Combination DNMT3a KO and IL10 signaling (SJ-21-0018)

St. Jude Reference #SJ-21-0018

Description

Researchers at St. Jude identified an approach for treating T cells with IL-10 and/or enhancing IL-10 signaling pathways to preserve the cell’s multipotent state during manufacturing and persistence after therapeutic administration. It can be used to preserve the developmental potential of T cells used for adoptive cellular therapies during product manufacturing and/or supplement the T cell response during application and prevent anergic programs acquired during chronic antigen stimulation.

Retention of a multipotent developmental status in T cells utilized for immune checkpoint blockade and CAR T cell therapies has been shown to be coupled to positive clinical outcomes. The researchers demonstrated in preclinical models that combining IL-10 with approaches that block acquisition of tolerance epigenetic programs will enable less differentiated cells to persist in therapeutic settings. In addition to supplementing T cells with exogenous IL-10 during CAR T cell manufacturing in the tumor microenvironment (ICB or CAR T cells), T cells used for adoptive cellular therapies could be engineered to express their own IL-10 to support their own multipotent preservation and the other T cells in the surrounding environment. Lastly, but not limited to, patients could receive IL-10 post T cell infusion to preserve multipotency or adoptive T cell therapy could be combined with gene therapy approaches to express IL-10 within tumors (or other tissues) including oncoloytic viruses or non-viral DNA/RNA delivery systems including nanoparticles.

The approach was successful for CAR T cells to preserve their multipotency, it could be readily applied to other immune cell populations in which multipotency programs are critical including, but not limited to, virus- and/or tumor-specific T cells that recognize their targets through conventional T cell receptors (TCRs), and immune cells that express other molecules than CARs to render them antigen-specific, including, but not limited to, bispecific antibodies or T cell antigen couplers (TACs).

Keywords

T cell, IL-10, multipotent, CAR, adoptive cellular therapy, tumors, oncoloytic viruses, non-viral DNA/RNA delivery systems, nanoparticles, T cell receptors (TCRs), immune cells, antigen-specific, bispecific antibodies, T cell antigen couplers (TACs), immunotherapy, gene therapy, cell therapy

Granted patents or published applications

Pending US patent.

Related scientific references

Prinzing et al., “Deleting DNMT3A in CAR T cells prevents exhaustion and enhances antitumor activity,” Sci. Transl. Med.13, eabh0272 (2021), 17 November 2021, Vol 13, Issue 620. DOI: 10.1126/scitranslmed.abh0272

Prior: https://www.sciencedirect.com/science/article/pii/S1471490620301320
https://www.sciencedirect.com/science/article/pii/S2211124721015709

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