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Recombinant Newcastle Disease Virus Immunotherapy Drives Oncolytic Effects and Durable Systemic Antitumor Immunity.
Harper, James; Burke, Shannon; Travers, Jon; Rath, Nicola; Leinster, Andrew; Navarro, Christel; Franks, Ruth; Leyland, Rebecca; Mulgrew, Kathy; McGlinchey, Kelly; Brown, Lee; Dovedi, Simon J; Koopmann, Jens-Oliver; Durham, Nicholas M; Cheng, Xing; Jin, Hong; Eyles, Jim; Wilkinson, Robert W; Carroll, Danielle.
Afiliação
  • Harper J; Oncology R&D, AstraZeneca, Cambridge, United Kingdom. james.harper@astrazeneca.com.
  • Burke S; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Travers J; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Rath N; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Leinster A; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Navarro C; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Franks R; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Leyland R; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Mulgrew K; Oncology R&D, AstraZeneca, Gaithersburg, Maryland.
  • McGlinchey K; Oncology R&D, AstraZeneca, Gaithersburg, Maryland.
  • Brown L; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Dovedi SJ; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Koopmann JO; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Durham NM; Oncology R&D, AstraZeneca, Gaithersburg, Maryland.
  • Cheng X; BioPharmaceutical R&D, AstraZeneca, South San Francisco, California.
  • Jin H; BioPharmaceutical R&D, AstraZeneca, South San Francisco, California.
  • Eyles J; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Wilkinson RW; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
  • Carroll D; Oncology R&D, AstraZeneca, Cambridge, United Kingdom.
Mol Cancer Ther ; 20(9): 1723-1734, 2021 09.
Article em En | MEDLINE | ID: mdl-34224361
ABSTRACT
A recombinant Newcastle Disease Virus (NDV), encoding either a human (NDVhuGM-CSF, MEDI5395) or murine (NDVmuGM-CSF) GM-CSF transgene, combined broad oncolytic activity with the ability to significantly modulate genes related to immune functionality in human tumor cells. Replication in murine tumor lines was significantly diminished relative to human tumor cells. Nonetheless, intratumoral injection of NDVmuGM-CSF conferred antitumor effects in three syngeneic models in vivo; with efficacy further augmented by concomitant treatment with anti-PD-1/PD-L1 or T-cell agonists. Ex vivo immune profiling, including T-cell receptor sequencing, revealed profound immune-contexture changes consistent with priming and potentiation of adaptive immunity and tumor microenvironment (TME) reprogramming toward an immune-permissive state. CRISPR modifications rendered CT26 tumors significantly more permissive to NDV replication, and in this setting, NDVmuGM-CSF confers immune-mediated effects in the noninjected tumor in vivo Taken together, the data support the thesis that MEDI5395 primes and augments cell-mediated antitumor immunity and has significant utility as a combination partner with other immunomodulatory cancer treatments.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Vírus da Doença de Newcastle / Fator Estimulador de Colônias de Granulócitos e Macrófagos / Terapia Viral Oncolítica / Imunomodulação / Microambiente Tumoral / Imunoterapia Idioma: En Ano de publicação: 2021 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Vírus da Doença de Newcastle / Fator Estimulador de Colônias de Granulócitos e Macrófagos / Terapia Viral Oncolítica / Imunomodulação / Microambiente Tumoral / Imunoterapia Idioma: En Ano de publicação: 2021 Tipo de documento: Article