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US-20260124277-A1 - TREATMENT OF IMMUNOSUPPRESSED SUBJECTS

US20260124277A1US 20260124277 A1US20260124277 A1US 20260124277A1US-20260124277-A1

Abstract

An IL-15 super agonist (IL-15N72D:IL-15RαSU/IgG1Fc; N-803) increases circulating NK cells, effector memory and effector memory RA cells in post-allogeneic hematopoietic stem cell transplant patients (HCT). Methods of treatment include administration of N-803 to subjects in need of such treatment.

Inventors

  • Patrick Soon-Shiong

Assignees

  • NANTCELL, INC.

Dates

Publication Date
20260507
Application Date
20250829

Claims (20)

  1. 1 - 38 . (canceled)
  2. 39 . A method of treating immunosuppression in a subject having a neoplasia or an infectious disease, comprising administering to the subject a composition comprising a therapeutically effective amount of an IL-15:IL-15Rα complex, wherein the IL-15:IL-15Rα complex modulates amounts of circulating immune effector cells, immune effector cell activity, and/or activates immune effector cells, wherein the immune effector cells comprise CD45RA − /CCR7 − effector memory (T EM ) T cells or CD45RA + /CCR7 − effector memory RA (T EMRA ) T cells.
  3. 40 . The method of claim 39 , wherein the IL-15:IL-15Rα complex is an IL-15N72D:IL-15RαSu/Fc complex (N-803) comprising a dimeric IL-15RαSu/Fc and two IL-15N72D molecules.
  4. 41 . The method of claim 39 , wherein the immune effector cells further comprise natural killer cells (NK), effector memory (T EM ), effector memory RA (T EMRA ) T cells, cytolytic T cells (CTLs), T helper cells (T H ), or a combination thereof.
  5. 42 . The method of claim 39 , wherein the activated immune effector cells comprise one or more markers comprising CD38, perforin, granzyme B, Ki-67, or a combination thereof.
  6. 43 . The method of claim 39 , wherein the subject is a subject having undergone organ transplantation, bone marrow transplantation, radiotherapy, chemotherapy and/or have a viral infection, chronic viral infection, recurrent viral infection, or a combination thereof.
  7. 44 . The method of claim 39 , comprising administering one or more chemotherapeutic agents, compounds, cytokine antagonists, cytokine receptor antagonists, cytokines, adoptive cell therapies, anti-viral agents, checkpoint inhibitors, adjuvants, or a combination thereof.
  8. 45 . The method of claim 44 , wherein the adoptive cell therapy comprises administration of natural killer (NK) cells and/or T cells.
  9. 46 . The method of claim 39 , wherein the IL-15:IL-15Rα complex is administered at a dose of about 1.0 μg/kg.
  10. 47 . The method of claim 39 , wherein the IL-15:IL-15Rα complex is administered at a dose of about 3.0 μg/kg.
  11. 48 . The method of claim 47 , wherein the IL-15:IL-15Rα complex is administered intravenously.
  12. 49 . The method of claim 39 , wherein the IL-15:IL-15Rα complex is administered at a dose of about 6.0 μg/kg.
  13. 50 . The method of claim 49 , wherein the IL-15:IL-15Rα complex is administered subcutaneously.
  14. 51 . The method of claim 39 , wherein CD34, CD8, and/or NK cells proliferate after each administration of the IL-15:IL-15Rα complex.
  15. 52 . The method of claim 39 , wherein anti-IL-15 antibodies do not form after administration of the IL-15:IL-15Rα complex.
  16. 53 . The method of claim 39 , wherein cytokine-related side effects do not occur after administration of the IL-15:IL-15Rα complex.
  17. 54 . A method of treating Progressive Multifocal Leukoencephalopathy (PML) in a subject, the method comprising administering to the subject a composition comprising a therapeutically effective amount of an IL-15:IL-15Rα complex, wherein the IL-15:IL-15Rα complex increases the number of circulating immune effector cells and/or activates immune effector cells
  18. 55 . The method of claim 54 , wherein the IL-15:IL-15Rα complex is an IL-15N72D:IL-15RαSu/Fc complex (N-803) comprising a dimeric IL-15RαSu/Fc and two IL-15N72D molecules.
  19. 56 . The method of claim 54 , wherein the immune effector cells comprise natural killer cells (NK), effector memory (T EM ) T cells (CD45RA − /CCR7 − ), effector memory RA (T EMRA ) T cells (CD45RA + /CCR7 − ), cytolytic T cells (CTLs), T helper cells (T H ) or combinations thereof.
  20. 57 . The method of claim 54 , wherein the therapeutically effective amount of the IL-15:IL-15Rα complex is from about 1 mcg/kg to about 6.0 mcg/kg.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. patent application Ser. No. 19/186,092, filed Apr. 22, 2025, now U.S. Pat. No. 12,427,184, which is a continuation application of U.S. patent application Ser. No. 18/808,392, filed Aug. 19, 2024, now U.S. Pat. No. 12,303,552, which is a divisional of U.S. patent application Ser. No. 18/326,293, filed May 31, 2023, now U.S. Pat. No. 12,156,901, which is a continuation of U.S. patent application Ser. No. 17/284,406, filed Apr. 9, 2021, now U.S. Pat. No. 11,701,408, which is a national stage under 35 U.S.C. 371 and claims the benefit of PCT Application No. PCT/US2019/55790 having an international filing date of Oct. 11, 2019, which designates the United States, which PCT claims the benefit of priority under 35 U.S.C. § 119 (e) to U.S. Provisional Application No. 62/744,601, filed on Oct. 11, 2018. The entire contents of each of the foregoing applications are herein incorporated by reference in their entireties. REFERENCE TO SEQUENCE LISTING This application contains a Sequence Listing submitted as an electronic XML file named “PAT_001418_US003.xml”, having a size of 8,439 bytes, and created on May 31, 2023. The information contained in this XML file is hereby incorporated by reference in its entirety. FIELD OF THE INVENTION Embodiments of the invention are directed to compositions for treating immunosuppressed patients, patients with neoplasia or virus infections. In particular, the compositions include a superagonist. BACKGROUND Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reaction to treatment of other conditions. In general, immunosuppression is the deliberate prevention or reduction of an immune response. It can result from the administration of immunosuppressive agents or from the deliberate depletion of immune cells, as well as from malnutrition, cancers and certain chronic infections such as HIV. Deliberately induced immunosuppression is performed to prevent the body from rejecting an organ transplant. Additionally deliberate immunosuppression is used for treating graft-versus-host disease after a bone marrow transplant, or for the treatment of auto-immune diseases such as systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome, or Crohn's disease. This is typically done using medications, but may involve surgery (splenectomy), plasmapheresis, or radiation. An unwanted side-effect of immunosuppression is immunodeficiency. SUMMARY Embodiments of the invention are directed, in part, to compositions which modulate immune cell responses, for example, immunosuppressed subjects such as those having undergone post-allogeneic hematopoietic stem cell transplant (HCT), patients with neoplasia or virus infections. Methods of treatment include administration of compositions comprising therapeutically effective amounts of an IL-15:IL-15Rα complex. In certain embodiments, a method of treating a subject suffering from a human immunodeficiency virus (HIV) infection comprises administering to the subject a composition comprising a therapeutically effective amount of an IL-15:IL-15Rα (N-803) complex, wherein the IL-15:IL-15Rα complex modulates amounts of circulating immune effector cells and/or activates immune effector cells. In embodiments, the IL-15:IL-15Rα complex is an IL-15N72D:IL-15RαSu/Fc complex (N-803) comprising a dimeric IL-15RαSu/Fc and two IL-15N72D molecules. The HIV infection is active or in a latent stage. In certain embodiments, the IL-15:IL-15Rα complex is administered to the subject in escalating therapeutically effective amounts over a period of time to maintain an HIV specific immune response. In certain aspects the dose is escalated to a maximum therapeutically effective amount which is not toxic to the subject as determined by a dose-limiting toxicity (DLT) assay. In certain embodiments, the IL-15:IL-15Rα complex is administered until the HIV is undetectable or eradicated from the subject. In certain embodiments, the therapeutically effective amount of the IL-15:IL-15Rα complex is from about 0.01 mcg/kg to about 100.0 mcg/kg. In certain embodiments, the therapeutically effective amount is from about 1 mcg/kg to about 6.0 mcg/kg. In certain embodiments, the routes of administration of the IL-15:IL-15Rα complex to the subject comprise: subcutaneous, intravenous, intraperitoneal, intramuscular, intratumoral or intradermal routes. In certain embodiments, the immune effector cells comprise natural killer cells (NK), cytolytic CD8+ T cells (CTLs), CD4+ T helper cells (TH), effector memory (TEM) T cells (CD45RA−/CCR7−), effector memory RA (TEMRA) T cells (CD45RA+/CCR7−), or combinations thereof. In certain embodiments, a subject is treated with the IL-15:IL-15Rα complex in combination with one or more therapeutics c