Targeted gene insertion for improved immune cells therapy
Inventors
BUSSER, Brian • Duchateau, Philippe • Juillerat, Alexandre • Poirot, Laurent • Valton, Julien
Assignees
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Publication Number
US-11873511-B2
Publication Date
2024-01-16
Expiration Date
Abstract
The invention pertains to the field of adaptive cell immunotherapy. It provides with the genetic insertion of exogenous coding sequence(s) that help the immune cells to direct their immune response against infected or malignant cells. These exogenous coding sequences are more particularly inserted under the transcriptional control of endogenous gene promoters that are sensitive to immune cells activation. Such method allows the production of safer immune primary cells of higher therapeutic potential.
Core Innovation
The invention relates to a population of engineered primary human NK or T cells. The cells comprise an exogenous coding sequence encoding an interleukin selected from IL-15, IL-12, or IL-2 inserted into an endogenous gene such that the interleukin is under transcriptional control of an endogenous gene promoter locus, while disrupting the coding sequence of the endogenous gene, wherein the endogenous gene encodes PD1.
The engineered primary human NK or T cells further comprise an exogenous coding sequence encoding a chimeric antigen receptor (CAR) or a recombinant TCR. The engineered cells secrete a level of the interleukin sufficient to enhance the antitumor activity of the cells.
The document also describes targeted gene insertion approaches in which exogenous coding sequences are integrated into endogenous loci with transcriptional control provided by endogenous activation- or tumor microenvironment-responsive promoters. Embodiments discuss PD1-associated loci and CAR-associated loci such as TRAC, including locus-specific insertion details and multiple endogenous loci for engineered cytokine expression.
Claims Coverage
The document includes one independent claim with four core inventive features: endogenous promoter-controlled interleukin insertion, disruption of a PD1-encoding endogenous gene, addition of a CAR or recombinant TCR, and interleukin secretion sufficient to enhance antitumor activity.
Endogenous promoter-controlled interleukin insertion
An engineered population of primary human NK or T cells comprising an exogenous coding sequence encoding an interleukin selected from IL-15, IL-12, or IL-2 inserted into an endogenous gene such that the interleukin is under transcriptional control of an endogenous gene promoter locus, while disrupting the coding sequence of the endogenous gene.
PD1 endogenous gene encoding
The endogenous gene encodes PD1.
CAR or recombinant TCR addition
The primary human NK or T cells further comprise an exogenous coding sequence encoding a chimeric antigen receptor (CAR) or a recombinant TCR.
Interleukin secretion sufficient for enhanced antitumor activity
The primary human NK or T cells secrete a level of the interleukin sufficient to enhance the antitumor activity of the cells.
Overall claim coverage is directed to engineered primary human NK or T cells with PD1 locus-based interleukin expression, concurrent CAR or recombinant TCR expression, and interleukin secretion sufficient to enhance antitumor activity.
Stated Advantages
Enhance the antitumor activity of the cells through secretion of the interleukin at a sufficient level.
Documented Applications
Engineered primary human NK or T cells for antitumor activity, including use with CAR or recombinant TCR and interleukin secretion controlled by endogenous gene promoter loci involving PD1 disruption.
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