Towards LNP Vaccine Immune-Interception for Childhood Cancer Predisposition Syndromes
Project Team
- Uri Tabori, MD, The Hospital for Sick Children
- David Malkin, MD, FRCP(C), The Hospital for Sick Children
- Drew Weissman, MD/PhD, University of Pennsylvania
- Gad Getz, PhD, Broad Institute
- Derin Keskin, PhD, Dana-Farber Cancer Institute
- Steve Lipkin, MD/PhD, Weill Cornell Medical College
- Trevor Pugh, PhD, University Health Network
- Cynthia Hawkins, MD/PhD, The Hospital for Sick Children
Children that inherit mutations causing cancer have cancer predisposition syndromes (CPS). The 2 most aggressive CPS are Li-Fraumeni syndrome (LFS) and replication repair deficiency (RRD). Each of these is associated with an almost 100% lifetime risk of cancer that can occur in almost any organ of the body. Moreover, RRD/LFS cancers are resistant to chemotherapy and radiation. Therefore, RRD/LFS are responsible for most CPS cancers and death in children and young adults.
Since both RRD/LFS have no ability to repair damaged DNA, their cancers are collecting many mutations causing tiny tumors which explode into fast-growing, deadly cancers. Although we are able to detect early cancers using tools such as imaging and liquid biopsy, the challenge is to find effective therapies to cure RRD/LFS cancers at their early phase.
Our team discovered that the immune system offers exciting new therapies in RRD/LFS cancers. Here we plan to use this approach to destroy cancer cells before they spread around the body and become deadly. This concept, called ‘immune interception’, is the basis for how vaccines work. Vaccines are designed to target proteins (antigens) that are newly created by mutations (‘neoantigens’). By attacking these neoantigens, vaccines cure cancer with milder and fewer side effects than chemotherapy or radiation. The newest form of vaccines which eliminated COVID is called RNA vaccines. Our team has focused on this technology to treat LFS/RRD cancer cell neoantigens.
Project Goal
Our global RRD/LFS groups have assembled an international team of experts in cancer genomics, liquid biopsy (monitoring presence of neoantigens that are shed from undetectable cancer cells into the bloodstream) and Nobel prize winning RNA vaccine development. Our goal is to create, for the first time, cancer vaccines that will treat all types of cancers in RRD/LFS. To achieve this ambitious goal, we will use 3 aims: Our first aim will be to find the shared neoantigens in a wide range of RRD/LFS cancers that specifically trigger the immune system to respond and attack them (these are called immunogenic neoantigens).Our second aim will be to package the most immune triggering neoantigens we discover in Aim 1 into RNA vaccines. The benefit of these new vaccines is in their ability to include many neoantigens at once.Our third aim will be to test these powerful vaccines both alone and in combination with different immunotherapy agents (to ‘boost’ the system) in our unique mouse models. We will test their ability to intercept progression of early tumors into deadly malignant cancer.
Serial liquid biopsies will be used throughout the project to detect whether the vaccine is eliminating cancer cells (and antigens) and whether new neoantigens develop over time which would mean that different vaccine strategies are needed. Success of our project will lead to development of vaccines to prevent cancers from starting at all in LFS and RRD – and eventually other cancers.
