METHODS OF MAKING CELLULAR THERAPIES
The present disclosure relates generally to methods of making immune effector cells, such as those engineered to express a Chimeric Antigen Receptor (CAR) including CAR-T cells, and compositions comprising the same, for use in treating cancer.
1 . A method of creating a population of immune effector cells, the method comprising:
administering a dual PI3Kδ/γ inhibitor to a subject; and
collecting a sample of a subjects' immune effector cells.
2 . The method of claim 1 , further comprising introducing a nucleic acid into the immune effector cells, resulting in expression of chimeric antigen receptors (CAR).
3 . The method of claim 1 or 2 , further comprising administering the immune effector cells to the subject in need thereof.
4 . The method of any one of claims 1 - 3 , wherein the population of immune effector cells are T cells.
5 . The method of any one of claims 1 - 3 , wherein the population of immune effector cells are tumor infiltrating lymphocytes.
6 . The method of claim 4 , wherein the T cells express a chimeric antigen receptor comprising an antigen binding-fragment directed against a tumor antigen, a hinge or transmembrane region, and an intracellular T-cell signaling component.
7 . The method of claim 6 , wherein the tumor antigen is selected from the list comprising CD19, BCMA, CD123, CD20, CD22, CD70, and CD37.
8 . The method of claim 7 , wherein the tumor antigen is CD19.
9 . The method of any one of claims 1 - 8 , wherein the immune effector cells are autologous.
10 . The method of any one of claims 1 - 8 , wherein the immune effector cells are allogeneic.
11 . The method of any one of claims 1 - 10 , wherein the dual PI3Kδ/γ inhibitor is duvelisib.
12 . The method of any one of claims 4 - 11 , wherein the population of T cells comprises early memory T cells or non-exhausted early memory T cells.
13 . The method of claim 12 , wherein the early memory T cells are CD27+ and/or CD45RO dim/ne .
14 . The method of claim 12 , wherein the non-exhausted early memory T cells are PD-1 negative, CD27 hi , CCR7 hi , CD45RO dim/neg , TIM3 dim/neg and/or LAG3 dim/neg .
15 . The method of any one of claims 12 - 14 , wherein the population of T cells has an increased amount of about 5-about 10%, about 10-about 20%, about 20-about 30%, about 30-about 50%, about 50-about 70%, or about 70-about 90% more early memory T cells or non-exhausted early memory T cells compared to an otherwise similar population of T cells in a subject not administered a dual PI3Kδ/γ inhibitor.
16 . The method of any one of claims 4 - 15 , wherein the T cells display an increased amount of about 5-about 10%, about 10-about 20%, about 20-about 30%, about 30-about 50%, about 50-about 70%, or about 70-about 90% more CD8/CD4 positive T cells compared to an otherwise similar population of T cells in a subject not administered a dual PI3Kδ/γ inhibitor.
17 . The method of claim 16 , wherein the increased amount comprises about 40% more CD8/CD4 positive T cells compared to an otherwise similar population of T cells in a subject not administered a dual PI3Kδ/γ inhibitor.
18 . The method of any one of claims 1 - 17 , wherein the administering the dual PI3Kδ/γ inhibitor increases mitochondrial area within the immune effector cells.
19 . The method of claim 18 , wherein the increase in mitochondrial area relative to total cell area is by 1-fold, 2-fold, 3-fold, 4-fold, or 5-fold compared to an otherwise similar population of immune effector cells in a subject not administered a dual PI3Kδ/γ inhibitor.
20 . The method of any one of claims 1 - 19 , wherein the dual PI3Kδ/γ inhibitor is duvelisib.
21 . The method of any one of claims 1 - 20 , wherein the dual PI3Kδ/γ inhibitor is administered twice daily (BID) to the subject.
22 . A method of treating a subject having cancer, the method comprising (i) administering to the subject a dual PI3Kδ/γ inhibitor, and (ii) administering to the subject a therapeutically effective amount of CAR-expressing immune effector cells.
23 . The method of claim 22 , wherein the dual PI3Kδ/γ inhibitor is administered prior to administration of CAR-expressing immune effector cells.
24 . The method of claim 22 , wherein the dual PI3Kδ/γ inhibitor is administered concurrently with administration of CAR-expressing immune effector cells.
25 . The method of claim 22 , wherein the dual PI3Kδ/γ inhibitor is administered subsequent to administration of CAR-expressing immune effector cells.
26 . The method of any one of claims 22 - 25 , wherein the dual PI3Kδ/γ inhibitor is duvelisib.
27 . The method of any one of claims 22 - 26 , wherein the CAR-expressing immune effector cells are CAR-T cells.
28 . The method of claim 27 , wherein the CAR-T cells are CD19 CAR-T cells.
29 . The method of claim 28 , wherein the CD19 CAR-T cells are administered as tisgenlecleucel, axicabtagene ciloleucel, or lisocabtagene maraleucel.
30 . The method of any one of claims 26 - 29 , wherein the duvelisib is administered at a dose sufficient to increase populations of early memory CAR-T cells in the subject.
31 . The method of any one of claims 26 - 30 , wherein the duvelisib is administered twice daily (BID) to the subject.
32 . The method of any one of claims 22 - 31 , wherein the method is used in combination with a second cancer treatment.
33 . The method of claim 32 , wherein the second cancer treatment is a chemotherapy.