Recombinant Newcastle Disease Virus Immunotherapy Drives Oncolytic Effects and Durable Systemic Antitumor Immunity

Area of Science:

• Oncolytic virotherapy
• Immunotherapy
• Cancer research

Background:

• Recombinant Newcastle Disease Virus (NDV) engineered to express granulocyte-macrophage colony-stimulating factor (GM-CSF) exhibits oncolytic properties.
• Understanding the immune-modulating effects of NDV-based therapies is crucial for optimizing cancer treatment strategies.

Purpose of the Study:

• To evaluate the oncolytic activity and immune-modulating potential of recombinant NDV encoding human or murine GM-CSF (NDVhuGM-CSF, MEDI5395 and NDVmuGM-CSF).
• To assess the efficacy of NDVmuGM-CSF as a combination therapy with immune checkpoint inhibitors or T-cell agonists in preclinical cancer models.

Main Methods:

• Generation of recombinant NDV encoding human or murine GM-CSF.
• Assessment of viral replication in human and murine tumor cell lines.
• Intratumoral administration of NDVmuGM-CSF in syngeneic mouse models, with or without anti-PD-1/PD-L1 or T-cell agonists.
• Ex vivo immune profiling, including T-cell receptor sequencing.
• CRISPR-Cas9 modification of tumors to enhance viral permissiveness.

Main Results:

• NDVhuGM-CSF and NDVmuGM-CSF demonstrated oncolytic activity and modulated immune-related genes in human tumor cells.
• NDVmuGM-CSF showed antitumor effects in vivo, which were enhanced by combination therapy.
• Immune profiling revealed TME reprogramming towards an immune-permissive state, with primed adaptive immunity.
• CRISPR-modified tumors showed increased permissiveness to NDV, leading to immune-mediated effects in non-injected tumors.

Conclusions:

• MEDI5395 (NDVhuGM-CSF) primes and augments cell-mediated antitumor immunity.
• This NDV-based oncolytic virus holds significant potential as a combination therapy partner for immunomodulatory cancer treatments.