5 results on '"Longino NV"'
Search Results
2. Naturally Occurring Genetic Alterations in Proximal TCR Signaling and Implications for Cancer Immunotherapy.
- Author
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Kent A, Longino NV, Christians A, and Davila E
- Subjects
- Animals, Biomarkers, CD3 Complex genetics, CD3 Complex metabolism, Carrier Proteins chemistry, Carrier Proteins metabolism, Disease Management, Disease Susceptibility, Genetic Engineering, Humans, Immunotherapy, Immunotherapy, Adoptive, Multiprotein Complexes, Mutation, Neoplasms pathology, Neoplasms therapy, Protein Binding, Protein Interaction Domains and Motifs, Receptors, Antigen, T-Cell chemistry, Structure-Activity Relationship, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Genetic Variation, Neoplasms etiology, Neoplasms metabolism, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell metabolism, Signal Transduction, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
T cell-based immunotherapies including genetically engineered T cells, adoptive transfer of tumor-infiltrating lymphocytes, and immune checkpoint blockade highlight the impressive anti-tumor effects of T cells. These successes have provided new hope to many cancer patients with otherwise poor prognoses. However, only a fraction of patients demonstrates durable responses to these forms of therapies and many develop significant immune-mediated toxicity. These heterogeneous clinical responses suggest that underlying nuances in T cell genetics, phenotypes, and activation states likely modulate the therapeutic impact of these approaches. To better characterize known genetic variations that may impact T cell function, we 1) review the function of early T cell receptor-specific signaling mediators, 2) offer a synopsis of known mutations and genetic alterations within the associated molecules, 3) discuss the link between these mutations and human disease and 4) review therapeutic strategies under development or in clinical testing that target each of these molecules for enhancing anti-tumor T cell activity. Finally, we discuss novel engineering approaches that could be designed based on our understanding of the function of these molecules in health and disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Kent, Longino, Christians and Davila.)
- Published
- 2021
- Full Text
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3. Intratumoral Delivery of Plasmid IL12 Via Electroporation Leads to Regression of Injected and Noninjected Tumors in Merkel Cell Carcinoma.
- Author
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Bhatia S, Longino NV, Miller NJ, Kulikauskas R, Iyer JG, Ibrani D, Blom A, Byrd DR, Parvathaneni U, Twitty CG, Campbell JS, Le MH, Gargosky S, Pierce RH, Heller R, Daud AI, and Nghiem P
- Subjects
- Aged, Aged, 80 and over, CD8-Positive T-Lymphocytes immunology, Carcinoma, Merkel Cell immunology, Carcinoma, Merkel Cell pathology, Cohort Studies, Female, Humans, Interleukin-12 genetics, Interleukin-12 metabolism, Male, Middle Aged, Neoplasm Metastasis, Patient Safety, Pilot Projects, Skin Neoplasms immunology, Skin Neoplasms pathology, Treatment Outcome, Carcinoma, Merkel Cell drug therapy, Electroporation methods, Gene Transfer Techniques, Immunotherapy methods, Interleukin-12 administration & dosage, Plasmids administration & dosage, Skin Neoplasms drug therapy
- Abstract
Purpose: IL12 promotes adaptive type I immunity and has demonstrated antitumor efficacy, but systemic administration leads to severe adverse events (AE), including death. This pilot trial investigated safety, efficacy, and immunologic activity of intratumoral delivery of IL12 plasmid DNA (tavo) via in vivo electroporation (i.t.-tavo-EP) in patients with Merkel cell carcinoma (MCC), an aggressive virus-associated skin cancer., Patients and Methods: Fifteen patients with MCC with superficial injectable tumor(s) received i.t.-tavo-EP on days 1, 5, and 8 of each cycle. Patients with locoregional MCC (cohort A, N = 3) received one cycle before definitive surgery in week 4. Patients with metastatic MCC (cohort B, N = 12) received up to four cycles total, administered at least 6 weeks apart. Serial tumor and blood samples were collected., Results: All patients successfully completed at least one cycle with transient, mild (grades 1 and 2) AEs and without significant systemic toxicity. Sustained (day 22) intratumoral expression of IL12 protein was observed along with local inflammation and increased tumor-specific CD8
+ T-cell infiltration, which led to systemic immunologic and clinical responses. The overall response rate was 25% (3/12) in cohort B, with 2 patients experiencing durable clinical benefit (16 and 55+ months, respectively). Two cohort A patients (1 with pathologic complete remission) were recurrence-free at 44+ and 75+ months, respectively., Conclusions: I.t.-tavo-EP was safe and feasible without systemic toxicity. Sustained local expression of IL12 protein and local inflammation led to systemic immune responses and clinically meaningful benefit in some patients. Gene electrotransfer, specifically i.t.-tavo-EP, warrants further investigation for immunotherapy of cancer., (©2019 American Association for Cancer Research.)- Published
- 2020
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4. Human CD4 + T Cells Specific for Merkel Cell Polyomavirus Localize to Merkel Cell Carcinomas and Target a Required Oncogenic Domain.
- Author
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Longino NV, Yang J, Iyer JG, Ibrani D, Chow IT, Laing KJ, Campbell VL, Paulson KG, Kulikauskas RM, Church CD, James EA, Nghiem P, Kwok WW, and Koelle DM
- Subjects
- Carcinogenesis metabolism, Carcinogenesis pathology, Carcinoma, Merkel Cell drug therapy, Carcinoma, Merkel Cell metabolism, Carcinoma, Merkel Cell pathology, Cell Line, Tumor, Healthy Volunteers, Humans, Oligopeptides immunology, Retinoblastoma Protein metabolism, Skin Neoplasms drug therapy, Skin Neoplasms metabolism, Skin Neoplasms pathology, CD4-Positive T-Lymphocytes immunology, Carcinogenesis immunology, Carcinoma, Merkel Cell immunology, Epitopes immunology, Merkel cell polyomavirus immunology, Skin Neoplasms immunology
- Abstract
Although CD4
+ T cells likely play key roles in antitumor immune responses, most immuno-oncology studies have been limited to CD8+ T-cell responses due to multiple technical barriers and a lack of shared antigens across patients. Merkel cell carcinoma (MCC) is an aggressive skin cancer caused by Merkel cell polyomavirus (MCPyV) oncoproteins in 80% of cases. Because MCPyV oncoproteins are shared across most patients with MCC, it is unusually feasible to identify, characterize, and potentially augment tumor-specific CD4+ T cells. Here, we report the identification of CD4+ T-cell responses against six MCPyV epitopes, one of which included a conserved, essential viral oncogenic domain that binds/disables the cellular retinoblastoma (Rb) tumor suppressor. We found that this epitope (WEDLT209-228 ) could be presented by three population-prevalent HLA class II alleles, making it a relevant target in 64% of virus-positive MCC patients. Cellular staining with a WEDLT209-228 -HLA-DRB1*0401 tetramer indicated that specific CD4+ T cells were detectable in 78% (14 of 18) of evaluable MCC patients, were 250-fold enriched within MCC tumors relative to peripheral blood, and had diverse T-cell receptor sequences. We also identified a modification of this domain that still allowed recognition by these CD4+ T cells but disabled binding to the Rb tumor suppressor, a key step in the detoxification of a possible therapeutic vaccine. The use of these new tools for deeper study of MCPyV-specific CD4+ T cells may provide broader insight into cancer-specific CD4+ T-cell responses., (©2019 American Association for Cancer Research.)- Published
- 2019
- Full Text
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5. Intratumoral G100, a TLR4 Agonist, Induces Antitumor Immune Responses and Tumor Regression in Patients with Merkel Cell Carcinoma.
- Author
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Bhatia S, Miller NJ, Lu H, Longino NV, Ibrani D, Shinohara MM, Byrd DR, Parvathaneni U, Kulikauskas R, Ter Meulen J, Hsu FJ, Koelle DM, and Nghiem P
- Subjects
- Aged, Aged, 80 and over, Cancer Vaccines administration & dosage, Carcinoma, Merkel Cell genetics, Carcinoma, Merkel Cell immunology, Carcinoma, Merkel Cell pathology, Gene Expression Regulation, Neoplastic drug effects, Humans, Immunity, Cellular drug effects, Immunity, Cellular immunology, Lipid A pharmacology, Lipid A therapeutic use, Male, Middle Aged, Neoplasm Recurrence, Local genetics, Neoplasm Recurrence, Local immunology, Neoplasm Recurrence, Local pathology, Pilot Projects, Toll-Like Receptor 4 genetics, Toll-Like Receptor 4 immunology, Tumor Microenvironment drug effects, Carcinoma, Merkel Cell drug therapy, Immunotherapy, Lipid A analogs & derivatives, Neoplasm Recurrence, Local drug therapy, Toll-Like Receptor 4 agonists
- Abstract
Purpose: G100 is a toll-like receptor 4 (TLR4) agonist that triggers innate and adaptive antitumor immune responses in preclinical models. This pilot study assessed the safety, efficacy, and immunologic activity of intratumoral (IT) administration of G100 in patients with Merkel cell carcinoma (MCC)., Patients and Methods: Patients with locoregional MCC ( n = 3; cohort A) received neoadjuvant IT G100 (2 weekly doses at 5 μg/dose) followed by surgery and radiotherapy; patients with metastatic MCC ( n = 7; cohort B) received 3 doses in a 6-week cycle and could receive additional cycles with/without radiotherapy., Results: IT G100 was safe and feasible in both neoadjuvant and metastatic settings. Treatment-related adverse events were mostly grade 1 or 2 injection-site reactions. IT G100 led to increased inflammation in the injected tumors with infiltration of CD8
+ and CD4+ T cells and activation of immune-related genes. These proinflammatory changes were associated with local tumor regression and appeared to promote systemic immunity. All 3 cohort A patients successfully completed therapy; 2 patients remain recurrence free at 44+ and 41+ months, including 1 with a pathologic complete response after G100 alone. In cohort B, 2 patients achieved sustained partial responses, both lasting 33+ months after 2 cycles of therapy., Conclusions: In this first-in-human study, IT G100 induced antitumor immune responses, demonstrated acceptable safety, and showed encouraging clinical activity.See related commentary by Marquez-Rodas et al., p. 1127., (©2018 American Association for Cancer Research.)- Published
- 2019
- Full Text
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