
Language	English
Publishing date	2022-05-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	121011-7
ISSN	1097-6825 ; 1085-8725 ; 0091-6749
ISSN (online)	1097-6825 ; 1085-8725
ISSN	0091-6749
DOI	10.1016/j.jaci.2022.04.027
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Article ; Online: Antitumor efficacy and safety of unedited autologous CD5.CAR T cells in relapsed/refractory mature T-cell lymphomas.

Blood

2023 Volume 143, Issue 13, Page(s) 1231–1241

Abstract: Abstract: Despite newer targeted therapies, patients with primary refractory or relapsed (r/r) T ... cell lymphoma have a poor prognosis. The development of chimeric antigen receptor (CAR) T-cell ... platforms to treat T-cell malignancies often requires additional gene modifications to overcome fratricide ...

Abstract	Abstract: Despite newer targeted therapies, patients with primary refractory or relapsed (r/r) T-cell lymphoma have a poor prognosis. The development of chimeric antigen receptor (CAR) T-cell platforms to treat T-cell malignancies often requires additional gene modifications to overcome fratricide because of shared T-cell antigens on normal and malignant T cells. We developed a CD5-directed CAR that produces minimal fratricide by downmodulating CD5 protein levels in transduced T cells while retaining strong cytotoxicity against CD5+ malignant cells. In our first-in-human phase 1 study (NCT0308190), second-generation autologous CD5.CAR T cells were manufactured from patients with r/r T-cell malignancies. Here, we report safety and efficacy data from a cohort of patients with mature T-cell lymphoma (TCL). Among the 17 patients with TCL enrolled, CD5 CAR T cells were successfully manufactured for 13 out of 14 attempted lines (93%) and administered to 9 (69%) patients. The overall response rate (complete remission or partial response) was 44%, with complete responses observed in 2 patients. The most common grade 3 or higher adverse events were cytopenias. No grade 3 or higher cytokine release syndrome or neurologic events occurred. Two patients died during the immediate toxicity evaluation period due to rapidly progressive disease. These results demonstrated that CD5.CAR T cells are safe and can induce clinical responses in patients with r/r CD5-expressing TCLs without eliminating endogenous T cells or increasing infectious complications. More patients and longer follow-up are needed for validation. This trial was registered at www.clinicaltrials.gov as #NCT0308190.
MeSH term(s)	Humans ; Immunotherapy, Adoptive/adverse effects ; Immunotherapy, Adoptive/methods ; Neoplasm Recurrence, Local/drug therapy ; T-Lymphocytes ; Chronic Disease ; Lymphoma, T-Cell/drug therapy ; Antigens, CD19
Chemical Substances	Antigens, CD19
Language	English
Publishing date	2023-12-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2023022204
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Article ; Online: Analysis of Butyrophilin-Mediated Activation of γδ T Cells from Human Spleen.

Wang, Chunyan / Lai, Anne Y / Baiu, Dana C / Smith, Kelsey A / Odorico, Jon S / Wilson, Keith / Schreiber, Taylor / de Silva, Suresh / Gumperz, Jenny E

Journal of immunology (Baltimore, Md. : 1950)

2023 Volume 212, Issue 2, Page(s) 284–294

Abstract: There is considerable interest in therapeutically engaging human γδ T cells. However, due ... to the unique TCRs of human γδ T cells, studies from animal models have provided limited directly applicable ... insights, and human γδ T cells from key immunological tissues remain poorly characterized. In this study ...

Abstract	There is considerable interest in therapeutically engaging human γδ T cells. However, due to the unique TCRs of human γδ T cells, studies from animal models have provided limited directly applicable insights, and human γδ T cells from key immunological tissues remain poorly characterized. In this study, we investigated γδ T cells from human spleen tissue. Compared to blood, where Vδ2+Vγ9+ T cells are the dominant subset, splenic γδ T cells included a variety of TCR types, with Vδ1+ T cells typically being the most frequent. Intracellular cytokine staining revealed that IFN-γ was produced by a substantial fraction of splenic γδ T cells, IL-17A by a small fraction, and IL-4 was minimal. Primary splenic γδ T cells frequently expressed NKG2D (NK group 2 member D) and CD16, whereas expression of DNAM-1 (DNAX accessory molecule 1), CD28, PD-1, TIGIT, and CD94 varied according to subset, and there was generally little expression of natural cytotoxicity receptors, TIM-3, LAG-3, or killer Ig-like receptors. In vitro expansion was associated with marked changes in expression of these activating and inhibitory receptors. Analysis of functional responses of spleen-derived Vδ2+Vγ9+, Vδ1+Vγ9+, and Vδ1+Vγ9- T cell lines to recombinant butyrophilin BTN2A1 and BTN3A1 demonstrated that both Vδ2+Vγ9+ and Vδ1+Vγ9+ T cells were capable of responding to the extracellular domain of BTN2A1, whereas the addition of BTN3A1 only markedly enhanced the responses of Vδ2+Vγ9+ T cells. Conversely, Vδ1+Vγ9+ T cells appeared more responsive than Vδ2+Vγ9+ T cells to TCR-independent NKG2D stimulation. Thus, despite shared recognition of BTN2A1, differential effects of BTN3A1 and coreceptors may segregate target cell responses of Vδ2+Vγ9+ and Vδ1+Vγ9+ T cells.
MeSH term(s)	Animals ; Humans ; Receptors, Antigen, T-Cell, gamma-delta ; Spleen/metabolism ; Butyrophilins ; NK Cell Lectin-Like Receptor Subfamily K ; T-Lymphocytes ; Antigens, CD
Chemical Substances	Receptors, Antigen, T-Cell, gamma-delta ; Butyrophilins ; NK Cell Lectin-Like Receptor Subfamily K ; BTN3A1 protein, human ; Antigens, CD
Language	English
Publishing date	2023-11-22
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	3056-9
ISSN	1550-6606 ; 0022-1767 ; 1048-3233 ; 1047-7381
ISSN (online)	1550-6606
ISSN	0022-1767 ; 1048-3233 ; 1047-7381
DOI	10.4049/jimmunol.2300588
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Article ; Online: Incidence of MACE in Patients Treated With CAR-T Cell Therapy: A Prospective Study.

Lefebvre, Bénédicte / Kang, Yu / Vakilpour, Azin / Onoue, Takeshi / Frey, Noelle V / Brahmbhatt, Priya / Huang, Brian / Oladuja, Kemi / Koropeckyj-Cox, Daniel / Wiredu, Courteney / Smith, Amanda M / Chittams, Jesse / Carver, Joseph / Scherrer-Crosbie, Marielle

JACC. CardioOncology

2023 Volume 5, Issue 6, Page(s) 747–754

Abstract: Background: Previous retrospective studies have shown that chimeric antigen receptor T (CAR-T ... observational study was to define the occurrence of MACE in adults undergoing treatment with CAR-T cell therapy ... were collected prior to and 2 days, 1 week, 1 month, and 6 months after CAR-T cell infusion, and charts ...

Abstract	Background: Previous retrospective studies have shown that chimeric antigen receptor T (CAR-T) cell therapy may be associated with major adverse cardiovascular events (MACE), especially in the context of cytokine-release syndrome (CRS) events. Objectives: The aim of this prospective observational study was to define the occurrence of MACE in adults undergoing treatment with CAR-T cell therapy and identify associated risk factors. Methods: Vital signs, blood samples, and an echocardiogram were collected prior to and 2 days, 1 week, 1 month, and 6 months after CAR-T cell infusion, and charts were consulted at 12 months. In the event of CRS, echocardiography was repeated within 72 hours. MACE were defined as cardiovascular death, symptomatic heart failure, acute coronary syndrome, ischemic stroke, and de novo cardiac arrhythmia. Results: A total of 44 patients were enrolled (mean age 58 ± 11 years, 77% men). The median follow-up duration was 487 days (Q1-Q3: 258-622 days). There were 24 episodes of CRS in 23 patients (52%) (13 grade 1, 10 grade 2, and 1 grade 3), with a median time to CRS of 4 days. Two patients had MACE (heart failure with preserved ejection fraction and atrial fibrillation) within 1 year and 6 and 7 days after CAR-T cell infusion. There was no change in left ventricular ejection fraction, but a modest decrease in global longitudinal strain was noted. Conclusions: There were few cardiac effects associated with contemporary CAR-T cell therapy. As MACE occurred after CRS episodes, aggressive treatment and close follow-up during CRS events are essential.
Language	English
Publishing date	2023-10-10
Publishing country	United States
Document type	Journal Article
ISSN	2666-0873
ISSN (online)	2666-0873
DOI	10.1016/j.jaccao.2023.07.009
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Article ; Online: GPRC5D-Targeted CAR T Cells for Myeloma.

Mailankody, Sham / Devlin, Sean M / Landa, Jonathan / Nath, Karthik / Diamonte, Claudia / Carstens, Elizabeth J / Russo, Douglas / Auclair, Romany / Fitzgerald, Lisa / Cadzin, Briana / Wang, Xiuyan / Sikder, Devanjan / Senechal, Brigitte / Bermudez, Vladimir P / Purdon, Terence J / Hosszu, Kinga / McAvoy, Devin P / Farzana, Tasmin / Mead, Elena /

Wilcox, Jessica A / Santomasso, Bianca D / Shah, Gunjan L / Shah, Urvi A / Korde, Neha / Lesokhin, Alexander / Tan, Carlyn R / Hultcrantz, Malin / Hassoun, Hani / Roshal, Mikhail / Sen, Filiz / Dogan, Ahmet / Landgren, Ola / Giralt, Sergio A / Park, Jae H / Usmani, Saad Z / Rivière, Isabelle / Brentjens, Renier J / Smith, Eric L

The New England journal of medicine

2022 Volume 387, Issue 13, Page(s) 1196–1206

Abstract: Background: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell ... in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity ... targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated ...

Abstract	Background: B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapies have generated responses in patients with advanced myeloma, but relapses are common. G protein-coupled receptor, class C, group 5, member D (GPRC5D) has been identified as an immunotherapeutic target in multiple myeloma. Preclinical studies have shown the efficacy of GPRC5D-targeted CAR T cells, including activity in a BCMA antigen escape model. Methods: In this phase 1 dose-escalation study, we administered a GPRC5D-targeted CAR T-cell therapy (MCARH109) at four dose levels to patients with heavily pretreated multiple myeloma, including patients with relapse after BCMA CAR T-cell therapy. Results: A total of 17 patients were enrolled and received MCARH109 therapy. The maximum tolerated dose was identified at 150×10 Conclusions: The results of this study of a GPRC5D-targeted CAR T-cell therapy (MCARH109) confirm that GPRC5D is an active immunotherapeutic target in multiple myeloma. (Funded by Juno Therapeutics/Bristol Myers Squibb; ClinicalTrials.gov number, NCT04555551.).
MeSH term(s)	B-Cell Maturation Antigen/therapeutic use ; Cytokine Release Syndrome/etiology ; Humans ; Immunotherapy, Adoptive/adverse effects ; Immunotherapy, Adoptive/methods ; Multiple Myeloma/drug therapy ; Neoplasm Recurrence, Local/etiology ; Receptors, Chimeric Antigen/therapeutic use ; Receptors, G-Protein-Coupled/therapeutic use ; T-Lymphocytes
Chemical Substances	B-Cell Maturation Antigen ; GPRC5D protein, human ; Receptors, Chimeric Antigen ; Receptors, G-Protein-Coupled
Language	English
Publishing date	2022-06-21
Publishing country	United States
Document type	Clinical Trial, Phase I ; Journal Article
ZDB-ID	207154-x
ISSN	1533-4406 ; 0028-4793
ISSN (online)	1533-4406
ISSN	0028-4793
DOI	10.1056/NEJMoa2209900
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Article ; Online: A Faster Prostate MRI: Comparing a Novel Denoised, Single-Average T

Kelleher, Colm B / Macdonald, Jacob / Jaffe, Tracy A / Allen, Brian C / Kalisz, Kevin R / Kauffman, Travis H / Smith, Jordan D / Maurer, Kimberly R / Thomas, Sarah P / Coleman, Aaron D / Zaki, Islam H / Kannengiesser, Stephan / Lafata, Kyle / Gupta, Rajan T / Bashir, Mustafa R

Journal of magnetic resonance imaging : JMRI

2023 Volume 58, Issue 2, Page(s) 620–629

Abstract: Background: The T: Purpose/hypothesis: To determine whether a denoised, single-average T ... Field strength/sequence: A 3 T; T: Assessment: Nine readers randomly assessed complete exams ... including T: Statistical tests: Generalized linear mixed effects models for differences in lesion ...

Abstract	Background: The T Purpose/hypothesis: To determine whether a denoised, single-average T Study type: Retrospective. Population: A total of 45 males (age range 60-75 years) who underwent clinically indicated prostate MRI examinations, 21 of whom had pathologically proven prostate cancer. Field strength/sequence: A 3 T; T Assessment: Nine readers randomly assessed complete exams including T Statistical tests: Generalized linear mixed effects models for differences in lesion detection, image quality features, and overall preference between T Results: There was no significant difference between sequences regarding identification of lesions with PI-RADS ≥3 (P = 0.10) or PI-RADS score (P = 0.77). Reader agreement was excellent for lesion identification (ICC = 0.84). There was no significant overall preference between the two sequences regarding image quality (P = 0.07, 95% CI: [-0.23, 0.01]). Reader agreement was good regarding sequence preference (ICC = 0.62). Data conclusion: Use of single-average, denoised T Evidence level: 3. Technical efficacy: Stage 3.
MeSH term(s)	Male ; Humans ; Middle Aged ; Aged ; Magnetic Resonance Imaging/methods ; Prostate/diagnostic imaging ; Prostate/pathology ; Prostatic Neoplasms/diagnostic imaging ; Prostatic Neoplasms/pathology ; Retrospective Studies ; Pelvis/pathology
Language	English
Publishing date	2023-01-06
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1146614-5
ISSN	1522-2586 ; 1053-1807
ISSN (online)	1522-2586
ISSN	1053-1807
DOI	10.1002/jmri.28577
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Article ; Online: Circulating cancer-specific CD8 T cell frequency is associated with response to PD-1 blockade in Merkel cell carcinoma.

Pulliam, Thomas / Jani, Saumya / Jing, Lichen / Ryu, Heeju / Jojic, Ana / Shasha, Carolyn / Zhang, Jiajia / Kulikauskas, Rima / Church, Candice / Garnett-Benson, Charlie / Gooley, Ted / Chapuis, Aude / Paulson, Kelly / Smith, Kellie N / Pardoll, Drew M / Newell, Evan W / Koelle, David M / Topalian, Suzanne L / Nghiem, Paul

Cell reports. Medicine

2024 Volume 5, Issue 2, Page(s) 101412

Abstract: Understanding cancer immunobiology has been hampered by difficulty identifying cancer-specific T ... with virus-driven MCC express MCPyV oncoproteins, facilitating identification of virus (cancer)-specific T ... cells. We studied MCPyV-specific T cells from 27 patients with MCC using MCPyV peptide-HLA-I multimers ...

Abstract	Understanding cancer immunobiology has been hampered by difficulty identifying cancer-specific T cells. Merkel cell polyomavirus (MCPyV) causes most Merkel cell carcinomas (MCCs). All patients with virus-driven MCC express MCPyV oncoproteins, facilitating identification of virus (cancer)-specific T cells. We studied MCPyV-specific T cells from 27 patients with MCC using MCPyV peptide-HLA-I multimers, 26-color flow cytometry, single-cell transcriptomics, and T cell receptor (TCR) sequencing. In a prospective clinical trial, higher circulating MCPyV-specific CD8 T cell frequency before anti-PD-1 treatment was strongly associated with 2-year recurrence-free survival (75% if detectable, 0% if undetectable, p = 0.0018; ClinicalTrial.gov: NCT02488759). Intratumorally, such T cells were typically present, but their frequency did not significantly associate with response. Circulating MCPyV-specific CD8 T cells had increased stem/memory and decreased exhaustion signatures relative to their intratumoral counterparts. These results suggest that cancer-specific CD8 T cells in the blood may play a role in anti-PD-1 responses. Thus, strategies that augment their number or mobilize them into tumors could improve outcomes.
MeSH term(s)	Humans ; Carcinoma, Merkel Cell/drug therapy ; Carcinoma, Merkel Cell/pathology ; CD8-Positive T-Lymphocytes/pathology ; Programmed Cell Death 1 Receptor ; Prospective Studies ; Skin Neoplasms/drug therapy ; Skin Neoplasms/pathology ; Clinical Trials as Topic
Chemical Substances	Programmed Cell Death 1 Receptor
Language	English
Publishing date	2024-02-10
Publishing country	United States
Document type	Journal Article
ISSN	2666-3791
ISSN (online)	2666-3791
DOI	10.1016/j.xcrm.2024.101412
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