SUV39H1-Inactivated CAR-T Cells for Exhaustion-Resistant Persistence
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Solution Overview
Problem
Existing adoptive T cell therapies face challenges with T cell exhaustion and sub-optimal persistence due to differentiation towards a more differentiated phenotype, which limits their ability to effectively target and destroy cancer cells, particularly in solid tumors.
Innovation Solution
Inactivation or inhibition of the SUV39H1 gene in immune cells, such as T cells, enhances central memory phenotype, survival, and persistence, and reduces exhaustion, while introducing antigen-specific receptors like CARs to improve tumor cell rejection efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If T cells are subjected to mitogenic activation for retroviral or lentiviral transduction and ex-vivo culture expansion, then T cell numbers are increased to required levels, but T cells differentiate towards a more differentiated effector phenotype which reduces persistence and increases exhaustion
Solution Approach 1:
The patent applies parameter changes by modulating the epigenetic state of T cells through inhibition of SUV39H1, a histone methyltransferase. This biochemical parameter modification prevents excessive differentiation during expansion while maintaining the ability to reach required cell numbers, thereby resolving the contradiction between quantity and persistence.
Solution Approach 2:
The patent introduces an intermediary mechanism - the SUV39H1 inhibitor - that mediates between the expansion process and the preservation of naive T cell characteristics. This intermediary prevents the harmful differentiation effect during the expansion process, allowing both high cell numbers and long persistence to be achieved simultaneously.
2Productivity
If T cells are activated to increase cytotoxic activity against tumor cells, then tumor cell destruction is enhanced, but T cell exhaustion increases which reduces sustained proliferative capacity
Solution Approach 1:
The patent converts the harmful effect of activation-induced exhaustion into a benefit by using SUV39H1 inhibition to maintain a differentiated state that preserves proliferative capacity. The mechanism transforms the typical activation-differentiation-exhaustion pathway into an activation-maintenance-of-naive-state pathway, allowing sustained productivity without the usual reliability loss.
3Reliability
If PD-1 blockade is used to restore T cell function at early stage, then some T cell function is restored, but the rescue is incomplete or transient
Solution Approach 1:
The patent applies preliminary action by preventing the development of exhaustion and differentiated phenotype during the expansion process itself, rather than attempting to reverse exhaustion after it occurs. This preventive approach establishes a more durable functional state that lasts longer than the transient rescue achieved by PD-1 blockade alone.
Data Source
AI summary
The present invention relates to an improved immune cell expressing an antigen-specific receptor such as a CAR or TCR, in which SUV39H1 is inactivated, optionally combined with disruption of the TRAC locus and/or deletion of one or more ITAMs. The invention also provides compositions comprising such cells, methods of producing such cells, and uses of such cells in adoptive cell therapy, e.g. in cancer or inflammatory diseases.