IMMUNE EFFECTOR CELL THERAPIES WITH ENHANCED EFFICACY
First Claim
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1. A method of treating a subject, comprising administering to said subject an LSD1 inhibitor and a population of immune effector cells engineered to express a CAR.
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Abstract
Provided are the use of LSD1 inhibitors in connection with use and manufacture of immune effector cells (e.g., T cells, NK cells), e.g., engineered to express a chimeric antigen receptor (CAR), to treat a subject having a disease, e.g., a disease associated with expression of a tumor antigen.
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Citations
75 Claims
- 1. A method of treating a subject, comprising administering to said subject an LSD1 inhibitor and a population of immune effector cells engineered to express a CAR.
- 5. A method of increasing the therapeutic efficacy of a population of immune effector cells engineered to express a CAR, e.g., a CART19 (e.g., CTL019), comprising a step of decreasing the activity or expression of LSD1 in said cells, transiently or permanently.
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8. A method of treating a subject, comprising:
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a) administering an LSD1 inhibitor to a subject; b) collecting a population of immune effector cells from the subject of step a), after said administration of the LSD1 inhibitor; c) providing said population of immune effector cells ex vivo; d) contacting said ex vivo population of immune effector cells with the LSD1 inhibitor, wherein the contacting with the LSD1 inhibitor causes one or more of the following to occur; 1) an increase in the proportion of naive T cells, e.g., TSCM cells; 2) an increase in the number of naive T cells, e.g., TSCM cells; 3) a decrease in the number of TEM cells; 4) a decrease in the proportion of TEM cells; 5) an increase in the proportion of CD45RA+CD62L+ T cells; 6) an increase in the number of CD45RA+CD62L+ T cells; 7) an increase in the proportion of CD45RA+CCR7+ T cells; 8) an increase in the number of CD45RA+CCR7+ T cells; 9) a decrease in the proportion of PD-1 positive immune effector cells; 10) an increase in the ratio of PD-1 negative immune effector cells/PD-1 positive immune effector cells; 11) a decrease in the proportion of PD-1+/Lag3+/Tim3+ immune effector cells; 12) an increase in the ratio of PD-1−
/Lag3−
/Tim3−
immune effector cells to PD-1+/Lag3+/Tim3+ immune effector cells;13) an increase in the proliferation of the immune effector cells; 14 an increase in the production of cytokines (e.g., IFNg and/or IL-2) from said population of immune effector cells;
or15) a combination of two or more of the above; as compared to a non-contacted ex vivo population of immune effector cells; and e) administering the population of immune effector cells to a subject. - View Dependent Claims (9, 10)
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11. A method of making a population of immune effector cells comprising:
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a) contacting a population of immune effector cells with an LSD1 inhibitor; thereby making a population of immune effector cells, wherein the contacting with the LSD1 inhibitor causes one or more of the following to occur; 1) an increase in the proportion of naive T cells, e.g., TSCM cells; 2) an increase in the number of naive T cells, e.g., TSCM cells; 3) a decrease in the number of TEM cells; 4) a decrease in the proportion of TEM cells; 5) an increase in the proportion of CD45RA+CD62L+ T cells; 6) an increase in the number of CD45RA+CD62L+ T cells; 7) an increase in the proportion of CD45RA+CCR7+ T cells; 8) an increase in the number of CD45RA+CCR7+ T cells; 9) a decrease in the proportion of PD-1 positive immune effector cells; 10) an increase in the ratio of PD-1 negative immune effector cells/PD-1 positive immune effector cells; 11) a decrease in the proportion of PD-1+/Lag3+/Tim3+ immune effector cells; 12) an increase in the ratio of PD-1−
/Lag3−
/Tim3−
immune effector cells to PD-1+/Lag3+/Tim3+ immune effector cells;13) an increase in the proliferation of the immune effector cells; 14 an increase in the production of cytokines (e.g., IFNg and/or IL-2) from said population of immune effector cells;
or15) a combination of two or more of the above; as compared to a non-contacted population of immune effector cells. - View Dependent Claims (12, 13, 14, 15, 54, 55, 56, 57, 58)
2) concurrently with; 3) after;
or4) any combination of two or more of
1) to
3) above;said inserting of step b).
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14. The method of any of claims 11-13, wherein the contacting of step a), and optionally the inserting of step b), is ex vivo.
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15. A population of immune effector cells, made by the method of any of claims 11-14.
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54. A method of treating a subject in need thereof, comprising administering to said subject an effective amount of the population of immune effector cells of any of claims 15-18.
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55. The method of claim 54, wherein the method further comprises administering to said subject an LSD1 inhibitor.
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56. The method of claim 55, wherein the subject receives a pre-treatment of the LSD1 inhibitor, prior to the administration of the population of immune effector cells.
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57. The method of any of claims 55-56, wherein the subject receives concurrent treatment with an LSD1 inhibitor and the population of immune effector cells.
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58. The method of any of claims 55-57, wherein the subject receives treatment with an LSD1 inhibitor after administration of the population of immune effector cells.
- 16. A population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen-binding domain, a transmembrane domain, and an intracellular signaling domain, and wherein expression and/or function of LSD1 in said cell has been reduced or eliminated.
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64. A compound selected from N,N-dimethyl-1-((4-(4-(4-(piperidin-4-yl)phenyl)-1H-indazol-1-yl)phenyl)sulfonyl)piperidin-4-amine and 5-(6-chloro-4′
- -(methylsulfonyl)biphenyl-3-yl)-2-(piperazin-1-yl)-1H-pyrrole-3-carbonitrile;
or a pharmaceutically acceptable salt thereof. - View Dependent Claims (65, 66)
- -(methylsulfonyl)biphenyl-3-yl)-2-(piperazin-1-yl)-1H-pyrrole-3-carbonitrile;
- 68. A composition for use in ex vivo manufacturing a population of immune effector cells, comprising an LSD1 inhibitor.
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73. An LSD1 inhibitor, for use in treating a subject, wherein said subject has received, is receiving, or is about to receive therapy comprising an immune effector cell, e.g., an immune effector cell engineered to express a CAR.
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74. An LSD1 inhibitor, for use in the manufacture of an immune effector cell, e.g., an immune effector cell engineered to express a CAR.
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75. A method of manufacturing an immune effector cells comprising introducing into said cells nucleic acid encoding a CAR, wherein the nucleic acid integrates into the genome of said cell within the LSD1 gene, such that LSD1 expression and/or function is reduced.
Specification