Identifying epigenetic and transcriptional targets to prevent and reverse T cell exhaustion
Inventors
Wherry, E. John • Khan, Omar • JORDAN, Martha
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-12698499-B2
Publication Date
2026-08-04
Expiration Date
Abstract
The present invention provides methods of preventing, reversing or increasing T cell exhaustion in a patient having a disease. The present invention also provides methods for treating a disease in a patient having the disease. The present invention also provides an engineered T cell comprising a high priority epigenetic pathway that has been targeted, and uses thereof.
Core Innovation
The invention relates to targeting transcriptional and epigenetic programs in exhausted CD8+ T lymphocytes (TEX), with TOX identified as a key transcription factor and epigenetic coordinator. The disclosed approach uses an epigenomic signature comprising TEX-specific gene expression and candidate transcriptional and epigenetic targets to guide which regulatory mechanisms to modulate in exhausted T cells. The focus is on transcriptional and epigenetic pathways associated with the exhausted state.
To address T cell exhaustion, the invention provides engineered T cells with altered epigenomes by reducing or eliminating expression of one or more genes required for the induction and/or maintenance of TEX. The relevant gene is specified as a transcription factor or a gene involved in epigenetic modification of DNA, and the transcription factor is TOX. The concept is to prevent, reverse, or increase resistance to exhaustion through modulation of TOX-driven or epigenetic regulator-driven programs.
The disclosure further relates to in vivo use of engineered T cells to prevent, reverse, or increase T-cell exhaustion, including T-cell exhaustion in CD8+ T cells. Immune checkpoint inhibitor activity, including PD-1/PD-L1, CTLA-4, TIM3, and 4-1BB, is described in relation to exhausted CD8 T cells and transient effector-like transcriptional and epigenetic changes. The overall context connects these engineered, exhaustion-modulated cells to treating cancer or infectious diseases, including immune checkpoint inhibitor contexts.
Claims Coverage
Two independent claims are present. The inventive coverage centers on reducing or eliminating expression of one or more genes required for the induction and/or maintenance of exhausted CD8+ T lymphocytes (TEX), with TOX identified as the specific transcription factor gene, and one claim further requiring engineering the lymphocytes to target a therapeutically relevant antigen.
TOX gene modulation for TEX induction and maintenance
Reducing or eliminating expression of one or more genes required for the induction and/or maintenance of exhausted CD8+ T lymphocytes (TEX) in lymphocytes, wherein the one or more genes required for induction and/or maintenance of TEX is a transcription factor or a gene involved in epigenetic modification of DNA and wherein the transcription factor is TOX.
Therapeutic antigen targeting engineering of exhaustion-modulated lymphocytes
Engineering the lymphocytes to target a therapeutically relevant antigen by introducing either a recombinant T cell receptor binding an antigen/MHC (or neo-antigen/MHC) combination or a chimeric antigen receptor binding a desired therapeutically relevant antigen.
Reducing or preventing CD8+ T cell exhaustion by TOX expression reduction or elimination
Reducing or preventing T cell exhaustion in a lymphocyte obtained from a subject by reducing or eliminating expression of one or more genes required for the induction and/or maintenance of exhausted CD8+ T lymphocytes (TEX), wherein the gene required for induction and/or maintenance of exhausted CD8+ T lymphocytes is TOX and wherein the lymphocyte is a CD8+ T cell.
Across the independent claims, the core inventive subject matter is modulation of TOX as a transcription factor required for TEX induction and/or maintenance by reducing or eliminating TOX expression in CD8+ T cells, combined in one claim with engineering the modified lymphocytes to target a therapeutically relevant antigen using a recombinant T cell receptor or a chimeric antigen receptor.
Stated Advantages
Improved cell therapy composition.
Reducing or preventing T cell exhaustion.
Prevent, reverse, or increase resistance to exhaustion.
TOX deficiency impairs TEX generation and reduces TEX transcription factors (Tcf1/Eomes).
Reducing or eliminating TOX expression skews cells away from exhaustion-associated states and toward KLRG1+ terminal effector fates.
Documented Applications
Treating cancer or infectious diseases, including immune checkpoint inhibitor contexts.
In vivo use of engineered T cells to prevent, reverse, or increase T-cell exhaustion, with mechanistic discussion of immune checkpoint inhibitors including PD-1/PD-L1 blockade and combination or sequence considerations.
Clinical or biological association of reinvigoration with exhaustion phenotypes and tumor burden or clinical response, including pembrolizumab in melanoma.
Improved cell therapy composition by engineering lymphocytes to target a therapeutically relevant antigen using TOX reduction or elimination to modulate exhausted CD8+ T lymphocytes.
Reducing or preventing T cell exhaustion in a CD8+ T cell by reducing or eliminating TOX expression.
Interested in licensing this patent?