Advancing CAR T cell therapy for solid tumors

PROJECT SUMMARY/ABSTRACT
Chimeric Antigen Receptors (CAR) are engineered receptors that direct the killing activity of T cells to targets of
interest and have had dramatic results in the treatment of B cell leukemia. However, the application of this
technology to lung tumor remains challenging in part due to inhibitory tumor microenvironments (TME). An
immunosuppressive TME is seen even at the earliest stages of human lung cancer. These tumors are infiltrated
with immunosuppressive cells including macrophages and T regulatory cells, and have a reduction in effector T
cells. Clinical trials using large doses of solid-tumor directed CAR T cells did not find clear radiographic
responses. While numerous approaches to improve CAR T cell persistence and killing of solid tumors have been
developed, to-date, it remains unclear why clinical responses to second-generation CAR T cells have not
reproduced the dramatic success seen in the treatment of B cell malignancies. Evidently, this challenge requires
mechanistic studies that are only possible in clinically meaningful solid tumor models. This proposal aims to
define the factors what have limited CAR T cell efficacy against solid tumors by building an immunocompetent
tumor model and testing novel therapeutic strategies. We propose to develop the first autochthonous solid tumor
model targeted by CAR T cells. This model will allow us to test CAR T cells on tumors that faithfully recapitulate
the immunosuppressive TME. Prior studies have suggested that radiation can alter the TME. We will use this
model to determine if and how radiotherapy can augment CAR T cell killing of solid tumors. Furthermore, recent
gene editing and delivery advances in CAR T cells have created new avenues to develop novel CAR T cell
therapies that require immunocompetent models for preclinical validation and safety testing. We will use this
platform to test different therapeutic strategies to overcome the immunosuppressive TME that include tumor-
directed radiotherapy, CAR T cell expansion, and gene editing of CAR T cells with CRISPR/Cas9 to avoid
immunosuppressive interactions or reverse them. These experiments will aid in the advancement of CAR T cell
therapy for solid tumors and provide a foundation to determine the applicability of TME-directed approaches to
other targetable solid malignancies.

Grant Number: 5DP5OD031828-05
NIH Institute/Center: NIH
Principal Investigator: Jalal Ahmed