JP-2022514219-A5 -

Dates

Publication Date

20221219

Application Date

20191209

Description

Furthermore, this specification provides cells prepared by the methods disclosed herein. In certain embodiments, the cells include chimeric antigen receptors (CARs) and/or T cell receptors (TCRs), for example, engineered TCRs. In some embodiments, the cells are T cells, tumor-infiltrating lymphocytes (TILs), lymphokine-activated killer cells, NK cells, or any combination thereof. In certain embodiments, for example, the following are provided: (Item 1) A method for treating a tumor of a target requiring such treatment, comprising administering modified cells expressing reduced levels of the NFE2L2 gene and/or Nrf2 protein to the target. (Item 2) The method according to item 1, wherein the expression level of the NFE2L2 gene and/or Nrf2 protein is reduced by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% compared to a reference cell (e.g., a corresponding cell that has not been modified to express a relatively low level of the NFE2L2 gene and/or Nrf2 protein). (Item 3) The method according to item 1 or 2, wherein the administration reduces the tumor volume in the subject compared to a reference tumor volume (for example, the tumor volume in the subject before the administration and/or the tumor volume in the subject that did not receive the administration). (Item 4) The method according to item 3, wherein the tumor volume is reduced after the administration by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% compared to the reference tumor volume. (Item 5) The method according to any one of items 1 to 4, wherein the administration reduces the tumor weight in the subject compared to a reference tumor weight (for example, the tumor weight in the subject before the administration and/or the tumor weight in the subject that did not receive the administration). (Item 6) The method according to item 5, wherein the tumor weight is reduced after the administration by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% compared to the reference tumor weight. (Item 7) The method according to any one of items 1 to 6, wherein the administration improves one or more characteristics of tumor-infiltrating lymphocytes (TILs) in the subject. (Item 8) The method according to item 7, wherein the TIL, when stimulated with a congener antigen, produces an increased amount of IFN-γ compared to a reference TIL (e.g., a TIL of a subject that did not receive the administration). (Item 9) The method according to item 8, wherein the amount of IFN-γ produced is increased by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% or more compared to the reference TIL. (Item 10) The method according to any one of items 7 to 9, wherein the TIL is CD8 + TIL. (Item 11) The method according to any one of items 7 to 9, wherein the TIL is CD4 + TIL. (Item 12) The method according to any one of items 1 to 11, wherein the modified cells exhibit increased oxidative stress tolerance compared to reference cells (for example, corresponding cells that have not been modified to express relatively low levels of Nrf2 protein). (Item 13) The method according to item 12, wherein the oxidative stress tolerance is increased by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 100% or more compared to the reference cell. (Item 14) The method according to item 12 or 13, wherein the increased oxidative stress tolerance includes the ability to produce IFN-γ and/or express granzyme B in the presence of high concentrations of reactive oxygen species. (Item 15) The method according to item 14, wherein the reactive oxygen species includes hydrogen peroxide ( H₂O₂ ) . (Item 16) The method according to any one of items 1 to 15, wherein the modified cells are immune cells. (Item 17) The method according to item 16, wherein the immune cells include lymphocytes, neutrophils, monocytes, macrophages, dendritic cells, or a combination thereof. (Item 18) The method according to item 17, wherein the lymphocytes include T cells, tumor-infiltrating lymphocytes (TILs), lymphokine-activated killer cells, natural killer (NK) cells, or any combination thereof. (Item 19) The method according to item 18, wherein the lymphocytes are T cells. (Item 20