Rhoc-based immunotherapy

Abstract

The present invention relates generally to the field of prophylaxis and therapy of metastatic cancer. In particular there is provided a protein; Ras Homology gene family, member C (RhoC) or peptide fragments thereof that are capable of eliciting anti-cancer immune responses. Specifically, the invention relates to use of RhoC or peptides derived thereof or RhoC specific T-cells for treatment of metastatic cancer. Hence, the invention in one aspect relates to RhoC specific T-cells adoptively transferred or induced in vivo by vaccination as a treatment of cancer. Also the use of RhoC and immunogenic peptide fragments hereof in cancer treatment, diagnosis and prognosis is provided.

1 . A vaccine composition comprising
 a) RhoC of SEQ ID no 1 or a functional homologue thereof having at least 70% identity to SEQ ID NO 1 or an immunogenically active peptide fragment comprising a consecutive sequence of said RhoC or said functional homologue thereof or a nucleic acid encoding said RhoC or said peptide fragment; and   b) an adjuvant   for use as a medicament.   
     
     
         2 . The vaccine composition according to  claim 1 , wherein said immunogenically active peptide fragment consists of a consecutive sequence of in the range of 8 to 50, preferably in the range of 9 to 25 amino acids of said RhoC of SEQ ID no 1 or said functional homologue thereof wherein at the most two amino acid have been substituted. 
     
     
         3 . The vaccine composition of  claim 1 , wherein the vaccine composition is capable of eliciting an immune response against a metastatic cancer expressing RhoC of SEQ ID no 1 or a functional homologue thereof wherein at the most two amino acid have been substituted, when administered to an individual suffering from a metastatic cancer expressing RhoC. 
     
     
         4 . An isolated immunogenically active peptide fragment from RhoC of SEQ ID no 1 or a functional homologue thereof consisting of 18 to 25 consecutive amino acids wherein at the most two amino acid have been substituted, wherein the peptide fragment contains at least one of amino acid residues I43, Q123, R140, S141, S152, L157, E165, G178, V181, K183, N184, R186, R187, R188, P191 or I192 of RhoC of SEQ ID no 1 or of 8 to 10 consecutive amino acids from RhoC of SEQ ID no 1 or a functional homologue thereof wherein at the most two amino acid have been substituted, wherein the peptide fragment contains at least one of amino acid residues I43, Q123, R140, S141, S152, L157, E165, G178, V181, K183, N184, R186, R187, R188, P191 or I192 of RhoC of SEQ ID no 1 or of 26 to 60 consecutive amino acids from RhoC of SEQ ID no 1 or a functional homologue thereof wherein at the most two amino acid have been substituted, wherein the peptide fragment contains at least one of amino acid residues I43, Q123, R140, S141, S152, L157, E165, G178, V181, K183, N184, R186, R187, R188, P191 or I192 of RhoC of SEQ ID no 1. 
     
     
         5 . The peptide fragment according to  claim 4 , which comprises the sequence RXGLQVRKNK, wherein X is selected from the group consisting of alanine and leucine and wherein said peptide fragment is at the most 60 amino acids in length. 
     
     
         6 . The peptide fragment according to  claim 4 , which is an MHC Class 1-restricted peptide or an MHC class 11-restricted peptide having at least one of the following characteristics:
 (i) capable of eliciting INF-γ-producing cells in a PBL population of a cancer patient at a frequency of at least 1 per 10 4  PBLs as determined by an ELISPOT assay, and/or   (ii) capable of in situ detection in a tumor tissue of CTLs that are reactive with the epitope peptide.   (iii) capable of inducing the growth of RhoC specific T-cells in vitro.   
     
     
         7 . The peptide fragment according to  claim 4 , wherein the peptide fragment consists of 8 to 10 or 18 to 25 or 26 to 60 consecutive amino acids from RhoC of SEQ ID no 1. 
     
     
         8 . The peptide fragment according to  claim 4 , wherein the peptide fragment consists of 8 to 10 or 18 to 25 or 26 to 60 consecutive amino acids from RhoC of SEQ ID no 1 wherein at least one amino acid of RhoC of SEQ ID no 1 has been substituted, deleted or added at least. 
     
     
         9 . The peptide fragment according to  claim 4  that is capable of eliciting INF-γ-producing cells in a PBL population of a cancer patient at a frequency of at least 10 per 10 4  PBLs. 
     
     
         10 . The peptide fragment according to  claim 4 , which is capable of eliciting INF-γ-producing cells in a PBL population of a patient having a cancer disease where RhoC of SEQ ID no 1 or a functional homologue thereof having at least 70% identity to SEQ ID 1 is expressed. 
     
     
         11 . The vaccine composition according to  claim 1 , wherein the peptide fragment consists of a consecutive sequence of RhoC of SEQ ID no 1 of in the range of 8 to 60 amino acids, preferably of in the range of 9 to 25 amino acids, sequence that is different from the sequences of RhoA of SEQ ID NO 2 or RhoB of SEQ ID NO 3 by at least one amino acid. 
     
     
         12 . The vaccine composition according to  claim 1 , wherein the peptide fragment consists of a sequence selected from the 60 most C-terminal amino acids of RhoC of SEQ ID no 1 or a functional homologue thereof having at least 70% identity to SEQ ID NO 1. 
     
     
         13 . The vaccine composition according to  claim 1  comprising the peptide fragment according to  claim 4 . 
     
     
         14 . A method of treating a metastatic cancer disease, the method comprising administering to a patient suffering from the disease an effective amount of the composition according to  claim 1 . 
     
     
         15 . The method of  claim 14  wherein the disease to be treated is a cancer disease where RhoC is expressed. 
     
     
         16 . The method of to  claim 15 , which is combined with a further cancer treatment. 
     
     
         17 . Isolated T-cells, wherein said T-cells are capable of specifically interacting with RhoC of SEQ ID No 1 or a functional homologue thereof having at least 70% identity to SEQ ID NO 1 or an immunogenically active peptide fragment comprising a consecutive sequence of said RhoC or a fragment thereof. 
     
     
         18 . The T-cells according to  claim 17 , wherein said T-cells are capable of specifically interacting with any of the RhoC peptides of  claim 4 . 
     
     
         19 . The T-cells according to  claim 17 , wherein said T-cells are CD8 T-cells. 
     
     
         20 . The T-cells according to  claim 17 , wherein said T-cells are CD4 T-cells. 
     
     
         21 . A method of treating a metastatic cancer disease, the method comprising administering to a patient suffering from the disease an effective amount of the peptide of  claim 4 . 
     
     
         22 . A method of treating a metastatic cancer disease, the method comprising administering to a patient suffering from the disease an effective amount of the T-cells of  claim 17 .