Methods for modifying endoplasmic reticulum processing of protein

Abstract

The present disclosure provides compositions and methods for modifying endoplasmic reticulum trafficking of proteins. Also disclosed herein are methods for treating cancer and/or enhancing cancer or viral immunotherapy in a subject by increasing the extracellular secretion levels of GRP94 in the subject. Such methods comprise administering to the subject an effective amount of 4-PBA and/or a 4-PBA analog selected from among methoxy-PBA, 3-PPA, 5-PVA, hydroxy-PPA, hydroxy-PBA, and tolyl-BA.

What is claimed is: 
     
         1 . A method for enhancing responsiveness of a subject to immune system stimulators comprising administering to the subject
 a) 4-phenylbutyrate (4-PBA), 4-(4-methoxyphenyl)butyrate (methoxy-PBA), 3-phenylpropionate (3-PPA), 5-phenylvalerate (5-PVA), 3-(4-hydroxyphenyl)propionate (hydroxy-PPA), 4-(4-hydroxyphenyl) butyrate (hydroxy-PBA), 4-(4-tolyl) butyrate (tolyl-BA), or a compound of Formula I:   
       
         
           
           
               
               
           
         
       
       wherein R 1  is H, C 1 -C 3  alkyl, C 1 -C 3  alkoxy, hydroxyl, thiol, C 1 -C 3  alkylthio, —S(O)R 2 , —S(O) 2 R 3 , or —S(O) 2 OR 4 ; R 2 , R 3 , and R 4  are independently C 1 -C 3  alkyl; and n is 2, 3, or 4, in an amount that is effective to elevate secretion of GRP94/viral antigen complexes or GRP94/neoantigen complexes in the subject compared to that in the subject prior to administration; and
 b) one or more immune system stimulators selected from the group consisting of a natural killer cell (NK) stimulator, an antigen presenting cell (APC) stimulator, a granulocyte macrophage colony-stimulating factor (GM-CSF), and a toll-like receptor stimulator. 
 
     
     
         2 . The method of  claim 1 , wherein the subject is diagnosed with cancer. 
     
     
         3 . The method of  claim 2 , wherein the cancer is bladder cancer, breast cancer, cervical cancer, colon cancer, esophageal cancer, endometrial cancer, gastric cancer, glioblastoma, head and neck cancer, hepatocellular carcinoma, leukemia, lung cancer, lymphoma, melanoma, Merkel cell carcinoma, multiple myeloma, neuroblastoma, neuroendocrine cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, rectal cancer, renal cell carcinoma, rhabdoid cancer, sarcoma, or urinary tract cancer. 
     
     
         4 . The method of  claim 2 , wherein the GRP94/neoantigen complexes comprise neoantigenic peptides that are about 5 to about 50 amino acids in length. 
     
     
         5 . The method of  claim 1 , wherein the subject is infected with a virus. 
     
     
         6 . The method of  claim 5 , wherein the virus is selected from the group consisting of human immunodeficiency virus (HIV), herpes simplex virus (HSV), influenza virus, EBV, Ebola virus, chicken pox virus, Hepatitis B virus, Hepatitis C virus, HPV, rubeola virus, rubulavirus, rubella virus, poliovirus, Rous Sarcoma Virus, rabies virus, and rotavirus. 
     
     
         7 . The method of  claim 1 , wherein the NK stimulator is selected from the group consisting of IL-2, IL-15, IL-15/IL-15RA complex, IL-18, and IL-12. 
     
     
         8 . The method of  claim 1 , wherein the NK stimulator is an antibody that stimulates one or more receptors selected from the group consisting of NKG2, KIR2DL1/S1, KRI2DL5A, NKG2D, NKp46, NKp44, and NKp30. 
     
     
         9 . The method of  claim 1 , wherein the APC stimulator is selected from the group consisting of CD28, inducible costimulatory (ICOS), CD40, CD30, CD27, OX-40, and 4-1BB. 
     
     
         10 . The method of  claim 1 , wherein one or more cells of the subject are under endoplasmic reticulum (ER) stress, 
     
     
         11 . The method of  claim 1 , wherein 4-PBA, the compound of Formula I, and/or the 4-PBA analog is administered orally, topically, intranasally, systemically, intravenously, subcutaneously, intraperitoneally, intradermally, intraocularly, iontophoretically, transmucosally, or intramuscularly. 
     
     
         12 . The method of  claim 1 , further comprising separately, sequentially or simultaneously administering one or more immune checkpoint inhibitors to the subject. 
     
     
         13 . The method of  claim 12 , wherein the one or more immune checkpoint inhibitors target PD-1, PD-L1 or CTLA-4. 
     
     
         14 . The method of  claim 12 , wherein the one or more immune checkpoint inhibitors are selected from the group consisting of ipilimumab, pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab, pidilizumab, AMP-224, MPDL3280A, MDX-1105, MEDI-4736, arelumab, tremelimumab, IMP321, MGA271, BMS-986016, lirilumab, urelumab, PF-05082566, IPH2101, MEDI-6469, CP-870,893, Mogamulizumab, Varlilumab, Galiximab, AMP-514, AUNP 12, Indoximod, NLG-919, INCB024360 (Incyte) and any combination thereof. 
     
     
         15 . The method of  claim 1 , wherein the subject is human.