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

**Assia Angelova 1,\* , Tiago Ferreira <sup>2</sup> , Clemens Bretscher <sup>2</sup> , Jean Rommelaere <sup>1</sup> and Antonio Marchini 2,3**


**Simple Summary:** Oncolytic virotherapy using oncolytic viruses with natural or engineered cancerdestroying capacities has emerged as a promising treatment concept in modern oncology. Rodent protoparvoviruses, in particular the rat H-1 parvovirus (H-1PV), have demonstrated their broadrange tumor-suppressive properties in both preclinical models and clinical studies. In addition to inducing selective tumor cell death, these viruses are also able to exert immunostimulating effects and reverse tumor-driven immune suppression. Parvovirotherapy holds therefore a potential for enhancing the efficacy of other cancer immunotherapies. The aim of this review is to provide an overview of all H-1PV-based combinatorial immunotherapeutic approaches against poor-prognosis human solid cancers that have been tested so far. Current challenges and future prospects of parvoviro-immunotherapy, notably parvovirus inclusion into various immunotherapeutic protocols against glioblastoma, pancreatic cancer, among other standard therapy-refractory solid malignancies, are also discussed in the light of H-1PV further clinical development.

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

**Citation:** Angelova, A.; Ferreira, T.; Bretscher, C.; Rommelaere, J.; Marchini, A. Parvovirus-Based Combinatorial Immunotherapy: A Reinforced Therapeutic Strategy against Poor-Prognosis Solid Cancers. *Cancers* **2021**, *13*, 342. https:// doi.org/10.3390/cancers13020342

Received: 17 December 2020 Accepted: 15 January 2021 Published: 19 January 2021

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