Discussion

With the recent successes of checkpoint inhibitor antibodies, the field of cancer immunotherapy is now focussing on combination treatment regimens to further improve efficacy benefits to patients. However, combining such systemically dosed agents is associated with a number of challenges, such as enhanced side effect profiles and high costs. One strategy being explored to overcome such issues is to dose the therapeutics directly into the tumour rather than systemically, but many tumours will not be accessible for this type of treatment.

We have developed a broadly applicable platform system, based on the potent chimeric oncolytic adenovirus, enadenotucirev (EnAd), for directing the selective local production of one or a combination of immunotherapeutic agents within the tumour. A systemic clinical dosing regimen has been established for EnAd, with data directly demonstrating selective virus delivery to and protein production in colorectal and other tumour types. The advantage of this approach is that immunotherapeutics encoded in the virus can be produced locally, both in tumours that are not directly injectable and in metastases while minimising systemic off-target effects.

We have generated a large panel of genetically “armed” EnAd viruses bearing one, two or three different transgene “payloads” encoding immunotherapeutic agents. These viruses have been shown to selectively infect and express their respective payloads in human tumour cells in vitro and in vivo, while retaining the potent oncolytic properties of the parental EnAd virus. We are now using this approach to promote local efficacious anti-tumour immunity by designing combination immunotherapies that synergistically target different immune mechanisms within the tumour microenvironment.