Structure Guided Design of T-Cell Receptors for Improved Immunotherapy
Student: David Hardwicke, 2016-2017
Sponsor: Prof. Brian Baker, Chemistry & Biochemistry, Notre Dame, IN
Adoptive cell transfer using engineered T cells allows one to introduce T cell receptor (TCR) modifications which can enhance the binding affinity needed for the interaction between the TCR and antigens bound to major histocompatibility complexes (MHC) on tumor cells. These modified T-Cells can then recognize, target and destroy the targeted tumor cells.Typically, TCRs possess only low-moderate affinity for their ligand antigenic peptide/MHC complex (pMHC). Because of the lower binding affinity of TCRs, much research has been focused on genetically engineering (GE) TCRs with higher binding affinities to be used as therapeutics and vaccines in cancer therapy. The hope is to increase binding affinity and thus increase the potency of the immune response. So far, scientists have managed to engineer TCRs to have a greater than normal binding affinity for tumor antigens.However, the problem which has come with this increased binding affinity is cross-reactivity -- an unwanted side effect which arises from the genetic engineering of TCRs. This results in the destruction of important, healthy cells in our bodies and can be fatal. Dr. Baker's research aims to fix this crucial problem by applying structured based computational design to TCR modification. By using in-depth models and computational design, Dr. Baker's technology can improve the binding affinity a TCR has for a cancer antigen (this improves the potency of the cancer treatment) while simultaneously decreasing the risk of cross-reactivity.This will hopefully lead to more effective cancer treatments with less risk for the patient.