Method of providing cellular therapy using modified natural killer cells or T lymphocytes
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Publication Number
US-10786532-B2
Publication Date
2020-09-29
Expiration Date
Abstract
A method of decreasing cytokine production and release is disclosed. In one embodiment, the method comprises the step of providing cytotoxic cells to a subject wherein the cells are preferably natural killer cells or T lymphocytes and are genetically modified to express a chimeric antigen receptor comprising a first element that is an extracellular antigen receptor and a second intracellular element that is a signaling moiety comprising altered ADAP-dependent or Fyn-dependent signaling such that downstream signaling causing cytokine release is decreased. Specific modifications of CD137 and NKG2D cytoplasmic tails are described. Additionally, methods to develop and screen drug compounds capable of compromising the binding between ADAP and Fyn and disrupting the downstream release of cytokines are described.
Core Innovation
The invention relates to a method of decreasing or preventing cytokine release syndrome (CRS) in a subject receiving chimeric antigen receptor cytotoxic cell therapy by disrupting release of at least one cytokine selected from IFN-γ, GM-CSF, MIP-1α, MIP-1β, and RANTES. The method is based on genetically modifying a CD8+ T lymphocyte or NK cytotoxic cell to express an inhibitor of ADAP-Fyn binding that disrupts cytokine release while decreasing or preventing CRS.
A genetically modified CD8+ T lymphocyte or NK cytotoxic cell is provided to the subject, wherein the genetically modified cell expresses both an inhibitor of ADAP-Fyn binding and a chimeric antigen receptor comprising an extracellular domain and a signaling moiety selected from the CD137 cytoplasmic domain and the NKG2D cytoplasmic domain. The cytotoxicity of the genetically modified CD8+ T lymphocyte or NK cytotoxic cell is substantially unchanged relative to the cytotoxic cell not expressing the inhibitor of ADAP-Fyn binding.
The disclosure further discusses engineered signaling and inhibitor constructs, including decoy polypeptide or decoy peptide inhibitor of ADAP-Fyn binding, and situates the approach within relationships among CD137 or NKG2D signaling, Lck/Fyn signaling, ADAP-dependent signaling, and downstream inflammatory signaling pathways. ADAP is described as critical for inflammatory cytokine and chemokine production, with disrupted ADAP-Fyn-related cytokine signaling intended to reduce CRS-associated cytokines without substantially impairing cytotoxicity during CAR therapy.
Claims Coverage
The partial content contains two independent methods covering CRS reduction during chimeric antigen receptor cytotoxic cell therapy. Across the independent claims, the inventive concept is jointly directed to disrupting ADAP-Fyn-dependent cytokine release and maintaining substantially unchanged cytotoxicity while using a CAR signaling moiety selected from CD137 or NKG2D cytoplasmic domains.
ADAP-Fyn binding inhibition with substantially unchanged cytotoxicity in CAR therapy
A method of decreasing or preventing cytokine release syndrome (CRS) by disrupting release of at least one cytokine selected from IFN-γ, GM-CSF, MIP-1α, MIP-1β, and RANTES in a subject receiving chimeric antigen receptor cytotoxic cell therapy, comprising genetically modifying a CD8+ T lymphocyte or NK cytotoxic cell to express an inhibitor of ADAP-Fyn binding and a chimeric antigen receptor comprising an extracellular domain and a signaling moiety selected from CD137 cytoplasmic domain and the NKG2D cytoplasmic domain, wherein cytotoxicity is substantially unchanged relative to a cytotoxic cell not expressing the inhibitor, and providing the genetically modified cell.
Decoy peptide inhibitor of ADAP-Fyn binding with CAR signaling moiety and substantially unchanged cytotoxicity
A method of decreasing or preventing cytokine release syndrome (CRS) by disrupting release of at least one cytokine selected from IFN-γ, GM-CSF, MIP-1α, MIP-1β, and RANTES in a subject receiving chimeric antigen receptor cytotoxic cell therapy, comprising genetically modifying a CD8+ T lymphocyte or NK cytotoxic cell to express a decoy peptide inhibitor of ADAP-Fyn binding comprising at least an ADAP polypeptide portion comprising at least 3 contiguous amino acids selected from residues 600-640 of SEQ ID NO: 1 and a chimeric antigen receptor comprising an extracellular domain and a signaling moiety selected from the CD137 cytoplasmic domain and the NKG2D cytoplasmic domain, wherein cytotoxicity is substantially unchanged relative to a cytotoxic cell not expressing the inhibitor, and providing the genetically modified cell.
Overall, the independent claims cover CRS reduction during CAR cytotoxic cell therapy by expressing an inhibitor that disrupts ADAP-Fyn binding, including decoy peptide inhibitor forms, in combination with a CAR signaling moiety selected from CD137 or NKG2D, while requiring cytotoxicity to remain substantially unchanged.
Stated Advantages
Decreases or prevents cytokine release syndrome (CRS) by disrupting release of IFN-γ, GM-CSF, MIP-1α, MIP-1β, and RANTES.
Disrupts release of at least one cytokine selected from IFN-γ, GM-CSF, MIP-1α, MIP-1β, and RANTES.
Substantially unchanged cytotoxicity relative to a CD8+ T lymphocyte or NK cytotoxic cell not expressing the inhibitor of ADAP-Fyn binding.
Documented Applications
Use of genetically modified CD8+ T lymphocytes or NK cytotoxic cells in a subject receiving chimeric antigen receptor cytotoxic cell therapy to decrease or prevent CRS.
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