MODIFIED IMMUNE CELLS HAVIG ENHANCED FUNCTION AND METHODS FOR SCREENING THE SAME

Smart overview of the Invention

Gene edited immune cells, particularly modified T cells, are engineered to enhance their functionality through the incorporation of exogenous T cell receptors (TCRs) or chimeric antigen receptors (CARs). These modifications include targeted insertions or deletions in specific endogenous gene loci that regulate T cell function, leading to improved immune responses. The advancements aim to address challenges in adoptive cell therapy, especially in treating cancers and chronic infections.

Challenges in T Cell Functionality

T cell exhaustion is a significant barrier in effective immunotherapy, characterized by diminished effector functions and increased expression of inhibitory receptors. This state hampers the ability of engineered T cells to effectively control infections and tumors. Additionally, the immunosuppressive tumor microenvironment further complicates the efficacy of TCR- or CAR-engineered T cells, necessitating innovative strategies to enhance their performance.

Screening for Enhanced Functionality

An unbiased, in vivo genome-wide screening method has been developed to identify genes that influence T cell efficacy, memory, and persistence. This approach has revealed specific genes whose downregulation correlates with enhanced immune functions in TCR- or CAR-engineered T cells. Such discoveries pave the way for creating more effective therapeutic strategies against various diseases.

Mechanisms of Genetic Modification

The modifications are primarily achieved using CRISPR-related systems, particularly CRISPR/Cas9 technology. Targeted insertions or deletions can be made in gene loci encoding transcriptional modulators or epigenetic regulators, such as SIX2 and KLF4. By downregulating these genes, the modified immune cells exhibit improved functionality against target antigens.

Potential Applications and Future Directions

The development of modified immune cells holds promise for advancing cancer therapies and addressing chronic infections. By utilizing specific modifications in genes like KLF4 and PAGR1, researchers can create T cells with heightened abilities to recognize and eliminate target cells. Future applications could lead to more robust treatment options for patients suffering from various malignancies and autoimmune diseases.