scholarly journals Breaking Bottlenecks for the TCR Therapy of Cancer

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2095 ◽  
Author(s):  
Lena Gaissmaier ◽  
Mariam Elshiaty ◽  
Petros Christopoulos
Keyword(s):  
Gene Editing ◽  
Checkpoint Inhibitors ◽  
Cell Receptor ◽  
Viral Gene ◽  
Next Generation ◽  
Heavily Pretreated ◽  
Immunosuppressive Tumor Microenvironment ◽  
Generation Sequencing ◽  
High Throughput Manner ◽  
Central Memory Phenotype

Immune checkpoint inhibitors have redefined the treatment of cancer, but their efficacy depends critically on the presence of sufficient tumor-specific lymphocytes, and cellular immunotherapies develop rapidly to fill this gap. The paucity of suitable extracellular and tumor-associated antigens in solid cancers necessitates the use of neoantigen-directed T-cell-receptor (TCR)-engineered cells, while prevention of tumor evasion requires combined targeting of multiple neoepitopes. These can be currently identified within 2 weeks by combining cutting-edge next-generation sequencing with bioinformatic pipelines and used to select tumor-reactive TCRs in a high-throughput manner for expeditious scalable non-viral gene editing of autologous or allogeneic lymphocytes. “Young” cells with a naive, memory stem or central memory phenotype can be additionally armored with “next-generation” features against exhaustion and the immunosuppressive tumor microenvironment, where they wander after reinfusion to attack heavily pretreated and hitherto hopeless neoplasms. Facilitated by major technological breakthroughs in critical manufacturing steps, based on a solid preclinical rationale, and backed by rapidly accumulating evidence, TCR therapies break one bottleneck after the other and hold the promise to become the next immuno-oncological revolution.

scholarly journals Immortalization and Functional Screening of Natively Paired Human T Cell Receptor Repertoires

2021 ◽  
Author(s):  
Ahmed S Fahad ◽  
Cheng Yu Chung ◽  
Sheila N. Lopez Acevedo ◽  
Nicoleen Boyle ◽  
Bharat Madan ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Functional Screening ◽  
Next Generation ◽  
Sequencing Technologies ◽  
Human T Cell ◽  
Screening Platform ◽  
Generation Sequencing

Functional analyses of the T cell receptor (TCR) landscape can reveal critical information about protection from disease and molecular responses to vaccines. However, it has proven difficult to combine advanced next-generation sequencing technologies with methods to decode the peptide-major histocompatibility complex (pMHC) specificity of individual TCRs. Here we developed a new high-throughput approach to enable repertoire-scale functional evaluations of natively paired TCRs. In particular, we leveraged the immortalized nature of physically linked TCRα:β amplicon libraries to analyze binding against multiple recombinant pMHCs on a repertoire scale. To exemplify the utility of this approach, we also performed affinity-based functional mapping in conjunction with quantitative next-generation sequencing to track antigen- specific TCRs. These data successfully validated a new immortalization and screening platform to facilitate detailed molecular analyses of human TCRs against diverse antigen targets associated with health, vaccination, or disease.

scholarly journals Complexities of Next-Generation Sequencing in Solid Tumors: Case Studies

2020 ◽  
Vol 18 (9) ◽  
pp. 1150-1155
Author(s):  
Alexandra O. Sokolova ◽  
Brian H. Shirts ◽  
Eric Q. Konnick ◽  
Ginger J. Tsai ◽  
Bernardo H.L. Goulart ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Case Studies ◽  
Checkpoint Inhibitors ◽  
Hereditary Cancer Syndrome ◽  
Next Generation ◽  
Cancer Syndrome ◽  
Expert Review ◽  
Tumor Boards ◽  
Tumor Sequencing ◽  
Generation Sequencing

With the promise and potential of clinical next-generation sequencing for tumor and germline testing to impact treatment and outcomes of patients with cancer, there are also risks of oversimplification, misinterpretation, and missed opportunities. These issues risk limiting clinical benefit and, at worst, perpetuating false conclusions that could lead to inappropriate treatment selection, avoidable toxicity, and harm to patients. This report presents 5 case studies illustrating challenges and opportunities in clinical next-generation sequencing interpretation and clinical application in solid tumor oncologic care. First is a case that dissects the origin of an ATM mutation as originating from a hematopoietic clone rather than the tumor. Second is a case illustrating the potential for tumor sequencing to suggest germline variants associated with a hereditary cancer syndrome. Third are 2 cases showing the potential for variant reclassification of a germline variant of uncertain significance when considered alongside family history and tumor sequencing results. Finally, we describe a case illustrating challenges with using microsatellite instability for predicting tumor response to immune checkpoint inhibitors. The common theme of the case studies is the importance of examining clinical context alongside expert review and interpretation, which together highlight an expanding role for contextual examination and multidisciplinary expert review through molecular tumor boards.

scholarly journals Preparing Unbiased T-Cell Receptor and Antibody cDNA Libraries for the Deep Next Generation Sequencing Profiling

2013 ◽  
Vol 4 ◽  
Author(s):  
Ilgar Z. Mamedov ◽  
Olga V. Britanova ◽  
Ivan V. Zvyagin ◽  
Maria A. Turchaninova ◽  
Dmitriy A. Bolotin ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
Cdna Libraries ◽  
Next Generation ◽  
Generation Sequencing

Lenvatinib plus checkpoint inhibitors in patients (pts) with advanced intrahepatic cholangiocarcinoma (ICC): Preliminary data and correlation with next-generation sequencing.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. 500-500 ◽  
Author(s):  
Jianzhen Lin ◽  
Weiwei Shi ◽  
Songhui Zhao ◽  
Jinwei Hu ◽  
Zheng Hou ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Checkpoint Inhibitors ◽  
Clinical Stage ◽  
Objective Response ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Cancer Genes ◽  
Next Generation ◽  
Multikinase Inhibitor ◽  
Generation Sequencing

500 Background: Lenvatinib (Len) is a multikinase inhibitor targeting VEGFR 1-3, FGFR 1-4 and other kinases. Pembrolizumab (Pem) and nivolumab (Nivo) are antibodies inhibiting programmed cell death 1 (PD-1) and reactivate T-cell cytotoxic effect. Len plus PD-1 inhibitors have shown promising results in treating various solid tumors. The role of this combination in ICC is undefined. Methods: 14 ICC pts (median age 49 years, range 34-68; 7 males and 7 females) with treatment of enrolled in a single center, observational study of Len plus Pem/Nivo. Objective response rate (ORR), disease control rate (DCR) and progression-free survival (PFS) were measured according to RECIST 1.1. Next generation sequencing (NGS) with deep coverage on 450 cancer genes and whole exome sequencing were performed in 7 pts to detect all classes of genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI) status. Results: All 14 pts had > = 2 prior anticancer therapy with clinical stage IV. ORR was 21.4% with 3 pts achieved partial response (PR), DCR was 92.9% and clinical benefit rate (ORR + durable stable disease > = 5 months) was 64.3%. Median PFS was 5.9 months (95% CI: 4.2-6.2). The most common adverse events (AEs) included hypertension, aminotransferase elevation and fatigue. The grade-3 AEs were occurred at 14% while no grade-4 AE was observed. The most altered genes in the 7 sequenced tumors were IDH1 (3 pts), ARID1A (3 pts), PIK3CA (3 pts), TP53 (2 pts) and BAP1 (2 pts). 4 out of the 7 pts had high TMB ( > 12 mut/Mb) and all responded to Len plus Pem/Nivo with 2 PR. One pt with low TMB and FGFR2 mutation had a response of 27% decreased target lesion. Two low TMB pts were progressed, including one with FGFR2 rearrangement. A responder harbored a 399 bp deletion on MLH1, and was identified as MSI-H. More data will be presented. Conclusions: Our study preliminarily indicates that combining Len with PD-1 inhibitors results in promising efficacy in advanced ICC. High TMB from 450-gene NGS panel was strongly associated with a better therapeutic response.

scholarly journals Capture-Based Next-Generation Sequencing Improves the Identification of Immunoglobulin/T-Cell Receptor Clonal Markers and Gene Mutations in Adult Acute Lymphoblastic Leukemia Patients Lacking Molecular Probes

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1505
Author(s):  
Roberta Cavagna ◽  
Marie L. Guinea Montalvo ◽  
Manuela Tosi ◽  
Michela Paris ◽  
Chiara Pavoni ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
T Cell Receptor ◽  
Lymphoblastic Leukemia ◽  
Cell Receptor ◽  
Molecular Probes ◽  
Next Generation ◽  
Mutational Status ◽  
Generation Sequencing

The monitoring of minimal residual disease (MRD) in Philadelphia-negative acute lymphoblastic leukemia (ALL) requires the identification at diagnosis of immunoglobulin/T-cell receptor (Ig/TCR) rearrangements as clonality markers. Aiming to simplify and possibly improve the patients’ initial screening, we designed a capture-based next-generation sequencing (NGS) panel combining the Ig/TCR rearrangement detection with the profiling of relevant leukemia-related genes. The validation of the assay on well-characterized samples allowed us to identify all the known Ig/TCR rearrangements as well as additional clonalities, including rare rearrangements characterized by uncommon combinations of variable, diversity, and joining (V-D-J) gene segments, oligoclonal rearrangements, and low represented clones. Upon validation, the capture NGS approach allowed us to identify Ig/TCR clonal markers in 87% of a retrospective cohort (MRD-unknown within the Northern Italy Leukemia Group (NILG)-ALL 09/00 clinical trial) and in 83% of newly-diagnosed ALL cases in which conventional method failed, thus proving its prospective applicability. Finally, we identified gene variants in 94.7% of patients analyzed for mutational status with the same implemented capture assay. The prospective application of this technology could simplify clonality assessment and improve standard assay development for leukemia monitoring, as well as provide information about the mutational status of selected leukemia-related genes, potentially representing new prognostic elements, MRD markers, and targets for specific therapies.

scholarly journals Repertoire comparison of the B-cell receptor-encoding loci in humans and rhesus macaques by next-generation sequencing

2016 ◽  
Vol 5 (7) ◽  
pp. e93 ◽  
Author(s):  
Vladimir Vigdorovich ◽  
Brian G Oliver ◽  
Sara Carbonetti ◽  
Nicholas Dambrauskas ◽  
Miles D Lange ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
B Cell ◽  
Rhesus Macaques ◽  
Cell Receptor ◽  
B Cell Receptor ◽  
Next Generation ◽  
Generation Sequencing

scholarly journals Next generation sequencing of PD-L1 for predicting response to immune checkpoint inhibitors

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Jeffrey M. Conroy ◽  
Sarabjot Pabla ◽  
Mary K. Nesline ◽  
Sean T. Glenn ◽  
Antonios Papanicolau-Sengos ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Next Generation ◽  
Generation Sequencing
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