Transgenic T cell and chimeric antigen receptor T cell compositions and related methods
Inventors
Sadelain, Michel W. J. • Eyquem, Justin Gabriel Andre Francois • Mansilla-Soto, Jorge
Assignees
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Publication Number
US-12404316-B2
Publication Date
2025-09-02
Expiration Date
Abstract
The invention provides a T cell wherein one or more therapeutic transgenes is integrated at a within the genome of the cell such that expression of the transgene is under control of an endogenous promoter of the T cell. The invention additional provides methods of making and using such cells to treat a subject with T cell therapy. The invention also provides a T cell wherein a recombinant nucleic acid sequence encoding a chimeric antigen receptor (CAR) is integrated at a first site within the genome of the cell such that the CAR is expressed by the cell at the surface of the cell, and wherein integration of the nucleic acid encoding the CAR at the first site reduces or prevents expression of a functional T cell receptor (TCR) complex at the surface of the cell. The invention additional provides methods of making and using such cells to treat a subject with CAR therapy.
Core Innovation
The invention is directed to treating a human subject with CAR therapy by administering a therapeutically effective amount of a human T cell in which a promoter-less recombinant nucleic acid sequence encoding a CAR is integrated at the first exon of the T cell receptor (TCR) alpha chain gene. The CAR is expressed under control of the endogenous TCR alpha chain gene promoter and is produced at the surface of the cell while preventing expression of a functional TCR alpha chain. The integrated nucleic acid sequence encoding the CAR is introduced by targeted homologous recombination at the selected genomic site.
The approach provides TCR-negative CAR T cells for therapeutic use and is applied to cancer treatment, infectious disease, and autoimmune disorder contexts. For cancer treatment, the CAR binds to a cancer antigen of the cancer in the subject, and the document further specifies that CAR targeting can include CD19. For infectious disease and autoimmune disorder embodiments, the CAR binds to a pathogen antigen responsible for the disease or to an autoimmune antigen associated with the disorder, including use of human T regulatory cells for immune suppression.
The framework also includes administration as an isolated population of T cells and in pharmaceutical compositions with a pharmaceutically acceptable carrier. Together, these elements define an endogenous-promoter-driven CAR expression strategy paired with disruption of TCR alpha chain expression.
Claims Coverage
The document provides coverage for two independent method claims. Both require a human T cell engineered to express a CAR from the endogenous TCR alpha chain promoter by promoter-less CAR integration at the TCR alpha chain first exon, while preventing functional TCR alpha chain expression. One independent claim is directed to general CAR therapy use, and the other is specifically directed to cancer treatment with CAR binding to a cancer antigen.
Endogenous-promoter car expression via first exon tcr alpha integration
A promoter-less recombinant nucleic acid sequence encoding a CAR is integrated at the first exon of the T cell receptor (TCR) alpha chain gene such that the CAR is expressed under control of the endogenous TCR alpha chain gene promoter to produce the CAR at the surface of the cell.
Prevention of functional tcr alpha expression by car integration
Integration of the nucleic acid sequence encoding the CAR at the first exon site prevents expression of a functional TCR alpha chain.
Cancer treatment using car-expressing t cells binding a cancer antigen
A method of treating cancer in a human subject wherein the CAR-expressing T cell produces a CAR at the surface and wherein the CAR binds to a cancer antigen of the cancer in the subject.
Targeted homologous recombination integration at the selected site
Integration of the nucleic acid sequence encoding the CAR at the selected site is performed via targeted homologous recombination.
Claim coverage centers on integrating a promoter-less CAR coding sequence into the TCR alpha chain first exon to drive CAR expression from the endogenous TCR alpha promoter while disrupting functional TCR alpha chain expression. The cancer-focused independent claim further requires CAR binding to a cancer antigen.
Stated Advantages
The T cells are described as TCR-negative for safety-related objectives, including reducing functional TCR-related effects such as GVHD/alloreactivity and enabling use in contexts where autoimmune risk is a concern.
Documented Applications
Treating a human subject with CAR therapy using human T cells with promoter-less CAR integrated at the TCR alpha chain first exon, with CAR surface expression under endogenous promoter control and prevention of functional TCR alpha chain expression.
Treating cancer in a human subject by administering human T cells with promoter-less CAR integrated at the TCR alpha chain first exon such that CAR is expressed under control of the endogenous TCR alpha chain gene promoter, functional TCR expression is prevented, and the CAR binds to a cancer antigen.
Treating an infectious disease in a subject by CAR therapy where the CAR binds to a pathogen antigen responsible for that disease.
Treating an autoimmune disorder by immune suppression using human T regulatory cells whose CAR binds an autoimmune antigen associated with the disorder.
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