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Publication Number
US-11045543-B2
Publication Date
2021-06-29
Expiration Date
Abstract
Glioblastoma (GB) remains the most aggressive primary brain malignancy; brain metastasis, such as breast cancer brain metastases (BCBMs), are also aggressive and are associated with poor prognosis. Adoptive transfer of chimeric antigen receptor (CAR)-modified immune cells has emerged as a promising anti-cancer approach, yet the potential utility of CAR-engineered cells to treat brain cancers has not been explored. The present disclosure presents compostions and methods for using CAR expressing cells in the treatment of various cancers, including brain cancers such as GB and BCBMs.
Core Innovation
The invention relates to an engineered chimeric antigen receptor (CAR) targeting Epidermal Growth Factor Receptor (EGFR) for recognition of both wild type Epidermal Growth Factor Receptor (wtEGFR) and the EGFR variant III mutant (EGFRvIII). The CAR includes an antigen binding domain derived from an anti-EGFR antibody heavy chain variable region CDR set and an anti-EGFR antibody light chain variable region CDR set, together with a hinge domain polypeptide, a costimulatory molecule or polypeptide, and a CD3 zeta signaling domain.
The disclosure further provides that the EGFR-directed CAR is implemented in CAR-encoding nucleic acids and vectors, including lentiviral vectors, and that immune cells expressing the CAR are provided, including T cells and especially NK cells. The engineered CAR recognizes EGFR on target cells and includes hinge/transmembrane and signaling architecture together with costimulatory signaling, including embodiments having CD28 and/or 4-1BB costimulation.
Preclinical evidence is provided showing enhanced cytotoxicity and IFN-gamma activity of EGFR CAR-modified NK-92/NKL and primary NK cells against EGFR+ glioma cell lines and patient-derived glioblastoma stem cells including EGFRvIII-positive cells. The disclosure also describes in vivo intracranial administration of EGFR CAR NK-92 showing inhibition of orthotopic glioma growth and prolongation of mouse survival, together with limited systemic migration detectable mainly in brain and absent in other organs by PCR/flow and supported by H&E.
The disclosure further extends EGFR CAR NK cells to brain metastases, including breast cancer brain metastases, where EGFR CAR NK cells lyse EGFR+ breast cancer cell lines, and in combination with oncolytic herpes simplex virus (oHSV-1) exhibit synergistic tumor suppression and improved survival in an intracranial metastasis model, including combination-therapy embodiments and kit/composition formats.
Claims Coverage
The partial content provides one independent claim. The independent claim contains three core inventive elements: an anti-EGFR antibody antigen binding domain configured to recognize both wtEGFR and EGFRvIII, a hinge domain polypeptide, and intracellular signaling including a costimulatory molecule and a CD3 zeta signaling domain.
Dual-specific anti-EGFR antigen binding domain for wtEGFR and EGFRvIII
An antigen binding domain of an anti-EGFR antibody that recognizes both wild type Epidermal Growth Factor Receptor (wtEGFR) and Epidermal Growth Factor Receptor variant III mutant (EGFRvIII), wherein the antigen binding domain comprises the three complementarity determining regions (CDRs) of an anti-EGFR heavy chain variable region and the CDRs of an anti-EGFR light chain variable region.
Hinge domain polypeptide inclusion
A hinge domain polypeptide.
Costimulatory molecule with CD3 zeta signaling domain
A costimulatory molecule or polypeptide and a CD3 zeta signaling domain.
Overall, the independent claim covers an EGFR CAR whose antigen-binding domain is configured to bind both wtEGFR and EGFRvIII using specified anti-EGFR heavy chain and light chain CDR sets, and that includes hinge domain structure plus costimulatory signaling and a CD3 zeta signaling domain.
Stated Advantages
Enhanced cytotoxicity and IFN-gamma activity against EGFR+ glioma cell lines and patient-derived glioblastoma stem cells, including EGFRvIII-positive cells.
In vivo inhibition of orthotopic glioma growth and prolongation of mouse survival after intracranial administration.
Limited systemic migration detectable mainly in brain and absent in other organs by PCR/flow, supported by H&E.
Synergistic tumor suppression and improved survival in an intracranial breast cancer brain metastasis model when combined with oncolytic HSV-1 (oHSV-1).
Documented Applications
Treatment of brain cancers, including glioblastoma and orthotopic glioma models, with EGFR CAR-expressing immune cells administered intracranially.
Treatment of brain metastases, including breast cancer brain metastases, using EGFR CAR NK cells and, in combination embodiments, oncolytic HSV-1 (oHSV-1) in an intracranial metastasis model.
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