Next-generation oncolytic virus with conditional nanobody-based tumor targeting and checkpoint blockade delivery – NANOVIR

Immunotherapy has proven to be a game changer in the treatment of cancer. The most emblematic clinical successes of cancer immunotherapy can arguably be attributed to the inhibition of the PD-1/PD-L1 axis using blocking antibodies referred to as immune checkpoint inhibitors (ICI). These drugs may rewire cytotoxic T cell activity, in turn potentially leading to the eradication of the tumor. The discovery of ICIs (i.e., anti-PD-1, anti-PD-L1 or anti-CTLA-4, a receptor triggering another inhibitory pathway) led to the attribution of the 2018 Medicine Nobel prize to James Allison and Tasuku Honjo. Unfortunately, these treatments are so far successful in a minority of patient. In fact, these approaches heavily rely on the presence of pre-infiltrated T cells within the tumor microenvironment (TME) prior to the initiation of the treatment. In many cases, T cells are either maintained at the periphery of the tumors, or totally absent. Consequently, those non-inflamed “cold” tumors are usually insensitive to ICI therapy, which spotlights the critical need to develop novel immunotherapy approaches to treat non-responding patients. Those include T cell retargeting via genetic engineering (CAR-T cells), or via bispecific antibodies simultaneously targeting the T cell activating receptor CD3 and a tumor associated antigen (TAA) (e.g. CD19 for B lymphoma in case of the FDA-approved blinatumomab). However, although such approaches are delivering very encouraging clinical results, they also suffer from major drawbacks associated via systemic delivery, including cytokine storms and neurotoxicity.
Instead of merely retargeting T cells, it would be attractive to stimulate a more physiological anti-tumor immune response. This is precisely the long standing goal of oncolytic virus (OV)-based tumor immunotherapies. Briefly, the principle of OV is based on the fact that such viruses mediate productive infections preferentially in tumor cells while letting healthy cells mainly unharmed. Beside virus-induced tumor lysis, growing evidence indicates that viral oncolysis is also accompanied by the release of potent danger signals, pro-inflammatory cytokines and TAAs; a process called immunogenic cell death (ICD). In brief, OV-induced ICD may not only act as an ideal ally to immunotherapy (by switching the TME from a limited (“cold”) to a high (“hot”) number of T cell-infiltrated lymphocytes), but the release of known and unknown TAA may additionally trigger a powerful in situ auto-vaccination against the tumor. However, while very promising, current OV-based approaches are currently limited by their anticancer potency.
NANOVIR proposes to synergize the recognized expertise of a French team specialized in the generation of small therapeutic antibodies (i.e. nanobodies), with the long-standing expertise of a Swiss team specialized in viral and OV engineering (i.e. Measles Virus [MeV] and its canine equivalent, Canine Distemper Virus [CDV]). Our proposal will explore the possibility of developing two innovative strategies to improve the OV platform. First, OVs will be conditionally retargeted to PD-L1- or IL13RA2-positive tumor cells through the use of novel bioengineered, nanobody-based, bispecific binders. Second, we will exploit the small size of nanobody genes to develop OVs directly secreting within the TME either T cell-retargeting bispecific antibodies and/or anti-PD-L1 ICI. Both strategies may pave the way to increase both biosafety and efficacy levels of the platform, while significantly reducing potential systemic side effects. Most importantly, because our OVs are based on the attenuated strain of CDV, this may enable us, in a near future, to directly investigate efficacy in dogs with spontaneous cancers. In turn, such a platform may act as a unique immuno-competent animal model linking mouse studies to human clinical trials (employing MeV as oncolytic vectors), and thus to contribute to improve our arsenal in modern precision cancer medicine.