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US-20260124301-A1 - IMMUNE CELL ENGINEERED WITH IL-8 RECEPTOR AND USE THEREOF

US20260124301A1US 20260124301 A1US20260124301 A1US 20260124301A1US-20260124301-A1

Abstract

The present invention provides a method for preparing an immune cell, such as a tumor-associated antigen-specific T cell (TAA-T cell), which is engineered with an IL-8 receptor. The present application also provides an immune cell, such as a T cell which is tumor-associated antigen-specific and is engineered with an IL-8 receptor. Immune cells (such as T cells) are genetically engineered to bind to IL-8 in the tumor environment that can serve as a potential strategy to improve immunotherapy for pediatric solid tumors.

Inventors

  • Conrad Russell Y. Cruz
  • Amy Hont
  • Catherine Mary Bollard

Assignees

  • CHILDREN'S NATIONAL MEDICAL CENTER

Dates

Publication Date
20260507
Application Date
20230517

Claims (20)

  1. 1 . An engineered immune cell engineered to express, on the cell surface, an IL-8-binding protein capable of binding to IL-8.
  2. 2 . The engineered immune cell of claim 1 , wherein the IL-8-binding protein comprises: (1) a dominant negative IL-8 receptor (DNR) incapable of transducing IL-8 signaling upon IL-8 binding, or (2) an antigen-binding portion of an antibody specific for IL-8.
  3. 3 . The engineered immune cell of claim 2 , wherein the IL-8-binding protein: (1) lacks intracellular signaling domain(s) of CXCR1/CXCR2, and/or (2) transmits an activating signal for the engineered immune cell upon binding IL-8.
  4. 4 . The engineered immune cell of claim 1 , wherein the IL-8-binding protein is encoded by an expression construct (e.g., a vector) introduced into said immune cell.
  5. 5 . The engineered immune cell of claim 4 , wherein the expression construct/vector is a retroviral vector.
  6. 6 . The engineered immune cell of claim 1 , wherein the engineered immune cell is specific for WTl, PRAME, or Survivin.
  7. 7 . The engineered immune cell of claim 1 , wherein the engineered immune cell is a B cell, a natural killer (NK) cell, or a T cell.
  8. 8 . The engineered immune cell of claim 7 , wherein the T cell is a helper T cell, a cytotoxic T cell, a NK T cell, an iNK T cell, a gamma delta T cell, an alpha beta T cell, an antigen-specific T cell, a tumor-infiltrating lymphocyte (TIL), an engineered T cell receptor (TCR) cells, an engineered CAR-T cell, or an antigen-specific T cell.
  9. 9 . The engineered immune cell of claim 8 , wherein the antigen-specific T cell is a tumor-associated antigen-specific T (TAA-T) cell, a neoantigen specific T cell, or a virus specific T cell.
  10. 10 . A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the immune cell of claim 1 .
  11. 11 . The method of claim 10 , wherein the cancer is a pediatric solid tumor.
  12. 12 . The method of claim 11 , wherein the pediatric solid tumor is Wilms tumor, rhabdomyosarcoma, neuroblastoma, or melanoma.
  13. 13 . The method of claim 10 , wherein the cancer expresses or over-expresses IL-8.
  14. 14 . The method of claim 10 , wherein the cancer is a chemo-refractory cancer.
  15. 15 . The method of claim 10 , wherein the immune cell is specific for WTl, PRAME, or Survivin.
  16. 16 . A method of producing the immune cell of claim 1 , the method comprising introducing, into an isolated immune cell, an expression construct (e.g., vector) encoding an IL-8-binding protein capable of binding to IL-8, in order to enable expression of the IL-8-binding protein on the surface of the immune cell.
  17. 17 . The method of claim 16 , wherein the expression construct is a lentiviral or retroviral vector.
  18. 18 . The method of claim 16 , wherein the IL-8-binding protein comprises: (1) a dominant negative IL-8 receptor (DNR) incapable of transducing IL-8 signaling upon IL-8 binding, or (2) an antigen-binding portion of an antibody specific for IL-8.
  19. 19 . The method of claim 16 , wherein the IL-8-binding protein: (1) lacks intracellular signaling domain(s) of CXCR1/CXCR2, and/or (2) transmits an activating signal for the engineered immune cell upon binding IL-8.
  20. 20 . The method of claim 16 , wherein the immune cell is specific for WTl, PRAME, or Survivin.

Description

REFERENCE TO RELATED APPLICATION This application claims priority to and the benefit of the filing date of U.S. Provisional Patent Application No. 63/343,215, filed on May 18, 2022, the entire contents of which are incorporated herein by reference. FIELD OF THE INVENTION The present invention pertains to the fields of immune cells, such as B lymphocytes (B cells), natural killer cells (NK cells), or T cells, such as tumor-associated antigen-specific T cells (TAA-T cells). BACKGROUND OF THE INVENTION The safety of tumor-associated antigen-specific T lymphocytes specific for WT1, PRAME, and Survivin against pediatric solid tumors, including Wilms tumor, were demonstrated previously in Phase I studies. The effects of attenuating interleukin 8 (IL-8) in the tumor environment on tumor and T cell function has not been previously explored. SUMMARY OF THE INVENTION The present application provides a method for preparing an immune cell, such as a tumor-associated antigen-specific T cells (TAA-T cell), which is engineered with an Interleukin 8 (IL-8) receptor. The present application also provides an immune cell, such as a tumor-associated antigen-specific T cell (TAA-T cell), which is engineered with an IL-8 receptor. Such immune cells, such as T cells, are genetically engineered to bind to IL-8 in the tumor environment that can serve as a potential strategy to improve immunotherapy for pediatric solid tumors. In an embodiment, a TAA-T cell is transduced with an IL-8 receptor to bind, to serve as an IL-8 sink (to “sink IL-8”), or to respond to IL-8 which is known to be a chemokine released by tumors and immune cells in the tumor microenvironment. The present application provides a mechanism to home immune cells, such as TAA-T cells, to areas of high IL-8 concentration and to sink IL-8 to decrease its effects. These immune cells, such as TAA-T cell products, can be infused into patients with high-risk malignancies to treat chemo-refractory diseases. The invention described herein is further presented in the following numbered paragraphs: 1. An engineered immune cell engineered to express, on cell surface, an IL-8-binding protein capable of binding to IL-8.2. The engineered immune cell of paragraph 1, wherein the IL-8-binding protein comprises: (1) a dominant negative IL-8 receptor (DNR) incapable of transducing IL-8 signaling upon IL-8 binding, or,(2) an antigen-binding portion of an antibody specific for IL-8. 3. The engineered immune cell of paragraph 2, wherein the IL-8-binding protein: (1) lacks intracellular signaling domain(s) of CXCR1/CXCR2, and/or,(2) transmits an activating signal for the engineered immune cell upon binding IL-8. 4. The engineered immune cell of any one of paragraphs 1-3, wherein the IL-8-binding protein is encoded by an expression construct (e.g., a vector) introduced into said immune cell.5. The engineered immune cell of paragraph 4, wherein the expression construct/vector is a retroviral vector.6. The engineered immune cell of any one of paragraphs 1-5, wherein the engineered immune cell is specific for WT1, PRAME, or Survivin.7. The engineered immune cell of any one of paragraphs 1-6, wherein the engineered immune cell is a B cell, a natural killer (NK) cell, or a T cell.8. The engineered immune cell of paragraph 7, wherein the T cell is a helper T cell, a cytotoxic T cell, a NK T cell, an iNK T cell, a gamma delta T cell, an alpha beta T cell, an antigen-specific T cell, a tumor-infiltrating lymphocyte (TIL), an engineered T cell receptor (TCR) cells, an engineered CAR-T cell, or an antigen-specific T cell.9. The engineered immune cell of paragraph 8, wherein the antigen-specific T cell is a tumor-associated antigen-specific T (TAA-T) cell, a neoantigen specific T cell, or a virus specific T cell.10. A method of treating cancer in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the immune cell of any one of paragraphs 1-9.11. The method of paragraph 10, wherein the cancer is a pediatric solid tumor.12. The method of paragraph 11, wherein the pediatric solid tumor is Wilms tumor, rhabdomyosarcoma, neuroblastoma, or melanoma.13. The method of any one of paragraphs 10-12, wherein the cancer expresses or over-expresses IL-8.14. The method of any one of paragraphs 10-13, wherein the cancer is a chemo-refractory cancer.15. The method of any one of paragraphs 10-14, wherein the immune cell is specific for WT1, PRAME, or Survivin.16. A method of producing the immune cell of any one of paragraphs 1-9, the method comprising introducing, into an isolated immune cell, an expression construct (e.g., vector) encoding an IL-8-binding protein capable of binding to IL-8, in order to enable expression of the IL-8-binding protein on the surface of the immune cell.17. The method of paragraph 16, wherein the expression construct is a lentiviral or retroviral vector.18. The method of paragraph 16 or 17, wherei