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1.
Front Immunol ; 12: 658611, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34012443

RESUMEN

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.


Asunto(s)
Variación Genética , Neoplasias/etiología , Neoplasias/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Biomarcadores , Complejo CD3/genética , Complejo CD3/metabolismo , Proteínas Portadoras/química , Proteínas Portadoras/metabolismo , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Ingeniería Genética , Humanos , Inmunoterapia , Inmunoterapia Adoptiva , Complejos Multiproteicos , Mutación , Neoplasias/patología , Neoplasias/terapia , Unión Proteica , Dominios y Motivos de Interacción de Proteínas , Receptores de Antígenos de Linfocitos T/química , Relación Estructura-Actividad , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
2.
Clin Cancer Res ; 26(3): 598-607, 2020 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-31582519

RESUMEN

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.


Asunto(s)
Carcinoma de Células de Merkel/tratamiento farmacológico , Electroporación/métodos , Técnicas de Transferencia de Gen , Inmunoterapia/métodos , Interleucina-12/administración & dosificación , Plásmidos/administración & dosificación , Neoplasias Cutáneas/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Linfocitos T CD8-positivos/inmunología , Carcinoma de Células de Merkel/inmunología , Carcinoma de Células de Merkel/patología , Estudios de Cohortes , Femenino , Humanos , Interleucina-12/genética , Interleucina-12/metabolismo , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Seguridad del Paciente , Proyectos Piloto , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Resultado del Tratamiento
3.
Clin Cancer Res ; 25(4): 1185-1195, 2019 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-30093453

RESUMEN

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.


Asunto(s)
Carcinoma de Células de Merkel/tratamiento farmacológico , Inmunoterapia , Lípido A/análogos & derivados , Recurrencia Local de Neoplasia/tratamiento farmacológico , Receptor Toll-Like 4/agonistas , Anciano , Anciano de 80 o más Años , Vacunas contra el Cáncer/administración & dosificación , Carcinoma de Células de Merkel/genética , Carcinoma de Células de Merkel/inmunología , Carcinoma de Células de Merkel/patología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Inmunidad Celular/efectos de los fármacos , Inmunidad Celular/inmunología , Lípido A/farmacología , Lípido A/uso terapéutico , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Proyectos Piloto , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/inmunología , Microambiente Tumoral/efectos de los fármacos
4.
Cancer Immunol Res ; 7(10): 1727-1739, 2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31405946

RESUMEN

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.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Carcinogénesis/inmunología , Carcinoma de Células de Merkel/inmunología , Epítopos/inmunología , Poliomavirus de Células de Merkel/inmunología , Neoplasias Cutáneas/inmunología , Carcinogénesis/metabolismo , Carcinogénesis/patología , Carcinoma de Células de Merkel/tratamiento farmacológico , Carcinoma de Células de Merkel/metabolismo , Carcinoma de Células de Merkel/patología , Línea Celular Tumoral , Voluntarios Sanos , Humanos , Oligopéptidos/inmunología , Proteína de Retinoblastoma/metabolismo , Neoplasias Cutáneas/tratamiento farmacológico , Neoplasias Cutáneas/metabolismo , Neoplasias Cutáneas/patología
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