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. and CARROLL, Danielle (2021). Recombinant Newcastle disease virus immunotherapy drives oncolytic effects and durable systemic antitumor immunity. Molecular Cancer Therapeutics.

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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 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/L-1 or T cell agonists. Ex vivo immune-profiling, including TCRseq, revealed profound immune-contexture changes; consistent with priming and potentiation of adaptive immunity and tumor-microenvironment (TME) re-programming towards an immune-permissive state. CRISPR modifications rendered CT26 significantly more permissive to NDV replication, and in this setting NDVmuGM-CSF confers immune-mediated¬¬¬¬¬¬ effects in the non-injected tumor in vivo. Taken together the data supports the thesis that MEDI5395 primes and augments cell mediated antitumor immunity and has significant utility as a combination partner with other immunomodulatory cancer treatments.

Item Type: Article
Additional Information: OnlineFirst version was published on June 17, 2021
Uncontrolled Keywords: Oncology & Carcinogenesis; 1112 Oncology and Carcinogenesis; 1115 Pharmacology and Pharmaceutical Sciences
Identification Number:
SWORD Depositor: Symplectic Elements
Depositing User: Symplectic Elements
Date Deposited: 28 Jun 2021 12:03
Last Modified: 16 Sep 2021 15:45

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