Pouring petrol on the flames: Using oncolytic virotherapies to enhance tumour immunogenicity

Abstract

Oncolytic viruses possess the ability to infect, replicate and lyse malignantly transformed tumour cells. This oncolytic activity amplifies the therapeutic advantage and induces a form of immunogenic cell death, characterized by increased CD8 ⁺ T-cell infiltration into the tumour microenvironment. This important feature of oncolytic viruses can result in the warming up of immunologically 'cold' tumour types, presenting the enticing possibility that oncolytic virus treatment combined with immunotherapies may enhance efficacy. In this review, we assess some of the most promising candidates that might be used for oncolytic virotherapy: immunotherapy combinations. We assess their potential as separate agents or as agents combined into a single therapy, where the immunotherapy is encoded within the genome of the oncolytic virus. The development of such advanced agents will require increasingly sophisticated model systems for their preclinical assessment and evaluation. In vivo rodent model systems are fraught with limitations in this regard. Oncolytic viruses replicate selectively within human cells and therefore require human xenografts in immune-deficient mice for their evaluation. However, the use of immune-deficient rodent models hinders the ability to study immune responses against any immunomodulatory transgenes engineered within the viral genome and expressed within the tumour microenvironment. There has therefore been a shift towards the use of more sophisticated ex vivo patient-derived model systems based on organoids and explant co-cultures with immune cells, which may be more predictive of efficacy than contrived and artificial animal models. We review the best of those model systems here.

Keywords: oncolytic viruses; CAR T cells; antibodies; immunotherapy; model systems; virotherapy.

FIGURE 1

Oncolytic viruses as a cancer therapeutic. Oncolytic viruses (OVs) can be engineered to selectively recognize tumour cells (1), replicate within those infected cells to produce thousands of daughter virions (2) and lyse tumour cells, releasing tumour antigens into the tumours microenvironment, where they can be processed by dendritic cells and presented to T cells (3)

FIGURE 2

Current immunotherapies selectively enhance immune response. Immune checkpoint inhibitors bind to and inactive negative regulators of immunity such as CTLA‐4 and PD‐L1. Depleting antibodies recognize tumour antigens and can be administered directly to a patient, where they bind the TAA on tumour cells and stimulate immune cell activation. CAR T cells are generated by removing T cells from cancer patients, genetically transforming them using a viral vector to present chimeric antigen receptors targeted selectively to TAAs, expanded ex vivo and reinfused into the patient. Bispecific molecules, BiKEs, BiTEs and ImmTACs, target the interaction between the T cell or NK cell and the TAA/pHLA presented on the tumour cell and physically synapse the two, activating the T cell and resulting in immune‐ mediated tumour cell killing

FIGURE 3

Oncolytic viruses, pieces of the puzzle. OVs can direct immunotherapies such as ICI, depleting antibodies, CAR T cells and bispecific antibodies to the tumour and consequently reduce off‐target and dose‐dependent toxicity, thereby increasing the efficacy of the treatment

FIGURE 4

Production of BiTEs expressed by adenovirus. OAd ICO15K is an engineered adenovirus expressing CBiTE (ICOVIR‐15K) or an FBITE (OAd ICO15K ‐FBiTE). BiTEs utilize the ScFv portion of the monoclonal antibody to target different proteins. In this case, the N‐terminal of the BiTE targets either EGFR (cBiTE) or FAP (fBiTE), whilst the c‐terminal of the BiTE was specific for CD3

FIGURE 5

Using viruses to target multiple pathways. The CAdTrio virus is able to produce (i) a BiTE specific for CD44v6⁺ cancer cells, thereby bringing these cells into contact with the T cells via the TCR, (ii) antibodies against anti‐PDL‐1 resulting in the prevention of PD‐ 1/PDL‐1 interaction and in immune checkpoint inhibition and (iii) IL‐12 to stimulate the growth and function of T cells. When this virus is used in combination with HER‐2‐specific T cells, this also induces the interaction between HER2⁺ cancer cells and the CAR molecules on the T cells resulting in the cell death of HER2⁺ and HER2^−/− CD44v6 tumours