Defining how unique properties of the pediatric immune system contribute to poor efficacy of checkpoint blockade in children
Novel therapies are desperately needed for pediatric solid tumors, where more than 30% of patients die from their disease. Immunotherapies offer a significant potential to meet this need. However, this potential has not yet been realized, largely due to differences in how the immune system reacts to pediatric cancers. Pediatric tumors have less mutations than adult tumors. To the immune system, few mutations means that pediatric tumors appear more similar to healthy tissue than do adult tumors. In turn, this provides an added layer of difficulty in trying to develop therapies that use the immune system to attack pediatric tumors, but spare healthy tissue. While pediatric tumors have only a few mutations, they do incorrectly make proteins that are typically only found in the developing fetus or in gonadal tissue, but not in other healthy tissue after birth (oncofetal/cancer-testis proteins). In theory, these proteins are targetable for next generation immunotherapies for children.
Project Goal:
Unfortunately, how the immune system regulates responses to these oncofetal/cancer-testis proteins is poorly understood, which currently limits development of novel immunotherapies for children. Our preliminary data suggest that mechanisms within the body that are designed to help prevent autoimmunity can hinder immune responses to some, but not all, oncofetal/cancer-testis proteins. Therefore, my overall objective is to define how the immune system recognizes and regulates immune responses to these oncofetal/cancer-testis proteins, in order to inform and drive development of the next generation of immunotherapies for pediatric cancers.
