Immune therapies have caused a paradigm shift in the treatment of melanoma and leukemias. However, the broad application of these therapies to all cancers has not yet materialised. One of the major reason for this failure is the presence of innate immune suppressive cell types in many tumour types, such as macrophages, NK-, dendritic, and myeloid cells. Tumour selective reactivation of these cells is considered one of the holy grails for the future of immune therapy.
Most endeavours in achieving this are severely hampered by the toxicity of innate immune activators: they cause strong off-site-on-target systemic immune activation, which can lead sepsis-like symptoms and death. Developing innate immune activating therapies that are both powerful and safe are therefore key to applying immune therapies across the cancer landscape.
As part of my ERC-CoG-Grant I have developed innnate immune activators of which the activity is blocked, but that can be reactivated chemically . This approach can potentially serve as exactly the safe and potent innate activator required. By targeting the innate activators to the tumour and only activating them locally once they have accumulated there, we can decouple the therapeutic activity from the systemic toxicity that plagues these approaches.
In this proposal, we aim to evaluate the first such a caged innate immune activator in a pre-clinical cancer model. We will validate its potency, pharmacokinetics and caging/decaging behaviour. In addition, we will broaden the scope of the innate activators, antibodies and uncaging chemistries that can be applied. We will also perform market research to determine the optimal tumour-immune activator-antibody combination to take forward into clinical development and begin to take the necessary steps to spin out a company based on this work to bring these non-toxic innate activators to the clinic.
