Parvovirus-Based Combinatorial Immunotherapy: A Reinforced Therapeutic Strategy against Poor-Prognosis Solid Cancers

Abstract

Resistance to anticancer treatments poses continuing challenges to oncology researchers and clinicians. The underlying mechanisms are complex and multifactorial. However, the immunologically "cold" tumor microenvironment (TME) has recently emerged as one of the critical players in cancer progression and therapeutic resistance. Therefore, TME modulation through induction of an immunological switch towards inflammation ("warming up") is among the leading approaches in modern oncology. Oncolytic viruses (OVs) are seen today not merely as tumor cell-killing (oncolytic) agents, but also as cancer therapeutics with multimodal antitumor action. Due to their intrinsic or engineered capacity for overcoming immune escape mechanisms, warming up the TME and promoting antitumor immune responses, OVs hold the potential for creating a proinflammatory background, which may in turn facilitate the action of other (immunomodulating) drugs. The latter provides the basis for the development of OV-based immunostimulatory anticancer combinations. This review deals with the smallest among all OVs, the H-1 parvovirus (H-1PV), and focuses on H-1PV-based combinatorial approaches, whose efficiency has been proven in preclinical and/or clinical settings. Special focus is given to cancer types with the most devastating impact on life expectancy that urgently call for novel therapies.

Keywords: colorectal cancer; combination therapy; glioblastoma; immunotherapy; melanoma; oncolytic; pancreatic cancer; parvovirus; tumor microenvironment.

Figure 1

H-1PV-induced modulation of tumor microenvironment immune landscape. (a) Immunosuppressive (“cold”) tumor microenvironment (TME) of a solid tumor. The tumor is often infiltrated with abundant immunosuppressive regulatory T cells (Treg)/myeloid-derived suppressor cells (MDSC). Tumor-infiltrating lymphocytes (TILs) (CD8+ CTLs, CD4+ Th cells) are scarce and/or anergic. Tumor and various TME cells produce anti-inflammatory cytokines to maintain immune suppression and facilitate tumor growth and dissemination. (b) Tumor infection with H-1PV results in immunogenic tumor cell death leading to the release proinflammatory cytokines, pathogen- and danger-associated molecular patterns (PAMPs and DAMPs), which alarm the immune system. The infection of tumor cells does not necessarily have to be productive for this immuno-stimulating effect to be achieved. Furthermore, abortive infection of immunocytes (CTLs, Th cells, monocytes/macrophages) with H-1PV can also lead to their activation. In contrast, H-1PV inhibits the immune suppressive functions of Treg cells. An immunological switch takes place and converts the “cold” TME into a “warmed up” (inflamed) one. Virus-mediated immuno-conversion of TME favors the mounting of enhanced antitumor immune responses.

Figure 2

Parvovirus-based viro-immunotherapeutic combinations under development against pancreatic ducatl adenocarcinoma (PDAC). H-1PV-induced tumor cell lysis cooperates with gemcitabine-triggered programmed tumor cell death, valproic acid (VPA)-dependent epigenetic transcription regulation or interferon (IFN)-γ-induced immuno-stimulation to suppress PDAC. Preclinical data suggest that the immune system mediates, at least in part, this cooperation. H-1PV infection of tumor cells leads to the release of PAMPs/DAMPs, such as high-mobility group box 1 protein (HMGB1), which in turn alert the immune system to danger and mobilize an inflammatory antitumor immune response. Various aspects of H-1PV-, gemcitabine-, VPA- and IFN-γ-exerted immunomodulation may converge and synergize upon exposure of the host immune system to the respective combinations. The underlying mechanisms remain to be elucidated in detail by gathering extensive clinical experience. For details and references, see main text.

Figure 3

Rationale for combining H-1PV administration with bevacizumab treatment in patients with recurrent glioblastoma multiforme (GBM). Bevacizumab antibody and H-1PV infection share the capacity for inhibiting vascular endothelial growth factor (VEGF) (production) (upper row) and triggering distinct immuno-modulations (lower rows), raising hopes to improve antitumor immunity by combining both treatments. In support of this strategy, bevacizumab and H-1PV were found to jointly achieve significant clinical improvement in GBM patients at second or third recurrence, leading to remission of the recurrent tumor. The precise mechanisms of this therapeutic potentiation remain to be determined. However, the establishment by H-1PV of an immunologically “improved” proinflammatory background, which facilitates bevacizumab-mediated immuno-stimulating effects, is a likely scenario. For details and references, see the main text.

Figure 4

H-1PV inclusion into combinatorial anticancer immunotherapy regimens. The development of H-1PV combinations with ionizing radiation, chemotherapeutics, histone deacetylase inhibitors (HDACis), angiogenesis inhibitors and immunomodulators holds significant promise for the future of poor-prognosis solid cancer treatment.