Compositions and methods related to engineered erythroid cells comprising il-15

Abstract

The invention includes compositions and methods related to multimodal therapies, e.g., for treating a cancer. A multimodal therapy described herein provides and/or administers a plurality of agents that function in a coordinated manner to provide a therapeutic benefit to a subject in need thereof, e.g., a subject having a cancer.

1 . A genetically engineered enucleated erythroid cell comprising an exogenous polypeptide that comprises IL-15 or an IL15Ra-binding fragment thereof, wherein the exogenous polypeptide is at the surface of the enucleated erythroid cell, and wherein the exogenous polypeptide does not comprise a sortase transfer signature. 
     
     
         2 . The genetically engineered enucleated erythroid cell of  claim 1 , further comprising a second exogenous polypeptide. 
     
     
         3 . The genetically engineered enucleated erythroid cell of  claim 2 , wherein the second exogenous polypeptide comprises 4-1BBL or a 4-1BB-binding fragment of 4-1BBL. 
     
     
         4 . The genetically engineered enucleated erythroid cell of  claim 2 , wherein the exogenous polypeptide and the second exogenous polypeptide have an abundance ratio of from about 2:1 to 1:2 by copy number. 
     
     
         5 . The genetically engineered enucleated erythroid cell of  claim 1 , which is a reticulocyte. 
     
     
         6 . The genetically engineered enucleated erythroid cell of  claim 1 , which is a mature red blood cell. 
     
     
         7 . The genetically engineered enucleated erythroid cell of  claim 1 , wherein the enucleated erythroid cell exhibits substantially the same osmotic membrane fragility as a corresponding isolated, unmodified, uncultured enucleated erythroid cell. 
     
     
         8 . The genetically engineered enucleated erythroid cell of  claim 1 , which is not a hypotonically loaded cell. 
     
     
         9 . The genetically engineered enucleated erythroid cell of  claim 1 , which is capable of promoting T cell proliferation. 
     
     
         10 . The genetically engineered enucleated erythroid cell of  claim 1 , wherein the exogenous polypeptide further comprises a transmembrane domain. 
     
     
         11 . The genetically engineered enucleated erythroid cell of  claim 10 , wherein the transmembrane domain comprises a type I red blood cell transmembrane domain. 
     
     
         12 . The genetically engineered enucleated erythroid cell of  claim 10 , wherein the transmembrane domain comprises a type II red blood cell transmembrane domain. 
     
     
         13 . The genetically engineered enucleated erythroid cell of  claim 10 , wherein the transmembrane domain comprises a polypeptide having at least 80% identity to the amino acid sequence of SEQ ID NO: 9. 
     
     
         14 . The genetically engineered enucleated erythroid cell of  claim 10 , wherein the transmembrane domain comprises a glycophorin A (GPA) transmembrane domain. 
     
     
         15 . A pharmaceutical composition comprising a plurality of the genetically engineered enucleated erythroid cells of  claim 1 . 
     
     
         16 . A method of treating cancer in a subject, comprising administering to the subject a plurality of the genetically engineered enucleated erythroid cells of  claim 1 , in an amount effective to treat cancer in the subject. 
     
     
         17 . The method of  claim 16 , wherein the cancer is a leukemia, a lymphoma, or a solid tumor. 
     
     
         18 . The method of  claim 16 , further comprising administering an anti-neoplastic drug to the subject. 
     
     
         19 . The method of  claim 18 , wherein the anti-neoplastic drug is chosen from a chemotherapeutic drug, a cancer growth blocker, a cancer vaccine, and a hormone therapy. 
     
     
         20 . A method of stimulating a T cell, comprising contacting the T cell with the genetically engineered enucleated erythroid cell of  claim 1 , thereby stimulating the T cell.