Mesothelin Vaccines and Model Systems

Abstract

Mesothelin can be used as an immunotherapeutic target. It induces a cytolytic T cell response. Portions of mesothelin which induce such responses are identified. Vaccines can be either polynucleotide- or polypeptide-based. Carriers for raising a cytolytic T cell response include bacteria and viruses. A mouse model for testing vaccines and other anti-tumor therapeutics and prophylactics comprises a strongly mesothelin-expressing, transformed peritoneal cell line.

We claim: 
     
         1 . A method of inducing a T-cell response to a tumor that overexpresses mesothelin relative to normal tissue from which the tumor is derived, said method comprising:
 administering to a patient who has said tumor or who has had said tumor removed, a vaccine comprising a polypeptide comprising at least one MHC Class I-binding epitopes of mesothelin selected from the group consisting of SEQ ID NOs: 2, 3, 4, 5, and 6, wherein at least one of the epitopes bind to an allelic form of MHC class I which is expressed by the patient, wherein said polypeptide does not comprise SEQ ID NO: 1, whereby a T-cell response to mesothelin is induced, wherein the vaccine does not comprise whole tumor cells.   
     
     
         2 . The method of  claim 1  wherein the tumor is selected from the group consisting of ovarian cancer, pancreatic cancer, mesothelioma, and squamous cell carcinoma. 
     
     
         3 . The method of  claim 1  wherein the tumor is a pancreatic cancer. 
     
     
         4 . The method of  claim 1  wherein the tumor is an ovarian cancer. 
     
     
         5 . The method of  claim 1  wherein the polypeptide comprises epitopes VLPLTVAEV (SEQ ID NO: 2); ELAVALAQK (SEQ ID NO: 3); ALQGGGPPY (SEQ ID NO: 4); FYPGYLCSL (SEQ ID NO: 5); and LYPKARLAF (SEQ ID NO: 6). 
     
     
         6 . The method of  claim 1  wherein the vaccine comprises  Listeria monocytogenes  bacteria. 
     
     
         7 . The method of  claim 1  wherein the T-cell response is induction of specific CD8+ T cells. 
     
     
         8 . The method of  claim 1  wherein the vaccine is acellular. 
     
     
         9 . The method of  claim 1  wherein the vaccine comprises a bacterium selected from the group consisting of:  Shigella flexneri, E. coli, Yersinia enterocolitica, Salmonella typhimurium, Salmonella typhi , and  mycobacterium.    
     
     
         10 . The method of  claim 1  wherein the vaccine is administered in sufficient amount to induce tumor regression. 
     
     
         11 . The method of  claim 1  wherein the vaccine is administered in sufficient amount to keep the patient tumor-free after removal of the tumor. 
     
     
         12 . A vaccine which induces a CD8+ T cell or CD4+ T cell response, comprising:
 a polypeptide comprising at least one of an MHC Class I- or Class II-binding epitope of mesothelin selected from the group consisting of SEQ ID NOs: 2, 3, 4, 5, and 6, wherein the epitope binds to an allelic form of MHC class I of class II which is expressed by the patient, whereby a CD8+ T cell or CD4+ T-cell response to mesothelin is induced, and wherein said polypeptide does not comprise SEQ ID NO: 1; and   a carrier for stimulating a CD8+ T cell or CD4+ T cell immune response, wherein the carrier is selected from the group consisting of (a) a protein that is fused to the polypeptide, said protein selected from the group consisting of CD40, CD40 ligand, OX-40, OX-40 ligand, CTLA-4 antagonist, and GM-CSF; and (b) a bacterial cell that is transformed to express the polypeptide; and (c) an antigen presenting cell on whose surface the polypeptide is bound; wherein the vaccine does not comprise whole tumor cells.   
     
     
         13 . The vaccine of  claim 12  wherein the polypeptide comprises an MHC Class I-binding epitope. 
     
     
         14 . The vaccine of  claim 12  wherein the polypeptide comprises between 6 and 20 amino acid residues. 
     
     
         15 . The vaccine of  claim 12  wherein the polypeptide comprises epitopes VLPLTVAEV (SEQ ID NO: 2); ELAVALAQK (SEQ ID NO: 3); ALQGGGPPY (SEQ ID NO: 4); FYPGYLCSL (SEQ ID NO: 5); and LYPKARLAF (SEQ ID NO: 6). 
     
     
         16 . The vaccine of  claim 12  wherein the carrier is CD40 or CD40 ligand. 
     
     
         17 . The vaccine of  claim 12  wherein the carrier is OX-40 or OX-40 ligand. 
     
     
         18 . The vaccine of  claim 12  wherein the carrier is a CTLA-4 antagonist. 
     
     
         19 . The vaccine of  claim 12  wherein the carrier is GM-CSF. 
     
     
         20 . The vaccine of  claim 12  which comprises a bacterial cell. 
     
     
         21 . The vaccine of  claim 20  wherein the bacterium is selected from the group consisting of:  Shigella flexneri, E. coli, Yersinia enterocolitica, Salmonella typhimurium, Salmonella typhi , and  mycobacterium.    
     
     
         22 . The vaccine of  claim 20  wherein the  Listeria monocytogenes.    
     
     
         23 . A fusion protein comprising a first and a second portion, wherein the first portion comprises a polypeptide comprising an epitope selected from the group consisting of VLPLTVAEV (SEQ ID NO: 2); ELAVALAQK (SEQ ID NO: 3); ALQGGGPPY (SEQ ID NO: 4); FYPGYLCSL (SEQ ID NO: 5); and LYPKARLAF (SEQ ID NO: 6), and the second portion comprises a segment of at least 6 amino acid residues, wherein the sequence of said second portion is not in mesothelin, wherein said polypeptide does not comprise SEQ ID NO: 1. 
     
     
         24 . The fusion protein of  claim 23  which is bound to an MHC Class I molecule. 
     
     
         25 . The fusion protein of  claim 24  wherein the MHC Class I molecule is on a dendritic cell. 
     
     
         26 . The polypeptide of  claim 24  wherein the MHC Class I molecule is on an antigen presenting cell.