Project Term
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Project Summary
This project will identify and engineer strategies to improve the function of chimeric antigen receptor (CAR) T cells in patients with relapsed/refractory large B-cell lymphoma. We will leverage our recent discoveries in lymphoma and CAR T cell therapy to (i) determine if the tumor influences the T cells that are harvested for CAR T manufacture, (ii) engineer T cells to be more resilient to suppressive signals in the tumor, and (iii) engineer T cells to have greater infiltration into tumors.
Lay Abstract
Autologous chimeric antigen receptor (CAR) T cell therapy was first approved for relapsed or refractory large B-cell lymphomas in 2017 and has transformed outcomes for these patients, likely curing approximately 40% of the patients that are able to receive the treatment. In lymphomas, the anti-cancer immune response is defective due to a variety of mechanisms. CAR T cell therapy takes the patient’s own T cells from the peripheral blood and uses a virus to introduce a receptor on their cell surface that recognizes lymphoma B cells and activates the T cell to kill them. However, the mechanisms that allow lymphomas to evade the immune response in the first place can also allow them to evade or suppress CAR T cell functions. We have recently discovered two important mechanisms contributing to the failure of CAR T cells: (i) direct suppression of CAR T cell function by cells within the lymphomas, and (ii) prevention of CAR T cells from entering the tumor. We hypothesize that these mechanisms will be reflected in different measures of T cell functionality when they are harvested for CAR T cell manufacture and can be overcome by data-driven CAR T cell reprogramming. To accomplish this, the labs of Dr. Michael Green, a lymphoma and CAR T cell expert at MD Anderson Cancer Center, and Dr. Isaac Hilton, an expert in bioengineering and cutting edge CRISPR reprogramming technologies at Rice University, are combining their expertise. We propose to (Aim 1) evaluate peripheral blood T cells from patients receiving CAR T cell therapy to determine whether their profiles reflect the immune state of their lymphomas; (Aim 2) use CRISPR reprogramming of CAR T cells to overcome the direct suppressive effects of immune cells within lymphomas; and (Aim 3) use our novel patient derived xenograft models to understand mechanisms of T cell exclusion from tumors and define CRISPR engineering strategies to overcome them. We envision moving from a one-size-fits-all model of CAR T cell therapy to a modular system in which patients receive one of a few different designs of CAR T cells that are most suited to target their lymphoma type.
Program
