Compositions and methods for treatment of cancers harboring an H3K27M mutation
The invention relates to immunotherapeutic treatment of cancer. In particular, the invention relates to methods of treating cancer carrying a histone H3K27M (H3K27M) mutation (e.g., diffuse midline glioma with H3K27M mutation) using immunotherapeutic compositions comprising immune cells engineered to express GD2-specific chimeric antigen receptors.
1. A method of treating an individual having cancer characterized by a histone H3 K27M (H3K27M) mutation comprising administering to the individual an effective amount of immune cells genetically modified to express a chimeric antigen receptor (CAR) specific for ganglioside GD2 (GD2).
2. The method of claim 1 , wherein the cancer characterized by a histone H3 K27M (H3K27M) mutation is a glioma.
3. The method of claim 2 , wherein the glioma is diffuse intrinsic pontine glioma (DIPG).
4. The method of claim 1 , wherein the cancer characterized by a histone H3 K27M (H3K27M) mutation is diffuse midline glioma.
5. The method of claim 1 , wherein the immune cells are T cells.
6. The method of claim 1 , wherein the immune cells are natural killer (NK) T cells.
7. The method of claim 1 , wherein the chimeric antigen receptor (CAR) specific for GD2 comprises an antigen binding domain of an antibody selected from the group consisting of 14G2a, ch14.18, hu14.18K322A, m3F8, hu3F8-IgG1, hu3F8-IgG4, HM3F8, and DMAb-20.
8. The method of claim 7 , wherein the antigen binding domain is a single-chain variable fragment (scFv).
9. The method of claim 7 , wherein the chimeric antigen receptor (CAR) specific for GD2 further comprises a T cell transmembrane domain, a T cell receptor signaling domain, and/or at least one co-stimulatory domain.
10. The method of claim 9 , wherein the co-stimulatory domain comprises part or all of one or more of CD28, OX40/CD134, 4-1BB/CD137/TNFRSF9, FcERIγ, ICOS/CD278, ILRB/CD122, IL-2RG/CD132, and CD40.
11. The method of claim 1 , wherein the chimeric antigen receptor (CAR) specific for GD2 comprises an antigen binding domain containing heavy and light chain variable regions (scFv) that bind with specificity to the GD2 epitope: GalNAcβ1-4(NeuAcα2-8NeuAcα2-3)Gal.
12. The method of claim 1 , wherein the CAR comprises the 14G2a scFv.
13. A method of treating or delaying the progression of cancer in a patient, comprising:
a) obtaining a biological sample comprising cancer cells from the patient;
b) determining presence of an H3K27M mutation within the cancer cells; and
c) administering to the patient a therapeutically effective amount of a composition comprising T cells genetically modified to express a chimeric antigen receptor (CAR) specific for ganglioside GD2 (GD2).
14. The method of claim 13 , wherein the cancer is selected from the group consisting of diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma.
15. The method of claim 13 , wherein the administering reduces the number of H3K27M positive cancer cells in the patient.
16. The method of claim 13 , wherein the administering reduces and/or clears tumor burden in the patient.
17. The method of claim 13 , further comprising administering to the patient one or more anticancer agents and/or one or more chemotherapeutic agents.
18. The method of claim 13 , wherein the administering occurs before, at the same time, and/or after the patient receives radiation therapy.