Targeted Immunocytokines by CaGing and local Release

Introduction

Immune therapies have caused a paradigm shift in the treatment of melanoma and leukemias. However, the broad application of these immune therapies to all cancers has not worked. One of the major reasons for this failure is the presence of innate immune suppressive cell types in many tumor types, such as macrophages, NK, dendritic, and myeloid cells. Tumor-selective reactivation of these cells is considered one of the holy grails for the future of immune therapy.

Challenges in Immune Activation

Most endeavors 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 to sepsis-like symptoms and death.

Developing innate immune activating therapies that are both powerful and safe is therefore key to applying immune therapies across the cancer landscape.

Proposed Solution

As part of my ERC-CoG-Grant, I have developed innate immune activators that are chemically blocked but can be reactivated locally. This approach can potentially serve as the safe and potent innate activator required.

By targeting the innate activators to the tumor and only activating them once they have accumulated there, we can decouple the therapeutic activity from the systemic toxicity that plagues these approaches.

Project Objectives

In this proposal, we aim to evaluate the first such caged innate immune activator in a pre-clinical cancer model. Our specific objectives include:

1. Validating its potency, pharmacokinetics, and caging/decaging behavior.
2. Broadening the scope of the innate activators, antibodies, and uncaging chemistries that can be applied.
3. Performing market research to determine the optimal tumor-immune activator-antibody combination to take forward into clinical development.
4. Taking the necessary steps to spin out a company based on this work to bring these non-toxic innate activators to the clinic.