Treatment of cancers with immunostimulatory hiv tat derivative polypeptides

Abstract

Disclosed herein are compositions comprising a Human Immunodeficiency Virus (HIV) trans-activator of transcription (Tat) derivative polypeptide with increased immunostimulatory properties relative to the native Tat polypeptide, pharmaceutical compositions comprising the Tat derivative polypeptide, and methods of treating cancer using the Tat derivative polypeptide.

What is claimed is: 
     
         1 . A polypeptide having an amino acid sequence comprising, in the following order:
 (i) the amino acid sequence of a transcription factor (TF) domain of a simian immunodeficiency virus (SIV) trans-activator of transcription (Tat) protein, wherein the SIV is African Green Monkey Vervet SIV (SIVagmVer),   (ii) the amino acid sequence of a cysteine-rich sequence of SIV, human immunodeficiency virus (HIV), or a defensin, and   (iii) the amino acid sequence of a C-terminal domain of HIV or SIV Tat protein; wherein the polypeptide is not SEQ ID NO: 3, and wherein the amino acid sequences of (i), (ii), and (iii) are not all from the same source.   
     
     
         2 . The polypeptide of  claim 1 , wherein the HIV of (ii) or (iii) is independently HIV-1 or HIV-2, or wherein the SIV. of (ii) or (iii) is independently from a host selected from Table 2. 
     
     
         3 . The polypeptide of  claim 2 , wherein the HIV-1 Tat is from a long-term non-progressor. 
     
     
         4 . The polypeptide of  claim 1 , wherein the TF domain comprises the sequence of any one of SEQ ID NOs: 97, 102, or 108. 
     
     
         5 . The polypeptide of  claim 1 , wherein the defensin is an α-defensin or a β-defensin. 
     
     
         6 . The polypeptide of  claim 1 , wherein the cysteine-rich domain comprises an amino acid sequence of one of SEQ ID NOs:124-132. 
     
     
         7 . The polypeptide of  claim 1 , wherein the C-terminal domain comprises an amino acid sequence of one of SEQ ID NOs:133-150. 
     
     
         8 . The polypeptide of  claim 1 , having greater than 85% sequence identity to one of SEQ ID NOs: 8, 9, 11, 13, 15, 17, 19-21, 46-49, 88-93, or 95. 
     
     
         9 . A pharmaceutical composition comprising a polypeptide according to  claim 1 . 
     
     
         10 . A method of treating cancer comprising:
 administering a therapeutically effective amount of the polypeptide of  claim 1 , or the pharmaceutical composition of  claim 10 , to a subject in need thereof; and   causing cessation of growth of the cancer or regression of the cancer in the subject.   
     
     
         11 . The method of  claim 11 , wherein the cancer is adrenocortical carcinoma, anal cancer, appendix cancer, astrocytoma, basal-cell carcinoma, bile duct cancer, bladder cancer, bone cancer, brain cancer, breast cancer, bronchial adenomas/carcinoids, carcinoid tumor, cervical cancer, chronic myeloproliferative disorders, colon cancer, desmoplastic small round cell tumor, endometrial cancer, ependymoma, esophageal cancer, Ewing's sarcoma, germ cell tumors, eye cancer, gallbladder cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor (GIST), gestational trophoblastic tumor, glioma, gastric carcinoid, head and neck cancer, heart cancer, hepatocellular cancer, Hodgkin's lymphoma, hypopharyngeal cancer, islet cell carcinoma, Kaposi sarcoma, kidney cancer, leukemias, lip and oral cavity cancer, liposarcoma, liver cancer, lung cancer, lymphomas, macroglobulinemia, medulloblastoma, melanoma, merkel cell carcinoma, mesothelioma, mouth cancer, multiple myeloma/plasma cell neoplasm, mycosis fungoides, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, neuroblastoma, oral cancer, oropharyngeal cancer, ovarian cancer, ovarian epithelial cancer, pancreatic cancer, parathyroid cancer, penile cancer, pharyngeal cancer, pheochromocytoma, pineal astrocytoma, pineal germinoma, pineoblastoma, pituitary adenoma, pleuropulmonary blastoma, prostate cancer, rectal cancer, renal cell carcinoma, retinoblastoma, rhabdomyosarcoma, salivary gland cancer, sarcoma, Sézary syndrome, skin cancer, squamous cell carcinoma, stomach cancer, testicular cancer, throat cancer, thymoma, thyroid cancer, urethral cancer, uterine cancer, uterine sarcoma, vaginal cancer, vulvar cancer, Waldenström macroglobulinemia, or Wlms tumor. 
     
     
         12 . The method of  claim 11 , wherein the cancer is breast cancer. 
     
     
         13 . A method of inhibiting the suppression of an anti-tumor immune response in a subject with cancer, the method comprising:
 administering a therapeutically effective amount of the polypeptide of  claim 1 , or the pharmaceutical composition of  claim 9 , to the subject; wherein the administration results in reduction or inhibition of growth of the cancer or in regression of the cancer in the subject.   
     
     
         14 . The method of  claim 13 , wherein at least one pre-treatment tumor from the subject contains at least 5% PD-L1-expressing cells. 
     
     
         15 . The method of  claim 13 , wherein at least one pre-treatment tumor from the subject contains at least 15% PD-L1-expressing cells.