A combined immunotherapy for melanoma using herpes simplex virus I derived oncolytic viruses and conventional dendritic cells

According to the World Health Organization (WHO), cancer is one of the leading causes of death worldwide. Among all different types of cancer, melanoma is situated in the top twenty most occurring cancer types in the world. For a long time, cancer treatment was largely based on three standard therapies; namely surgery, chemotherapy and radiotherapy. During the last decade, immunotherapy has taken an increasingly prominent place in cancer treatment. A successful immunotherapy must aim to enhance effector mechanisms, while reduce the suppressive mechanisms. The most successful type of immunotherapy so far is based on targeting the so-called immune checkpoint molecules, which suppresses immune cells targeting the tumor. Although this type of therapy has been shown to be very successful, a significant number of patients still do not respond to this therapy, indicating that additional therapeutic modalities are still necessary.
A more recent type of immunotherapy are oncolytic viruses (OVs), characterized by their ability to specifically infect and replicate within tumor cells and eventually induce tumor cell death which is linked to the release of mature virions that are able to infect neighbouring tumor cells. Although there is a lot of evidence that OVs are able to generate potent anti tumor responses due to the release of the so-called pathogen associated molecular patterns (PAMPs, e.g. viral DNA), also the type of cell death that the tumor cells subjected to plays an important role in the induction of strong anti-tumor immune responses. In that respect, the release of various so-called danger associated molecular patterns (DAMPs) and tumor associated antigens (TAAs) from the dying tumor cells can lead to a strong activation of the immune system, a process which is called immunogenic cell death (ICD).
Next to checkpoint inhibitors and OVs, dendritic cell (DCs) vaccines, often based on monocyte derived DCs (moDCs), are capable of inducing anti-tumor responses but their efficacy remains rather limited. Many different types of DCs, each with a different phenotype and function, have been identified. Of these, type 1 conventional DCs (cDC1s) possess an excellent antigen processing capability and cross-presentation activity which makes them an interesting partner to use in combined therapies.
In this dissertation, we studied Talimogene laherparepvec (T-VEC), an oncolytic herpes simplex virus type I (oHSV-1) encoding for granulocyte-macrophage colony stimulating factor (GM-CSF), which received regulatory approval by both European Medicines Agency (EMA) and Food and Drug Administration (FDA), alone or in combination with cDC1s. We demonstrated that T-VEC is able to infect and replicate within both human derived (624-mel, 938-mel and CHL-1) and murine derived (D4M.3A) cell lines and induce ICD. Furthermore, T-VEC is capable of maturing human blood derived BDCA-1+ and BDCA-3+ myeloid DCs myDCs, cDC2 and cDC1, respectively) as well as the murine DC cell line DC2.4 and in vitro generated murine CD103+ DCs. Both human and murine derived DCs can engulf tumor fragments deriving from T-VEC treated cells and cross-present them towards antigen-specific T cells. Finally, we could show, in a preliminary preclinical in vivo study, that a combination therapy including T-VEC and in vitro generated CD103+ DCs is able to control tumor progression more effectively than T-VEC or DCs alone. Taken together, data suggest that combination therapies consisting of OVs and cDC1s, potentially supplemented with immune checkpoint inhibitors, are a promising avenue for further investigations in the clinical development of novel cancer therapies.