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.

Keywords: TAA; active-specific immunotherapy (ASI); adoptive T cell immunotherapy; bone marrow (BM); cancer vaccine; dendritic cell (DC); interferon-I; memory T cell (MTC); therapy resistance; tumor dormancy.

Figure 1

Schematic illustration of mechanisms of anti-tumor activity of NDV, exemplified with a migratory and invasive glioblastoma (GBM) cell. 1. Macropinocytosis/endocytosis of NDV targeting Rac1, which plays a cardinal role in oncogenic alterations and in development of drug resistance. The direction of cell movement is accompanied by an increase in Rac1 expression from the trailing edge (left) to the leading edge at the lamellipodia (right). 2. Targeting the cap-dependent translational machinery, viral mRNA to protein translation in the cytosol and later in the double-membraned autophagosome. This is achieved through the MNK1/2-eIF4E axis. 3. Tumor-selective virus replication in autophagosomes. The clam shaped symbol stands for the helical nucleocapsid structure composed of L, P, and NP proteins. 4. Virus progeny encapsulation, budding, and virus release mediated via M, HN, and F. 5. Antiviral response of healthy normal cells, including immune cells (APC; T, NK) initiated through recognition of HN by NKp46 and other PAMPs by TLRs and RLRs leading to IFN-I secretion and to DC1 and Th1 polarized adaptive immunity responses. 6. NDV-induced tumor cell death responses (oncolysis). These involve extrinsic (immune-mediated) and intrinsic cell death signaling pathways. ICD-derived components feed into APCs which present TAAs to T cells. Several rounds of such cycles (1–6) drive oncolytic effects and lead to immunological memory and systemic antitumor immunity. Figure taken with permission from [93].