**Hitting the Target but Missing the Point: Recent Progress towards Adenovirus-Based Precision Virotherapies**

#### **Tabitha G. Cunli**ff**e** † **, Emily A. Bates** † **and Alan L. Parker \***

Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff CF14 4XN, UK; cunliffetg@cardiff.ac.uk (T.G.C.); batese@cardiff.ac.uk (E.A.B.)

**\*** Correspondence: parkeral@cardiff.ac.uk

† Authors contributed equally to this work.

Received: 4 October 2020; Accepted: 9 November 2020; Published: 11 November 2020

**Simple Summary:** If harnessed appropriately, oncolytic viruses offer significant potential as anti-cancer agents. Such virotherapies can be engineered to replicate inside cancerous cells, stimulating the immune system, spreading daughter virions to surrounding cells and producing additional anticancer agents as a by-product of infection. To achieve this necessitates deep understanding of the biology of the virus and tumour cell, to tailor viruses from naturally pathogenic agents into refined, tumour selective "precision virotherapies" suitable for clinical translation. Here, we focus on the adenovirus, which in its pathogenic form causes transient and mild ocular, respiratory or gastrointestinal tract infections, depending on the serotype. We highlight advances that have been made in refining adenovirus to ablate natural means of infection and the strategies that have been employed to engineer viral tropism and selectivity for tumour cells. Further advances in these strategies will be required to deliver fully bespoke and efficacious precision virotherapies to the clinic.

**Abstract:** More people are surviving longer with cancer. Whilst this can be partially attributed to advances in early detection of cancers, there is little doubt that the improvement in survival statistics is also due to the expansion in the spectrum of treatments available for efficacious treatment. Transformative amongst those are immunotherapies, which have proven effective agents for treating immunogenic forms of cancer, although immunologically "cold" tumour types remain refractive. Oncolytic viruses, such as those based on adenovirus, have great potential as anti-cancer agents and have seen a resurgence of interest in recent years. Amongst their many advantages is their ability to induce immunogenic cell death (ICD) of infected tumour cells, thus providing the alluring potential to synergise with immunotherapies by turning immunologically "cold" tumours "hot". Additionally, enhanced immune mediated cell killing can be promoted through the local overexpression of immunological transgenes, encoded from within the engineered viral genome. To achieve this full potential requires the development of refined, tumour selective "precision virotherapies" that are extensively engineered to prevent off-target up take via native routes of infection and targeted to infect and replicate uniquely within malignantly transformed cells. Here, we review the latest advances towards this holy grail within the adenoviral field.

**Keywords:** adenovirus; oncolytic; virotherapy; targeting; immunotherapy; immunogenic cell death; αvβ6 integrin
