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  • br Heating Up Immunologically Cold Tumours With an

    2018-10-23


    Heating Up Immunologically Cold Tumours With an Oncolytic Virus As discussed our immune systems have evolved elaborate mechanisms to react against invading pathogens and rapidly mount immune responses to eliminate the pathogen and in some instances, the cells they infect. OVs are natural pathogens that have been selected or designed to specifically infect and destroy cancer cells. Tumour cell infection by an OV leads to an inflammatory response with localized production of cytokines that favour the elaboration of an immune response (Breitbach et al., 2007; Worschech et al., 2009). At the same time, it is thought that virus mediated tumour lysis leads to the liberation of tumour associated antigens and/or mutant proteins that have arisen during tumour evolution. Indeed Woller and colleagues have shown in a mouse tumour model that oncolytic adenovirus tumour therapy stimulates therapeutically beneficial immune responses against mutanome peptides (Woller et al., 2015). Imlygic has provided the first convincing human data supporting the idea that direct tumour lysis by a replicating virus can locally stimulate sufficient anti-tumour immune responses to provide systemic, long lasting, cancer killing immune responses in advanced cancer patients (Senzer et al., 2009; Kaufman et al., 2010; Andtbacka et al., 2015). This product was administered multiple times via direct intratumoral injection and, in the OPTiM pivotal phase III trial as a mono-therapy, generated durable responses in over 16% of patients (Andtbacka et al., 2015). At the time of FDA approval, Imlygic was shown to have improved overall survival versus treatment with GM-CSF (p=0.049, Hazard Ratio=0.79). In earlier phase I and II studies, Imlygic therapy was shown to increase T cell infiltration into tumours and generate a systemic immune response against tumour associated antigens like MART1 (Kaufman et al., 2010).
    Timing is Everything! – Making a Good Therapeutic Great! In a follow-up retrospective analysis of the OPTiM trial, Imlygic was found to generate complete responses in 17% of advanced cancer patients thus providing the oncologist with a new monotherapy treatment option for melanoma patients. However the better news is that Imlygic arrived on the scene coincident with the tremendous clinical excitement surrounding the approval of order C646 targeting immune checkpoint molecules (e.g. Yervoy [Bristol-Meyers Squibb] directed against CTLA4 and Keytruda [Merck], Opdivo [Bristol-Meyers Squibb] against PD1). As mentioned above, these immune checkpoint inhibitor antibodies interrupt negative feedback systems within the tumour bed effectively “taking the brakes off” pre-existing anti-tumour immune responses (Pardoll, 2012) and can create durable responses that are on a trajectory for cure as monotherapies in as many as 20% of patients (Topalian et al., 2012) (depending upon the indication). For the remaining 80% of patients it appears that a lack of anti-tumour immune responses or other immune suppressive aspects of the tumour microenvironment still need to be corrected before immune checkpoint inhibitors (ICIs) can provide benefit. Infection of tumours by an OV triggers induction of anti-tumour immunity and recruitment of T cells to tumours; addition of the ICI ensures those T cells remain active (Fig. 1). Indeed, Imlygic seems to be a perfect complement to ICIs and as predicted, in ongoing phase I studies Imlygic used in combination with Yervoy significantly increases durable response rates in melanoma patients over what would be expected from either agent alone, perhaps providing benefit in as many as 50% of patients treated including many with significant tumour burden (Puzanov et al., 2016). The anti-PD1 immune checkpoint inhibitor Keytruda is also being studied in combination with Imlygic in patients with melanoma and head and neck cancer (NCT02263508, NCT02626000). Thus Imlygic continues to provide clinical evidence for the “in situ vaccine” paradigm for oncolytic viruses demonstrating that virus oncolysis, even in a limited number of tumours, can generate systemic anti-tumour immunity. These early clinical results are encouraging but they also raise a number of questions. Why do only a minority of patients experience complete response on Imlygic monotherapy even though direct injection of tumours should be the optimal way to deliver a maximum dose of virus to the tumour bed? Are the majority of tumours injected by this route only marginally infectable? Could a more potent OV have more profound tumour lytic and in situ vaccine effect? Can outcomes be improved with optimized Imlygic dosing strategies? Are uninfected tumours in the majority of patients resistant to the systemic immunity that local Imlygic therapy initiates? Will other tumour indications beside melanoma respond systemically after locoregional virus therapy?