Compositions and methods related to engineered erythroid cells comprising IL-15
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 IL15Rα-binding fragment thereof, wherein the exogenous polypeptide is at the surface of the enucleated erythroid cell, wherein the exogenous polypeptide does not comprise a sortase transfer signature, and
wherein the enucleated erythroid cell was produced by a process comprising:
introducing an exogenous nucleic acid encoding the exogenous polypeptide into a nucleated erythroid cell, or a precursor thereof; and
culturing the nucleated erythroid cell under conditions suitable for enucleation of the nucleated erythroid cell and for production of the exogenous polypeptide.
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. A method of treating cancer in a subject, comprising administering to the subject a plurality of the enucleated erythroid cells of claim 1 , in an amount effective to treat cancer in the subject.
5. The method of claim 4 , wherein the cancer is a leukemia, a lymphoma, or a solid tumor.
6. The method of claim 4 , further comprising administering an anti-neoplastic drug to the subject.
7. The method of claim 6 , wherein the anti-neoplastic drug is chosen from a chemotherapeutic drug, a cancer growth blocker, a cancer vaccine, and a hormone therapy.
8. A method of stimulating a T cell, comprising contacting the T cell with the enucleated erythroid cell of claim 1 , thereby stimulating the T cell.
9. A method of making 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, wherein the exogenous polypeptide does not comprise a sortase transfer signature, and
wherein the method comprises:
introducing an exogenous nucleic acid encoding the exogenous polypeptide into a nucleated erythroid cell, or a precursor thereof; and
culturing the nucleated erythroid cell under conditions suitable for enucleation of the nucleated erythroid cell and for production of the exogenous polypeptide,
thereby making the enucleated erythroid cell.
10. The enucleated erythroid cell of claim 3 , wherein the exogenous polypeptide and the second exogenous polypeptide have an abundance ratio of from about 2:1 to 1:2 by copy number.
11. The enucleated erythroid cell of claim 1 , which is a reticulocyte.
12. The 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.
13. The enucleated erythroid cell of claim 1 , which is not a hypotonically loaded cell.
14. The enucleated erythroid cell of claim 1 , which is capable of promoting T cell proliferation.
15. The enucleated erythroid cell of claim 1 , wherein the exogenous polypeptide further comprises a transmembrane domain.
16. The enucleated erythroid cell of claim 15 , wherein the transmembrane domain comprises a glycophorin A (GPA) transmembrane domain.
17. The enucleated erythroid cell of claim 1 , which is a mature red blood cell.
18. The enucleated erythroid cell of claim 1 , wherein culturing the nucleated erythroid cell comprises expanding the nucleated erythroid cell by at least 1,000 fold.