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Publication Number
US-10639359-B2
Publication Date
2020-05-05
Expiration Date
Abstract
The invention provides improved compositions for adoptive T cell therapies for B cell related conditions.
Core Innovation
The invention relates to a population of cells comprising T cells and immune effector cells comprising a lentiviral vector with a left (5′) lentiviral LTR, a Psi (Ψ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a retroviral export element, and a right (3′) lentiviral LTR. A promoter is operably linked to a polynucleotide sequence encoding a chimeric antigen receptor (CAR), where the polynucleotide sequence is set forth in SEQ ID NO: 10.
The invention further covers a lentiviral vector engineered with defined regulatory elements, including a left (5′) lentiviral LTR having a promoter replaced with a CMV promoter, together with a Psi (Ψ) packaging signal, cPPT/FLAP, and a Rev response element (RRE). In this population, an MND promoter is operably linked to a polynucleotide sequence encoding a CAR set forth in SEQ ID NO: 10, and a right (3′) lentiviral self-inactivating (SIN) LTR is included.
The disclosed CAR system is described in the context of adoptive T cell therapy targeting BCMA, using a murine anti-BCMA antigen-binding fragment and CAR architecture that includes hinge/spacer and transmembrane domains as well as co-stimulatory and primary signaling domains. The documentation also describes CAR T cell manufacturing and immune effector preparation using T cells genetically modified with a lentiviral vector, ex vivo activation/expansion approaches including anti-CD3/CD28 and surrogate APC/artificial APC feeder approaches, and PI3K signaling pathway modulation during activation and expansion.
PI3K pathway modulators, especially PI3K inhibitors, are used to enrich for developmentally potent or naive-like T cell phenotypes, with increased CD62L, CCR7, CD28, CD27, CD122, CD127, CD197, and CD38 and reduced expression of differentiation or exhaustion-associated markers such as CD57, PD-1, CTLA4, TIM3, LAG3, CD244, and CD160. The document ties the PI3K-modulator approach to CAR T cell function and in vivo therapeutic effects, including reduced antigen-independent IFNγ/tonic activity, changes in marker expression, and improved tumor control and regression in mouse models for lymphoma and multiple myeloma.
Claims Coverage
The relevant independent claims provide two main scopes of coverage: a lentiviral-vector-containing T cell population with a defined set of transfer and regulatory elements driving a CAR-encoding polynucleotide (SEQ ID NO: 10), and a lentiviral-vector-containing immune effector cell population with specific LTR promoter replacement, defined regulatory transfer elements, SIN LTR, and a heterologous polyadenylation sequence, also driving the same CAR polynucleotide (SEQ ID NO: 10). Across both independent claims, the core inventive structure is the combination of specified lentiviral vector architecture with operable promoter control of a CAR polynucleotide identified as SEQ ID NO: 10.
Lentiviral LTR/Psi/cPPT/FLAP transfer architecture driving a CAR polynucleotide set forth in SEQ ID NO: 10
A population of T cells wherein the T cells comprise a lentiviral vector having a left (5′) lentiviral LTR, a Psi (Ψ) packaging signal, a central polypurine tract/DNA flap (cPPT/FLAP), a retroviral export element, a promoter operably linked to a polynucleotide sequence encoding a CAR set forth in SEQ ID NO: 10, and a right (3′) lentiviral LTR.
Engineered immune effector lentiviral vector with CMV 5′ LTR replacement, MND promoter-linked CAR (SEQ ID NO: 10), SIN 3′ LTR, and heterologous polyadenylation sequence
A population of immune effector cells wherein the immune effector cells comprise a lentiviral vector including a left (5′) lentiviral LTR with the promoter of the 5′ LTR replaced with a CMV promoter, a Psi (Ψ) packaging signal, a cPPT/FLAP, a Rev response element (RRE), an MND promoter operably linked to a polynucleotide sequence encoding a CAR set forth in SEQ ID NO: 10, a right (3′) lentiviral self-inactivating (SIN) LTR, and a heterologous polyadenylation sequence.
Overall, the claims cover genetically modified cell populations where specified lentiviral vector components and promoter/transfer-element configurations drive expression of a CAR polynucleotide identified as SEQ ID NO: 10, with one independent claim directed to a general lentiviral LTR/Psi/cPPT/FLAP/retroviral export element arrangement in T cells and the other directed to a more specifically engineered lentiviral design in immune effector cells.
Stated Advantages
PI3K pathway modulators, especially PI3K inhibitors, enrich for developmentally potent or naive-like T cell phenotypes.
The approach is associated with reduced antigen-independent IFNγ/tonic activity.
The approach is associated with improved tumor control and regression in mouse models for lymphoma and multiple myeloma.
Documented Applications
CAR T cell manufacturing and immune effector preparation using T cells genetically modified with a lentiviral vector.
Ex vivo activation and expansion of CAR T cells, including anti-CD3/CD28 and surrogate APC/artificial APC feeder approaches.
Adoptive T cell therapy targeting BCMA.
B cell malignancies.
Mouse models for lymphoma and multiple myeloma.
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