Abstract
Virotherapy research involves the development, exploration, and application of oncolytic viruses that combine direct killing of cancer cells by viral infection, replication, and spread (oncolysis) with indirect killing by induction of anti-tumor immune responses. Oncolytic viruses can also be engineered to genetically deliver therapeutic proteins for direct or indirect cancer cell killing. In this review—as part of the special edition on “State-of-the-Art Viral Vector Gene Therapy in Germany”—the German community of virotherapists provides an overview of their recent research activities that cover endeavors from screening and engineering viruses as oncolytic cancer therapeutics to their clinical translation in investigator-initiated and sponsored multi-center trials. Preclinical research explores multiple viral platforms, including new isolates, serotypes, or fitness mutants, and pursues unique approaches to engineer them towards increased safety, shielded or targeted delivery, selective or enhanced replication, improved immune activation, delivery of therapeutic proteins or RNA, and redirecting antiviral immunity for cancer cell killing. Moreover, several oncolytic virus-based combination therapies are under investigation. Clinical trials in Germany explore the safety and potency of virotherapeutics based on parvo-, vaccinia, herpes, measles, reo-, adeno-, vesicular stomatitis, and coxsackie viruses, including viruses encoding therapeutic proteins or combinations with immune checkpoint inhibitors. These research advances represent exciting vantage points for future endeavors of the German virotherapy community collectively aimed at the implementation of effective virotherapeutics in clinical oncology.
Highlights
Virotherapy research covers a continuum of activities, ranging from endeavors for screening and engineering viruses as oncolytic cancer therapeutics, using cutting edge technology to concerted programs for their clinical translation and implementation
While the German virotherapy landscape was introduced in a review in 2017 [28], here we present an update with a focus on recent and on-going research activities in pre-clinical and translational virotherapy research
Oncolytic adenovirus engineering and development has been a pillar of German preclinical virotherapy research over the last decades with several groups exploring a spectrum of strategies for developing novel oAds or optimizing them: (i) shielding of oAd particles; (ii) targeting, controlling, or enhancing oAd replication; (iii) “arming” of oAds with therapeutic or imaging genes; (iv) oAd-based immunotherapeutic approaches; and (v) oAd combination treatment
Summary
Virotherapy research covers a continuum of activities, ranging from endeavors for screening and engineering viruses as oncolytic cancer therapeutics, using cutting edge technology to concerted programs for their clinical translation and implementation. The defining feature of OVs is a tumor-selective infection or replication This oncotropism can be achieved by, e.g., the exploitation of defective anti-viral host responses in cancer cells, allowing for the application of interferon-sensitive viruses or virus vaccine strains [6]. Limitations that need to be overcome include virus-neutralizing blood factors and virus-sequestering phagocytes [25,26,27], blocks to viral replication and spread in cancer cells and in the tumor microenvironment (TME) [2,6,9], and sub-optimal immune activation or an immunosuppressive TME [1,3,5,7,8,10] These roadblocks must be addressed to facilitate effective systemic virus application, more potent direct tumor cell killing, and/or immune cell-mediated systemic cancer cell eradication (even after local OV application), respectively. While the German virotherapy landscape was introduced in a review in 2017 [28], here we present an update with a focus on recent and on-going research activities in pre-clinical and translational virotherapy research
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