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Publication Number
US-11479755-B2
Publication Date
2022-10-25
Expiration Date
Abstract
The invention provides improved T cell compositions and methods for manufacturing T cells. More particularly, the invention provides methods of T cell manufacturing that result in adoptive T cell immunotherapies with improved survival, expansion, and persistence in vivo.
Core Innovation
The invention relates to manufacturing chimeric antigen receptor (CAR) T cells for adoptive immunotherapy by controlling T-cell behavior during activation and expansion. A population of T cells is activated and stimulated to proliferate, transduced with a viral vector comprising a polynucleotide encoding a CAR, and cultured so that the transduced T cells proliferate further. The steps are performed in the presence of a phosphatidylinositol-3 kinase (PI3K) inhibitor that is a small organic molecule.
The approach decouples T-cell proliferation from differentiation by modulating PI3K signaling during activation and expansion. PI3K inhibitor selection includes pan-PI3K inhibitors and selective PI3K inhibitors, with named examples such as ZSTK474. The resulting T-cell phenotypes include increased developmentally potent or young phenotypes with increased CD62L, CD127, CD197, and CD38, and reduced differentiation markers such as CD57 and KLRG1/PD-1-related markers.
The patent links the strategy to improved in vivo persistence and expansion and anti-tumor activity in CAR models, including multiple myeloma contexts such as BCMA CAR models. It also frames the method in a viral-vector context for CAR and TCR expression, including retroviral and lentiviral vector systems.
Claims Coverage
The claim set includes one independent claim directed to a method for manufacturing CAR T cells, with dependent claims refining the PI3K inhibitor identity and specifying CAR structural components and related constraints. The inventive feature centers on performing CAR T-cell manufacturing steps in the presence of a small organic PI3K inhibitor.
Manufacturing CAR T cells with PI3K inhibitor during activation and proliferation
A method for manufacturing CAR T cells comprising activating a population of T cells and stimulating the population of T cells to proliferate; transducing the T cells with a viral vector comprising a polynucleotide encoding a CAR; and culturing the transduced T cells to proliferate, wherein the steps are performed in the presence of a phosphatidylinositol-3 kinase (PI3K) inhibitor and wherein the PI3K inhibitor is a small organic molecule.
Pan-PI3K inhibitor selection for CAR T-cell manufacturing
The PI3K inhibitor is a pan-PI3K inhibitor selected from BEZ235, LY294002, TG100713, or GDC-0941.
Selective PI3K inhibitor selection for CAR T-cell manufacturing
The PI3K inhibitor is a selective PI3K inhibitor chosen from BYL719, GSK2636771, TGX-221, AS25242, CAL-101, or IPI-145.
ZSTK474 as the PI3K inhibitor
The PI3K inhibitor is ZSTK474.
CAR T-cell manufacturing duration constraint
The method is carried out for a duration of 10 days.
CAR architecture with specified extracellular, transmembrane, costimulatory, and CD3ζ domains
The CAR includes an extracellular antigen-binding domain, a specified transmembrane domain, one or more intracellular costimulatory signaling domains, and a CD3ζ signaling domain.
The claims center on manufacturing CAR T cells by activation, proliferation, viral-vector CAR transduction, and further culturing in the presence of a small organic PI3K inhibitor, with dependent claims narrowing the inhibitor choice and defining CAR structural constraints.
Stated Advantages
Decouples T-cell proliferation from differentiation by modulating PI3K signaling during activation and expansion.
Maintains proliferation and increases developmentally potent or young phenotypes.
Increases developmentally potent T-cell phenotype markers including CD62L, CD127, CD197, and CD38.
Reduces differentiation markers such as CD57 and KLRG1/PD-1-related markers.
Improves in vivo persistence and expansion and anti-tumor activity in CAR models.
Documented Applications
Adoptive immunotherapy using CAR T cells manufactured by PI3K-inhibitor-treated activation and expansion.
Anti-tumor activity and persistence in CAR models, including multiple myeloma contexts such as BCMA CAR models.
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