US2022202856A1PendingUtilityA1

Chimeric antigen receptor dendritic cell (car-dc) for treatment of cancer

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Assignee: MYELOID THERAPEUTICS INCPriority: Feb 19, 2015Filed: Feb 15, 2022Published: Jun 30, 2022
Est. expiryFeb 19, 2035(~8.6 yrs left)· nominal 20-yr term from priority
Inventors:Samuel C. WagnerThomas IchimJulia S. SzymanskiSantosh KesariAmit PatelBoris Minev
A61K 40/4205A61K 40/31A61K 40/24A61K 40/17C12N 5/0645C07K 16/00C12N 2510/00C07K 2319/33C07K 16/32C07K 16/30C07K 2317/622C07K 2319/03C12N 2501/599A61K 38/177A61K 35/15
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Claims

Abstract

The current invention provides monocytic cells transfected with chimeric antigen receptor (CAR) to selectively home to tumors and upon homing differentiate into dendritic cells capable of activating immunity which is inhibitory to said tumor in one embodiment of the invention, monocytic cells are transfected with a construct encoding an antigen binding domain, a transcellular or structural domain, and an intracellular signaling domain. In one specific aspect of the invention, the antigen binding domain interacts with sufficient affinity to a tumor antigen, capable of triggering said intracellular domain to induce an activation signal to induce monocyte differentiation into DC.

Claims

exact text as granted — not AI-modified
1 .- 20 . (canceled) 
     
     
         21 . A modified macrophage or a monocyte comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an anti-HER2 antigen binding domain, a transmembrane domain, and an intracellular domain of a stimulatory and/or co-stimulatory molecule. 
     
     
         22 . The modified macrophage or a monocyte of  claim 21 , wherein the CAR further comprises a hinge domain. 
     
     
         23 . The modified macrophage or a monocyte of  claim 22 , wherein the hinge domain comprises a CD8 hinge domain. 
     
     
         24 . The modified macrophage or a monocyte of  claim 21 , wherein the transmembrane domain comprises a CD8 transmembrane domain. 
     
     
         25 . The modified macrophage or a monocyte of  claim 21 , wherein the intracellular domain comprises CD80 and/or CD86 and/or CD40L and/or OX40L signaling domains. 
     
     
         26 . The modified macrophage or a monocyte of  claim 21 , wherein the intracellular domain comprises a CD3 zeta intracellular domain or an intracellular domain capable of activating TLR4 signaling. 
     
     
         27 . The modified macrophage or a monocyte of  claim 21 , wherein the antigen binding domain is selected from a group consisting of a chimeric antibody, synthetic antibody, humanized antibody, single heavy chain antibody, single light chain antibody, scFv, and antigen-binding fragments thereof. 
     
     
         28 . The modified macrophage or a monocyte of  claim 21 , wherein the modified macrophage or a monocyte expresses HLA DR. 
     
     
         29 . The modified cell of  claim 21 , wherein the modified macrophage or a monocyte is a human macrophage or a monocyte. 
     
     
         30 . The modified macrophage or a monocyte of  claim 21 , further comprising linkers linking the transmembrane domain to the antigen binding domain. 
     
     
         31 . The modified macrophage or a monocyte of  claim 21 , further comprising an agent, wherein the agent is selected from the group consisting of a nucleic acid, a peptide and any combination thereof. 
     
     
         32 . A pharmaceutical composition comprising the modified macrophage or a monocyte of  claim 21  and a pharmaceutically acceptable carrier. 
     
     
         33 . A method of treating a malignancy in a subject, comprising: administering to the subject a therapeutically effective amount of a pharmaceutical composition comprising a modified macrophage or a monocyte comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain, a transmembrane domain and an intracellular domain of a stimulatory and/or co-stimulatory molecule, wherein the antigen binding domain targets a tumor antigen. 
     
     
         34 . The method of  claim 33 , wherein the tumor antigen is Receptor tyrosine-protein kinase ERBB2 (HER2). 
     
     
         35 . The method of  claim 33 , wherein the malignancy is a carcinoma, a sarcoma, a leukemia, or melanoma. 
     
     
         36 . The method of  claim 33 , wherein the antigen binding domain of the CAR comprises an antibody selected from the group consisting of a chimeric antibody, synthetic antibody, humanized antibody, single heavy chain antibody, single light chain antibody, scFv, and antigen-binding fragments thereof. 
     
     
         37 . The method of  claim 33 , wherein the transmembrane domain of the CAR comprises a CD8 transmembrane domain. 
     
     
         38 . The method of  claim 33 , wherein the intracellular domain of the CAR comprises CD80 and/or CD86 and/or CD40L and/or OX40L signaling domains. 
     
     
         39 . The method of  claim 33 , wherein the intracellular domain of the CAR comprises a CD3 zeta intracellular domain. 
     
     
         40 . The method of  claim 33 , wherein the modified macrophage or a monocyte exhibits targeted effector activity. 
     
     
         41 . The method of  claim 40 , wherein the targeted effector activity is directed against a target cell comprising the tumor antigen. 
     
     
         42 . The method of  claim 40 , wherein the targeted effector activity is selected from the group consisting of phagocytosis, cytotoxicity, and antigen presentation. 
     
     
         43 . The method of  claim 40 , wherein the targeted effector activity is enhanced by inhibition of CD47 or signal-regulatory protein α activity. 
     
     
         44 . The method of  claim 33 , wherein the pharmaceutical composition further comprises an agent, wherein the agent is selected from the group consisting of a nucleic acid, a peptide and any combination thereof. 
     
     
         45 . The method of  claim 33 , wherein >75% of the modified cells in the pharmaceutical composition express the CAR or wherein the modified human monocytes in the population of cells are genetically modified to stably express the CAR. 
     
     
         46 . The method of  claim 33 , wherein the modified macrophage or a monocyte is obtained from the individual patient to be treated or allogeneic to the patient. 
     
     
         47 . The method of  claim 33 , wherein the modified macrophages or monocytes are administered by intratumoral injection. 
     
     
         48 . The method of  claim 33 , wherein the modified macrophages or monocytes are administered intratumorally. 
     
     
         49 . The method of  claim 33 , wherein the modified macrophage or monocyte is administered to a patient in conjunction with at least one other treatment modality. 
     
     
         50 . The method of  claim 49 , wherein the at least one other treatment modality comprises an agent that induces immunogenic cell death; chemotherapy; and/or immune modulators including BCG, CpG DNA, interferon alpha, tumor bacterial therapy, checkpoint inhibitors, Treg depleting agents, and low dose cyclophosphamide.

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