Universal anti-tag chimeric antigen receptor-expressing T cells and methods of treating cancer
The present invention provides a universal, yet adaptable, anti-tag chimeric antigen receptor (AT-CAR) system which provides T cells with the ability and specificity to recognize and kill target cells, such as tumor cells, that have been marked by tagged antibodies. As an example, αFITC-CAR-expressing T cells have been developed that specifically recognize various human cancer cells when those cells are bound by cancer-reactive FITC-labeled antibodies. The activation of αFITC-CAR-expressing T cells is shown to induce efficient target lysis, T cell proliferation, and cytokine/chemokine production. The system can be used to treating subjects having cancer.
1. A method of treating cancer in a subject, comprising:
(a) administering a formulation of tagged proteins to a subject in need of treatment, wherein the tagged proteins bind a cancer cell in the subject, and
(b) administering a therapeutically-effective population of anti-tag chimeric receptor (AT-CAR)-expressing T cells to the subject, wherein the AT-CAR-expressing T cells bind the tagged proteins and induce cancer cell death, thereby treating cancer in a subject.
2. A method of treating cancer in a subject, comprising:
(a) administering one or more formulations of tagged proteins to a subject in need of treatment, wherein the tagged proteins bind a cancer cell in the subject, and
(b) administering one or more therapeutically-effective populations of AT-CAR-expressing T cells to the subject, wherein the AT-CAR-expressing T cells bind the tagged proteins and induce cancer cell death, thereby treating cancer in a subject.
3. A method of treating cancer in a subject, comprising:
(a) administering at least two formulations of tagged proteins to a subject in need of treatment, wherein the tagged proteins bind a cancer cell in the subject, and
(b) administering at least two therapeutically-effective populations of AT-CAR-expressing T cells to the subject, wherein the AT-CAR-expressing T cells bind the tagged proteins and induce cancer cell death, thereby treating cancer in a subject.
4. The method of claim 1 , wherein the tagged proteins are tagged with a tag selected from the group consisting of fluorescein isothiocyanate (FITC), streptavidin, biotin, dinitrophenol, peridinin chlorophyll protein complex, green fluorescent protein, phycoerythrin (PE), horse radish peroxidase, palmitoylation, nitrosylation, alkalanine phosphatase, glucose oxidase, and maltose binding protein.
5. The method of claim 1 , wherein the protein of the tagged proteins is an antibody or an antigen-binding fragment thereof.
6. The method of claim 5 , wherein the antibody or antigen-binding fragment thereof is cetuximab, nimotuzumab, panitumumab, retuximab, omalizumab, tositumomab, trastuzumab, gemtuzumab, or alemtuzumab, or an antigen-binding fragment of any one thereof.
7. The method of claim 1 , wherein the AT-CAR of the AT-CAR-expressing T cells comprises a tag-binding domain, a transmembrane domain, and a T cell activation domain.
8. The method of claim 7 , wherein the tag-binding domain is an antibody or an antigen-binding fragment thereof.
9. The method of claim 7 , wherein the tag-binding domain specifically binds FITC, biotin, PE, or streptavidin.
10. The method of claim 8 , wherein the antigen-binding fragment is a single chain variable fragment (scFv).
11. The method of claim 8 , wherein the antigen-binding fragment is a single chain variable fragment (scFv) that specifically binds FITC, biotin, PE, or streptavidin.
12. The method of claim 7 , wherein the transmembrane domain is the hinge and transmembrane regions of the human CD8α chain.
13. The method of claim 7 , wherein the T cell activation domain comprises one or more of the cytoplasmic region of CD28, the cytoplasmic region of CD137 (41BB), the cytoplasmic region of OX40, the cytoplasmic region of HVEM, CD3ξ and FcRε.
14. The method of claim 1 , wherein the T cells of the population of AT-CAR-expressing T cells are selected from the group consisting of T cells of any HLA-background from peripheral blood mononuclear cells (PBMC), T cells isolated from a tumor explant of the subject, and intratumoral T cells of the subject.
15. The method of claim 1 , wherein the T cells of the population of AT-CAR-expressing T cells consist of HLA-A2+ peripheral blood mononuclear cells (PBMC).
16. The method of claim 1 , wherein the formulation of tagged proteins is administered to the subject prior to administration of the therapeutically-effective population of AT-CAR-expressing T cells.
17. The method of claim 1 , wherein the formulation of tagged proteins are administered to the subject concurrently with administration of the therapeutically-effective population of AT-CAR-expressing T cells.
18. The method of claim 1 , wherein the formulation of tagged proteins are administered to the subject after administration of the therapeutically-effective population of AT-CAR-expressing T cells.
19. The method of claim 1 , wherein the formulation of tagged proteins and the therapeutically-effective population of AT-CAR-expressing T cells are administered to the subject in any order.
20. The method of claim 1 , wherein AT-CAR-expressing T cell binding to the tagged proteins, which are bound to a cancer cell, induces cytolytic activation of the T cells.
21. The method of claim 1 , wherein the subject is a human.