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Definitions

• the inventors also contemplate a method of conditioning a patient for immunotherapy of a cancer.
• Preferred methods include a step of administering to the patient an immune competent cell (e.g., NK cell, T-cell, B-cell, macrophage, or dendritic cell) that is genetically modified to express CXADR.
• an immune competent cell e.g., NK cell, T-cell, B-cell, macrophage, or dendritic cell
• suitable vectors will contains an origin of replication functional in at least one organism, a promoter sequence, convenient restriction endonuclease sites, and one or more selectable markers (e.g., WO 01/96584; WO 01/29058; and U.S. Pat. No. 6,326, 193).
• selectable markers e.g., WO 01/96584; WO 01/29058; and U.S. Pat. No. 6,326, 193
• contemplated promoters may also be sensitive to one or more environmental conditions to drive the transcription of the CXADR gene.
• expression may be driven under the control of a temperature sensitive promoter (see e.g., BMC Biotechnol. 2011; 12;11:51) or under the control of a hypoxia and metal sensitive promoter (see e.g., Gene Ther. 2006; 13(10):857-68).
• a temperature sensitive promoter see e.g., BMC Biotechnol. 2011; 12;11:51
• a hypoxia and metal sensitive promoter see e.g., Gene Ther. 2006; 13(10):857-68.
• the promoter will be operably linked to the CXADR sequence to so drive expression in the host cell (i.e., cell transformed with the vector or other expression construct).
• the recombinant nucleic acid construct may include various additional elements, including transcription termination elements, intronic sequences, and/or polyadenylation signals. Construction of expression constructs can be accomplished using any suitable genetic engineering techniques, including, inter alia, restriction endonuclease digestion, ligation, transformation, plasmid purification, and DNA sequencing. Such techniques are well known in the art and are described elsewhere (see e.g., in Sambrook et al., Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory, N.Y., (1989)).
• the expression vectors described herein are useful both for producing recombinant non-mammalian NK cells and human NK cells, which may be freshly isolated, cultured from precursor or stem cells, or from existing cultures (which may be genetically modified).
• NK cells non-mammalian NK cells
• human NK cells which may be freshly isolated, cultured from precursor or stem cells, or from existing cultures (which may be genetically modified).
• the vector can be readily introduced into a NK cell or other host cell (and especially immune competent cells capable of presenting an antigen via MHC complexes) by any method known in the art.
• the expression vector can be transferred into a host cell by physical, chemical, or biological means.
• introduction of a polynucleotide into a host cell is calcium phosphate transfection or lipofection.
• Biological methods for introducing a polynucleotide of interest into a host cell include the use of DNA and RNA vectors.
• Viral vectors, and especially retroviral vectors have become the most widely used method for inserting genes into mammalian, e.g., human cells.
• Other viral vectors can be derived from lentivirus, poxviruses, herpes simplex virus I, adenoviruses and adeno-associated viruses, etc (see, for example, U.S. Pat. Nos. 5,350,674 and 5,585,362).
• Chemical means for introducing a polynucleotide into a host cell include colloidal dispersion systems, such as macromolecule complexes, nanocapsules, microspheres, beads, and lipid-based systems including oil-in-water emulsions, micelles, mixed micelles, and liposomes.
• An exemplary colloidal system for use as a delivery vehicle in vitro and in vivo is a liposome (e.g., an artificial membrane vesicle).
• Other methods of state-of-the-art targeted delivery of nucleic acids are available, such as delivery of polynucleotides with targeted nanoparticles or other suitable sub-micron sized delivery system.
• Lipids are fatty substances which may be naturally occurring or synthetic lipids.
• lipids include the fatty droplets that naturally occur in the cytoplasm as well as the class of compounds which contain long-chain aliphatic hydrocarbons and their derivatives, such as fatty acids, alcohols, amines, amino alcohols, and aldehydes.
• Such assays include, for example, "molecular biological” assays well known to those of skill in the art, such as Southern and Northern blotting, RT-PCR and PCR; "biochemical” assays, such as detecting the presence or absence of a particular peptide, e.g., by immunological means (ELISAs and Western blots) or by assays described herein to identify agents falling within the scope of the invention.
• “molecular biological” assays well known to those of skill in the art, such as Southern and Northern blotting, RT-PCR and PCR
• biochemical assays, such as detecting the presence or absence of a particular peptide, e.g., by immunological means (ELISAs and Western blots) or by assays described herein to identify agents falling within the scope of the invention.
• suitable cells include immune competent cells, such as NK cells, T-cells (CD8+, CD4+, etc.), B-cells, macrophages, and dendritic cells, but also cells from kidney, placenta, thymus, and spleen, and certain tumor cells (advanced bladder cancer, primary prostate cancer, etc.) that have low levels of CXADR expression.
• adenoviral vector in general, and viewed from another perspective, it is contemplated that all cells are suitable for transfection that are desired to be transfected with an adenoviral vector at a later time (i.e., after expressing the recombinant CXADR).
• immune competent cells, and especially NK cells and modified NK cells are particularly preferred as expression of CXADR in such cells allows transfection in vivo with a recombinant nucleic acid (via adenoviral delivery) that can deliver one or more antigens (and particularly neoantigens, tumor associated antigens, or chimeric molecules comprising such antigens) to the immune system in a host.
• KIR KIR2DL1
• KIR2DL2 KIR2DL2
• such antibodies are commercially available and can be used in conjunction with the cells (e.g., bound to the Fcy receptor).
• such cells may also be commercially obtained from NantKwest as haNK cells ('high-affinity natural killer cells).
• haNK cells 'high-affinity natural killer cells.
• Such cells may then be further modified to express the CXCL12 or portion thereof or to have reduced or abolished expression of CXCR4 as also further discussed below.
• the genetically engineered NK cell may also be genetically engineered to express a chimeric T-cell receptor.
• the chimeric T-cell receptor will have a scFv portion or other ectodomain with binding specificity against a tumor associated antigen, a tumor specific antigen, and a cancer neoepitope.
• an NK cell may also be commercially obtained from NantKwest as taNK cells ('target-activated natural killer cells'). Such cells may then be further modified to express the CXCL12 or portion thereof or to have reduced or abolished expression of CXCR4 as discussed below.
• cancer associated antigens include CEA, MUC- 1, CYPB 1 , etc.
• cancer specific antigens include PSA, Her- 2, PSA, brachyury, etc.
• the NK or other host cells may express at least a portion of IL2RA, optionally together with one or more of IL2RB and IL2RG to provide an extra avenue for NK cell activation and to so enhance a more robust immune response.
• Genetically engineered NK cells will most preferably be activated NK cells, high-affinity NK cells, or target activated NK cells.
• Preferred IL2RA include full length or high-affinity variants of IL2RA.
• the genetically engineered NK cells may also express one or more cytokines, and especially IL- 12.
• the so prepared NK cells may outcompete the hosts T-cells for IL2.
• contemplated NK or other host cells may also express IL-15 or a IL- 15 superagonist (e.g., ALT- 803) to so provide increased activation.
• the NK or other host cells may express one or more immune checkpoint inhibitors to further enhance or stimulate the host immune response.
• the inventors contemplate transfection of genetically engineered NK or other host cells to express one or more co- stimulatory molecules to so enhance an immune response.
• the genetically engineered NK cells will most preferably be activated NK cells, high-affinity NK cells, or target activated NK cells.
• modified NK cells may also present at least a portion of CXCL12, more preferably a full length CXCL12, and/or that the NK cells are genetically modified to reduce or even entirely silence expression of the CXCR4.
• CXCL12 a portion of CXCL12
• the so modified cells will be less subject to recognition and allograft rejection by the host and will have a reduced propensity to aggregate, while still retaining killing activity via NK cell- specific pathways.
• immune competent cells are generally preferred for expression of the CXADR
• non-immune competent cells are also deemd suitable and especially include established cells lines suitable for recombinant protein production.
• various mammalian and insect cell lines are particularly contemplated, including CHO cells, HEK-293 cells, mouse myeloma lymphoblastoid cells, BHK cells, Sf9, CV- 1, COS- 1 cells, etc.

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• 2017
  • 2017-02-03 CA CA3012472A patent/CA3012472A1/en not_active Abandoned
  • 2017-02-03 JP JP2018541222A patent/JP2019504631A/ja not_active Abandoned
  • 2017-02-03 EP EP17748289.0A patent/EP3411474A4/en not_active Withdrawn
  • 2017-02-03 KR KR1020187022005A patent/KR20180102108A/ko not_active Withdrawn
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