GEORGETOWN UNIVERSITY

Provided herein are methods of targeting PD-1 + CD38 hi CD8 + T cells to reduce apoptosis of white blood cells (e.g., lymphocytes). Further provided are methods of inducing apoptosis of white blood cells in a subject by using adoptive cell therapy with PD-1 + CD38 hi CD8 + T cells.

Method of treating secondary cancer in a lung of a subject in need thereof, comprising administering a pharmaceutical composition comprising an effective amount of an inhibitor of transcriptional enhanced associate domain (TEAD) to the subject. In addition, methods of inhibiting growth of a secondary tumor in a lung of a subject in need thereof, of increasing number of T-cells at a secondary tumor in a lung of a subject in need thereof, of increasing number of alveolar macrophages in a lung of a subject in need thereof, of decreasing number of infiltrating monocytes/macrophages in a lung of a subject in need thereof, methods of reducing lung metastases in a subject in need thereof, method of inducing polarization of one or more M2 macrophages to M1 macrophages in the lung of a subject with lung cancer, and methods of activating IL12 signaling in lung of a subject with lung cancer.

Provided herein are methods for treating a cholecystokinin (CCK) receptor-expressing cancerous tumor in a subject. The methods comprising administering to the subject an effective amount of a CCK receptor inhibitor and an effective amount of an immune checkpoint inhibitor, wherein the CCK receptor inhibitor inhibits one or more CCK receptors selected from the group consisting of a CCK-A receptor, a CCK-B receptor and a CCK-C receptor, and wherein the immune checkpoint inhibitor is a programmed cell death protein 1 (PD1) inhibitor or a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) inhibitor.

This invention provides methods to overcome the current limitations of immune checkpoint immunotherapy to provide more effective methods of treating cancer. In embodiments this invention provides a means of using of p53 gene therapy to augment immune checkpoint inhibition by combining antibodies targeting immune checkpoint molecules with SGT-53, a nanomedicine carrying a plasmid encoding human wild-type p53. This invention provides means of increasing tumor immunogenicity, enhancing both innate and adaptive immune responses, and reducing tumor-induced immunosuppression, sensitizing otherwise refractory tumors to anti-immune checkpoint antibodies. In other embodiments this invention also unexpectedly reduces immune-related toxicities that are seen with immunotherapies.

Disclosed are small molecule c-kit inhibitors useful in reducing or eliminating mast cell mediated inflammation. Pharmaceutical formulations containing the c-kit inhibitors are also disclosed. Additionally, methods of treating or preventing a condition, disorder, or disease using the c-kit inhibitors or pharmaceutical formulations thereof are disclosed. The condition, disorder, or disease may be an inflammatory condition, including flares of the inflammatory condition. Exemplary inflammatory conditions relevant to this disclosure include, but are not limited to, mastocytosis, mast cell activation syndrome, hereditary alpha tryptasemia, urticaria, Lyme disease, mast cell leukemia, chronic obstructive pulmonary disease, long COVID, asthma, inflammatory bowel disease, arthritis, allergy, and gout.

Methods for the treatment of cutaneous vascular conditions and cutaneous proliferative conditions are provided. The methods employ topical administration of mammalian target of rapamycin (mTOR) inhibitors such as sirolimus (rapamycin) and everolimus. Conditions treatable by the disclosed methods include venolymphatic malformations, acne, acne rosacea, periorificial dermatitis, acne vulgaris, cutaneous capillary malformation-arteriovenous malformation (CM-AVM) syndrome, RASopathies, Langerhans cell histiocytosis, non-Langerhans cell histiocytosis, scars, hypertrophic or keloidal scars, Proteus syndrome, PIK3CA-related overgrowth spectrum (PROS), PTEN hamartoma tumor syndromes, cutaneous malignancies and tumors associated with PI3K/AKT/mTOR mutations, keratodermas, acanthosis nigricans, Birt-Hogg-Dubé syndrome, Brooke-Speigler syndrome, cylindromas, and epidermal nevi. Also provided are formulations and pharmaceutical compositions having mTOR inhibitor as principal therapeutically active ingredient useful in practicing the methods.

Provided herein is a method of treating medulloblastoma or glioblastoma in a subject by administering to the subject a PI3K activator (e.g., thymosin β-4 or a derivative thereof) and one or more chemotherapeutic agents and/or radiation. The combination therapy is effective in the treatment of medulloblastoma or glioblastoma characterized by cells with elevated p53 levels.

Provided herein is a method of treating medulloblastoma or glioblastoma in a subject by administering to the subject a PI3K activator (e.g., thymosin β-4 or a derivative thereof) and one or more chemotherapeutic agents and/or radiation. The combination therapy is effective in the treatment of medulloblastoma or glioblastoma characterized by cells with elevated p53 levels.

Provided herein are compositions and methods for the treatment and prevention of cadherin-11 (CDH11) related diseases. The compositions include CDH11 inhibitors that are formulated for use in combination with chemotherapy and/or immunotherapy, to treat or prevent cancer, fibrosis, and autoimmune diseases.

Aspects of the technology described herein relate to a method of treating a malignancy in a subject. This method involves selecting a subject having a malignancy and administering dimethyl-3-beta-hydroxy-cholenamide (DMHCA) or derivative thereof to the subject in an amount effective to treat the malignancy. Methods of reducing malignancy-associated fibrosis in a subject and pharmaceutical combinations comprising (i) DMHCA or derivative thereof and (ii) one or more immune checkpoint inhibitors are also disclosed.