Method of increasing tumor killing activity of macrophages or monocytes comprising chimeric antigen receptor
Inventors
KLICHINSKY, Michael • Minutolo, Nicholas G. • Anderson, Nicholas R.
Assignees
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Publication Number
US-11739297-B2
Publication Date
2023-08-29
Expiration Date
Abstract
The present disclosure pertains to immune cells comprising chimeric antigen receptors (CARs) and methods of using immune cells comprising CARs.
Core Innovation
The invention relates to ex vivo modification of a macrophage or monocyte with a chimeric antigen receptor (CAR) comprising an extracellular domain, a transmembrane domain, and an intracellular domain. The macrophage or monocyte is treated with a CD40 agonist, and the modified cell exhibits increased tumor killing ability relative to an unmodified macrophage or monocyte.
The modified macrophage or monocyte also exhibits increased polarization to an M1 phenotype and increased expression of one or more markers of an M1 phenotype, with decreased expression of one or more markers of an M2 phenotype compared with unmodified cells. The disclosure further describes CAR expression modification and priming strategies to support functional activity in macrophages or monocytes.
These include lentiviral vector approaches to enhance CAR transduction and long-term CAR surface expression, including strategies involving Vpx to overcome SAMHD1 restriction, while avoiding induction of an M1-skewing phenotype associated with a comparator adenoviral vector (Ad5f35).
Claims Coverage
The claim coverage centers on 1 core inventive concept: ex vivo CAR modification of macrophages or monocytes combined with CD40 agonist treatment to increase tumor killing ability. Dependent claims refine this concept with M1 polarization, marker-expression changes, a defined M1 marker set, decreased M2 marker expression, and specification of CD40L.
Ex vivo car modification with cd40 agonist for increased tumor killing
A method of modifying ex vivo a macrophage or monocyte comprising a chimeric antigen receptor (CAR) having an extracellular domain, a transmembrane domain, and an intracellular domain, and treating the macrophage or monocyte with a CD40 agonist, thereby producing a modified macrophage or monocyte which exhibits increased tumor killing ability relative to an unmodified macrophage or monocyte.
Increased M1 polarization relative to unmodified cells
The modified macrophage or monocyte shows increased polarization to the M1 phenotype compared with an unmodified macrophage or monocyte.
Increased expression of M1 phenotype markers
The modified macrophages or monocytes show increased expression of one or more markers of M1 phenotype compared with unmodified macrophages or monocytes.
Defined M1 phenotype marker set
The markers for the M1 phenotype include one or more of CD86, CD80, MHC II, IL-1R, TLR2, TLR4, iNOS, SOCS3, CD83, PD-L1, CD69, MHC I, CD64, CD32, CD16, IL1R, an IFIT family member, and an ISG family member.
Decreased expression of M2 phenotype markers
The modified macrophage or monocyte shows decreased expression of one or more markers of M2 phenotype compared with an unmodified macrophage or monocyte.
Cd40 agonist comprises or is cd40l
The CD40 agonist comprises or is CD40L.
Overall, the claims focus on ex vivo CAR modification of macrophages or monocytes with CD40 agonist treatment to achieve increased tumor killing ability, with dependent features tied to M1 polarization, increased M1 marker expression, decreased M2 marker expression, a defined M1 marker set, and CD40L.
Stated Advantages
Increased tumor killing ability of modified macrophages or monocytes relative to unmodified macrophages or monocytes.
Increased polarization to the M1 phenotype compared with unmodified macrophages or monocytes.
Increased expression of one or more M1 phenotype markers compared with unmodified macrophages or monocytes.
Decreased expression of one or more M2 phenotype markers compared with unmodified macrophages or monocytes.
Documented Applications
Ex vivo modification of macrophages or monocytes using a CAR and CD40 agonist treatment to produce cells with increased tumor killing ability.
Producing modified macrophages or monocytes with increased M1 polarization and marker expression and decreased M2 marker expression in connection with tumor-killing activity.
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