Engineered immune cells resistant to tumor microenvironment
Inventors
Duchateau, Philippe • GAUTRON, Anne-Sophie • Poirot, Laurent • Valton, Julien
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11903968-B2
Publication Date
2024-02-20
Expiration Date
Abstract
The invention pertains to the field of adoptive cell immunotherapy. It provides with engineered immune cells comprising genetic alteration into genes which are involved into immune functions downregulation, especially in response to environment signals such as nutrients depletion. Such method allows the production of more potent immune cells in the context of tumors' microenvironment.
Core Innovation
The described invention relates to engineered immune cells for adoptive cell immunotherapy that are genetically modified to resist tumor microenvironment-mediated dysfunction. The dysfunction is addressed by genetic inactivation that interrupts calcium transport and signaling under low glucose conditions.
The engineered immune cells include intracellular expression of a rare-cutting endonuclease selected from TALEN, RNA-guided endonuclease, ZFN, meganuclease, and megaTAL. This rare-cutting endonuclease cleaves an endogenous polynucleotide sequence encoding SERCA3, thereby inactivating the expression of the SERCA3 protein and interrupting calcium transport and signaling.
The engineered immune cells further express a chimeric antigen receptor (CAR). The inactivation of SERCA3 protein expression is stated to result in increased proliferation of the engineered immune cell at low glucose level, and the engineered immune cells can be provided, selected, and optionally formulated as a pharmaceutical composition.
Claims Coverage
Two independent claims are provided. Across the independent claims, the coverage centers on CAR expression combined with rare-cutting endonuclease-mediated inactivation of SERCA3, with one claim also reciting increased proliferation at low glucose.
Rare-cutting endonuclease-mediated SERCA3 inactivation with CAR expression for low-glucose proliferation
An engineered immune cell genetically modified by intracellular expression of a rare-cutting endonuclease selected from TALEN, RNA-guided endonuclease, ZFN, meganuclease, and megaTAL that cleaves an endogenous polynucleotide sequence encoding a SERCA3 protein to inactivate the expression of the SERCA3 protein and interrupt calcium transport and signaling, wherein the engineered immune cell further expresses a chimeric antigen receptor (CAR), and wherein the inactivation results in increased proliferation at low glucose level.
Method for generating CAR-expressing engineered immune cells with sequence-specific SERCA3-targeting nuclease and selection
An engineered immune cell or population obtained by providing a population of primary immune cells; introducing into the primary immune cells at least one nucleic acid comprising an exogenous polynucleotide sequence to express a chimeric antigen receptor; introducing at least one sequence-specific reagent selected from TALEN, RNA-guided endonuclease, ZFN, meganuclease, and megaTAL that specifically targets an endogenous coding sequence encoding SERCA3 to inactivate SERCA3 expression and interrupt calcium transport and signaling; and selecting engineered immune cells.
The inventive coverage combines CAR expression with SERCA3 inactivation using a sequence-specific rare-cutting endonuclease, and in one claim ties this configuration to increased proliferation at low glucose.
Stated Advantages
Increased proliferation of the engineered immune cell at low glucose level.
Documented Applications
Therapeutic use as adoptive cell immunotherapy using engineered immune cells that resist tumor microenvironment-mediated dysfunction.
Interested in licensing this patent?