Tumor targeting through a TME-specific regulatory code and programmable CAR T cells

Descripción del proyecto

Un caballo de Troya contra el cáncer

Los linfocitos T con receptor quimérico para el antígeno (CAR, por sus siglas en inglés) constituyen un nuevo y potente método para enseñar al sistema inmunitario a combatir las neoplasias malignas. A pesar del gran potencial de los linfocitos T CAR, su eficacia clínica contra tumores sólidos se ha visto limitada por la toxicidad y la inmunosupresión. Para superar estas limitaciones, el equipo del proyecto TRAP-CART, financiado con fondos europeos, se propone inducir un microambiente tumoral favorable para la función de los linfocitos T CAR. Su idea es genomodificar células madre hematopoyéticas para producir una progenie capaz de enviar señales inflamatorias y de activación de linfocitos T CAR en las proximidades del tumor. Esta estrategia permite emplear linfocitos T CAR parcialmente inactivos que se activan en el microambiente tumoral, lo que evita la toxicidad colateral.

Objetivo

Two major issues hamper successful treatment of solid cancers with CAR T cells. First, immunosuppression imposed by the tumor microenvironment (TME) can compromise CAR T cell function. Second, CAR T cells require specific antigens for precise tumor recognition to limit/avoid toxicities associated with on-target/off-tumor activity. Initial attempts to overcome these challenges included immune checkpoint blockade and tunable CAR T cells. Here, we propose to develop a conceptually new framework for solid tumor therapy that introduces genetically modified, blood-derived TME cells as Trojan horses to deliver inflammation and broadcast “intratumor” signals that activate programmable CAR T cells. Overall, we will design a hematopoietic stem cell (HSC)-directed strategy for Tumor microenvironment-Regulated Activation of Programmable CAR T (TRAP-CART). This project builds on the host lab’s expertise in high-throughput genomics, bioinformatics, and CAR T cells, and on my own background in HSC engineering.

Through epigenome/transcriptome profiling, we will systematically identify gene-regulatory elements that are specific to blood-derived cells in the TME. We will use such regulatory sequences for HSC-directed gene therapy, such that their progeny will express a programmed transgene only in the immediate vicinity of tumor cells. This TME-regulated transgene will induce inflammation (to help overcome the hostile immune environment of many solid tumors) and/or release localized activatory signals for CAR T-cells (making it possible to use weakly specific CARs while avoiding on-target/off-tumor activity elsewhere in the body). We will focus on melanoma as our “model cancer”, which has a high mutational burden, good mouse models and is widely used for testing cutting-edge immunotherapies.

Specific Objectives:

1)Develop a promoter/enhancer toolbox for HSC gene therapy targeting the TME
2)Induce a CAR T-supportive TME that activates programmable CAR T-cells in situ