Counteracting Immunosuppression in the Tumor Microenvironment by Oncolytic Newcastle Disease Virus and Cellular Immunotherapy

Abstract

An apparent paradox exists between the evidence for spontaneous systemic T cell- mediated anti-tumor immune responses in cancer patients, observed particularly in their bone marrow, and local tumor growth in the periphery. This phenomenon, known as “concomitant immunity” suggests that the local tumor and its tumor microenvironment (TME) prevent systemic antitumor immunity to become effective. Oncolytic Newcastle disease virus (NDV), an agent with inherent anti-neoplastic and immune stimulatory properties, is capable of breaking therapy resistance and immunosuppression. This review updates latest information about immunosuppression by the TME and discusses mechanisms of how oncolytic viruses, in particular NDV, and cellular immunotherapy can counteract the immunosuppressive effect of the TME. With regard to cellular immunotherapy, the review presents pre-clinical studies of post-operative active-specific immunotherapy and of adoptive T cell-mediated therapy in immunocompetent mice. Memory T cell (MTC) transfer in tumor challenged T cell-deficient nu/nu mice demonstrates longevity and functionality of these cells. Graft-versus-leukemia (GvL) studies in mice demonstrate complete remission of late-stage disease including metastases and cachexia. T cell based immunotherapy studies with human cells in human tumor xenotransplanted NOD/SCID mice demonstrate superiority of bone marrow-derived as compared to blood-derived MTCs. Results from clinical studies presented include vaccination studies using two different types of NDV-modified cancer vaccine and a pilot adoptive T-cell mediated therapy study using re-activated bone marrow-derived cancer-reactive MTCs. As an example for what can be expected from clinical immunotherapy against tumors with an immunosuppressive TME, results from vaccination studies are presented from the aggressive brain tumor glioblastoma multiforme. The last decades of basic research in virology, oncology and immunology can be considered as a success story. Based on discoveries of these research areas, translational research and clinical studies have changed the way of treatment of cancer by introducing and including immunotherapy.

CD44 targeted delivery of oncolytic Newcastle disease virus encapsulated in thiolated chitosan for sustained release in cervical cancer: a targeted immunotherapy approach

“…One of the biggest concerns in oncolytic virotherapy is host immunity that mediates viral clearance through complement mediated antibody-dependent neutralization. Therefore, a biocompatible, polymer based targeted drug delivery system with ability of sustained release can enhance oncolytic potential and prolong availability of virus in tumor microenvironment ( 32 ). As reported, mesenchymal cells encapsulating NDV for selective delivery to murine TC-1 cells and in tumor models showed significantly enhanced oncolytic effect as compared to naked virus ( 6 ).…”

Individualized Multimodal Immunotherapy (IMI): Scientific Rationale and Clinical Experience from a Single Institution

“…How immunosuppression in the TME can be counteracted by oncolytic NDV and IMI has been reviewed [39]. Twelve anti-neoplastic effects of NDV in non-permissive hosts as well as 11 immune stimulatory effects have been described [3].…”

Bone Marrow: The Central Immune System

“…The topic of counteracting immunosuppression in the TME by oncolytic NDV and cellular immunotherapy has recently been reviewed [179]. Importantly, OVs and cancer vaccines exert profoundly lower side effects in cancer patients than other systemic therapies [180].…”