Mesothelin Vaccines and Model Systems
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.
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.