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US-20260124223-A1 - CANCER IMMUNOTHERAPIES

US20260124223A1US 20260124223 A1US20260124223 A1US 20260124223A1US-20260124223-A1

Abstract

The present disclosure generally relates to technologies for treating cancer, including brain cancers such as a glioblastoma, methods of increasing the concentration of anthracy clines and immune checkpoint modulators in the brain of a subject, and methods of improving use of immune checkpoint modulators in brain cancers. Also disclosed herein are compositions and methods for treating a brain tumor.

Inventors

  • Victor Andres Arrieta GONZALEZ
  • Roger Stupp
  • Christina Marie AMIDEI
  • Adam Mendel SONABEND WORTHALTER
  • Kwang-Soo Kim

Assignees

  • NORTHWESTERN UNIVERSITY

Dates

Publication Date
20260507
Application Date
20231002

Claims (20)

  1. 1 .- 53 . (canceled)
  2. 54 . A method for treating a glioblastoma in a subject in need thereof comprising: (a) administering to the subject a therapeutically effective amount of an anthracycline; (b) administering to the subject a therapeutically effective amount of an anti-PD-1 antibody; and (c) disrupting the blood-brain barrier of the subject by administering low-intensity pulsed ultrasound and microbubbles.
  3. 55 . The method of claim 54 , wherein the therapeutically effective amount of the anthracycline and the low-intensity pulsed ultrasound and microbubbles are administered simultaneously.
  4. 56 . The method of claim 54 , wherein the therapeutically effective amount of the anthracycline, the therapeutically effective amount of the anti-PD-1 antibody, and the low-intensity pulsed ultrasound and microbubbles are administered simultaneously.
  5. 57 . The method of claim 54 , wherein the therapeutically effective amount of anthracycline is administered immediately after the low-intensity pulsed ultrasound and microbubbles are administered.
  6. 58 . The method of claim 54 , wherein the therapeutically effective amount of the anti-PD-1 antibody is administered first, then the low-intensity pulsed ultrasound and microbubbles are administered, and the therapeutically effective amount of the anthracycline is administered last.
  7. 59 . The method of claim 58 , wherein there is a period of time between administering the therapeutically effective amount of the anti-PD-1 antibody and administering the low-intensity pulsed ultrasound and microbubbles.
  8. 60 . The method of claim 59 , wherein the period of time is about 1 hour to about 8 hours.
  9. 61 . The method of claim 54 , wherein the anthracycline is doxorubicin.
  10. 62 . The method of claim 61 , wherein the doxorubicin is liposomal doxorubicin.
  11. 63 . The method of claim 54 , wherein disrupting the blood-brain barrier increases the concentration of the anthracycline in the brain of the subject relative to the concentration of the anthracycline in the brain of the subject in the absence of disrupting the blood-brain barrier.
  12. 64 . The method of claim 54 , wherein disrupting the blood-brain barrier increases the concentration of the anti-PD-1 antibody in the brain of the subject relative to the concentration of the anti-PD-1 antibody in the brain of the subject in the absence of disrupting the blood-brain barrier.
  13. 65 . The method of claim 54 , wherein the microbubbles are administered intravenously.
  14. 66 . The method of claim 54 , wherein the low-intensity pulsed ultrasound is administered by an ultrasound device.
  15. 67 . The method of claim 66 , wherein the ultrasound device is implanted in a cranial window in the skull of the subject.
  16. 68 . The method of claim 54 , wherein the subject was previously treated with a radiotherapy, a chemotherapy, an immunotherapy, or any combination thereof.
  17. 69 . The method of claim 54 , wherein the low-intensity pulsed ultrasound is administered in a plurality of pulsed steps.
  18. 70 . The method of claim 54 , further comprising monitoring the subject for one or more toxicities.
  19. 71 . The method of claim 54 , further comprising assessing disruption of the blood-brain barrier by contrast magnetic resonance imaging.
  20. 72 . A method for treating a tumor or cancer in a subject in need thereof comprising: (a) administering to the subject a therapeutically effective amount of an anthracycline; (b) administering to the subject a therapeutically effective amount of checkpoint inhibitor.

Description

CROSS REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63/412,718, filed on Oct. 3, 2022, and U.S. Provisional Patent Application No. 63/539,291, filed on Sep. 19, 2023, the contents of each of which are incorporated herein by reference in its entirety. GOVERNMENT LICENSING RIGHTS STATEMENT This invention was made with Government support under Grant Nos. CA264338 and CA245969 awarded by the National Institutes of Health (NIH). The government has certain rights in the invention. BACKGROUND Many cancers, including glioblastoma, remain resistant to immunotherapy. Recent clinical trials demonstrate unprecedented efficacy against immunologically inactive (‘cold’) tumors using botensilimab, an Fc-enhanced anti-CTLA-4 (FcE-aCTLA-4) antibody with a novel mechanism of action. Immune checkpoint blockade (ICB) targeting cytotoxic T-lymphocyte antigen 4 (aCTLA-4) is an established form of immunotherapy and has been investigated in clinical trials for GBM (NCT02311920, NCT04396860) (21-23). Further, recent studies have demonstrated that the ability of aCTLA-4 antibody to co-engage FcγRIIIA on antigen-presenting cells (APCs) such as dendritic cells or macrophages is critical for promoting T cell priming and activation (24) and to drive myeloid activation and type I interferon signaling (30), key mechanisms that are thought to be important for treating poorly immunogenic and ‘cold’ tumors. The importance of co-engaging FcγRIIIA with aCTLA-4 have also been shown clinically (29). Moreover, conventional aCTLA-4 antibodies may have limited therapeutic activity due to suboptimal co-engagement of activating FcγRs. There is a need for improved immunotherapy methods for treating cancer, including brain tumors, and in particular, gliomas and GBM. SUMMARY OF THE INVENTION The present disclosure provides, among other things, methods for treating cancer, including but not restricted to primary brain cancers such as a glioblastoma or glioma, methods of increasing the concentration of anthracyclines and immune checkpoint modulators in the brain of a subject, and methods of improving use of immune checkpoint modulators in cancer. Also disclosed herein are compositions and methods for treating a cancer. In one embodiment, the present disclosure provides a method for treating cancer in a subject in need thereof comprising, consisting of, or consisting essentially of administering to the subject a therapeutically effective amount of an anthracycline. In some embodiments, the method further comprises, consists of, or consists essentially of administering to the subject a therapeutically effective amount of a checkpoint inhibitor. In some aspects, the checkpoint inhibitor comprises, consists of, or consists essentially of an anti-CTLA-4 antibody. In some embodiments, the method further comprises, consists of, or consists essentially of administering to the subject a therapeutically effective amount of an anti-PD-1 antibody. In some embodiments, the method comprises, consists of, or consists essentially of disrupting the blood-brain barrier of the subject by administering low-intensity pulsed ultrasound and microbubbles. In some embodiments, the effective amount of the anthracycline is below the established human cytotoxic or cardiotoxic amount. In some embodiments, the therapeutically effective amount of the anthracycline comprises 30 mg or less. In some aspects, the effect amount of the anthracycline comprises 35 mg or less, or 40 mg or less, or 45 mg or less, or 50 mg or less. In some embodiments, the therapeutically effective amount of the anthracycline comprises an amount that results in a tumor concentration of at least 0.1 mM of anthracycline 0.2 mM or greater, 0.3 mM or greater, or 0.4 mM or greater, or 0.5 mM or greater. In some embodiments, the therapeutically effective amount of the anthracycline comprises an amount that results in a blood serum concentration of at least 0.1 mM of anthracycline, 0.2 mM or greater, 0.3 mM or greater, or 0.4 mM or greater, or 0.5 mM or greater. In some aspects the effective amount of the anthracycline does not result in cytotoxicity in the subject. In some aspects, the effective amount of the anthracycline is a non-cytotoxic dose of an anthracycline. In some aspects, the effective amount of the anthracycline is sufficient to increase expression of FcyRIIA in the subject. In some embodiments, the therapeutically effective amount of the anthracycline and the therapeutically effective amount of the checkpoint inhibitor are administered simultaneously. In other embodiments, the therapeutically effective amount of anthracycline is administered immediately after the therapeutically effective amount of the checkpoint inhibitor is administered. In some embodiments, the therapeutically effective amount of anthracycline is administered before the therapeutically effective amount of the checkpoint inhibitor is administered. In some