Combination product for use in tumor vaccination

Abstract

The present invention relates to a combination product for use in eliciting an immune response against a tumor in a subject, said product comprising: —an immunogenic composition comprising a non-human antigenic polypeptide as an immunogen, or comprising a nucleic acid encoding said immunogen, and optionally one or more pharmaceutically-acceptable carriers, adjuvants, excipients and/or diluents; and —said non-human antigenic polypeptide, or a nucleic acid encoding said polypeptide; wherein said polypeptide or said nucleic acid is prepared for intratumoral delivery. The invention also provides fusion proteins and protein-protein conjugates that can be used in the medical methods described herein.

1 . An immunogenic composition that elicits an immune response against a tumor in a subject comprising a first part comprising a non-tumor antigen or a nucleic acid sequence encoding the non-tumor antigen, and optionally one or more pharmaceutically-acceptable carriers, adjuvants, excipients and/or diluents; and
 a second part comprising the non-tumor antigen or nucleic acid sequence encoding the non-tumor antigen, and optionally one or more pharmaceutically-acceptable carriers, adjuvants, excipients and/or diluents,   wherein the immunogenic composition.   
     
     
         2 . The composition of  claim 1 , wherein:
 the composition marks the tumor as a target for an immune response following intratumoral delivery;   the composition elicits an immune response against a tumor that is marked as a target for said immune response;   the immune response is a T-cell mediated immune response; or   the non-tumor antigen or nucleic acid is prepared for intratumoral administration.   
     
     
         3 - 6 . (canceled) 
     
     
         7 . The immunogenic composition of  claim 1 , wherein:
 said non-tumor antigen is non-mammalian optionally a microbial polypeptide or a synthetic polypeptide;   said non-tumor antigen is selected from the group consisting of keyhole limpet hemocyanin (KLH), beta-galactosidase and green fluorescent protein (GFP);   said non-tumor antigen is selected from the group consisting of enhanced green fluorescent protein (eGFP), luciferase and diphtheria toxin;   said non-tumor antigen is CRM-197;   said non-tumor antigen was previously used for a prior vaccination of said subject, optionally wherein said prior vaccination was against an infectious disease that was optionally selected from the group consisting of one or any combination of hepatitis A, hepatitis B, diphtheria, tetanus, pertussis, influenza,  Haemophilus influenzae  type b, polio, measles, mumps, rubella, varicella, human papillomavirus,  Streptococcus pneumoniae, Neisseria meningitides  and rotavirus; or   said non-tumor antigen is selected from the group consisting of hepatitis A virus VP3,  Clostridium tetani  toxin,  Bordetella pertussis  toxin,  Haemophilus influenzae  protein D, poliovirus Vp1, measles virus hemagglutinin, mumps virus nucleoprotein, rubella virus E1, rubella virus E2, varicella zoster virus 1E62, HPV16 E6, HPV16 E7, HPV18 E6, HPV18 E7, Spr96/2021, PV7, PV13,  Neisseria  NHBA,  Neisseria meningitides  fHbp,  Neisseria meningitides  nadA, rotaviruses VP6, rotavirus VP8, and  Corynebacterium diphtheria  toxin.   
     
     
         8 - 10 . (canceled) 
     
     
         11 . The composition of  claim 1 , wherein said non-tumor antigen or nucleic acid sequence encoding said non-tumor antigen is tumor-targeted by one or more of:
 a tumor-specific virus, including an oncolytic virus, comprising a nucleic acid encoding said non-tumor antigen; and/or   a tumor-specific nanoparticle comprising said non-tumor antigen or a nucleic acid encoding said non-tumor antigen.   
     
     
         12 . The composition of  claim 1 , wherein said non-tumor antigen or nucleic acid sequence encoding said non-tumor antigen is for intratumoral administration and is selected from:
 a cell comprising said non-tumor antigen or nucleic acid sequence encoding said non-tumor antigen, optionally wherein said cell:
 has a dendritic cell phenotype; 
 is a CD34-positive, CD1a-positive, and CD83-positive mature dendritic cell; 
 is a dendritic cell is derived from DCOne; or 
 DCOne as deposited at the DSMZ under accession number DSMZ ACC3189 on 15 Nov. 2012; 
   an aqueous suspension or solution comprising said non-tumor antigen; and/or   a virus comprising a nucleic acid sequence encoding said non-tumor antigen.   
     
     
         13 . (canceled) 
     
     
         14 . The composition of  claim 1 , wherein said non-tumor antigen is:
 a fusion protein or protein-protein conjugate comprising a first protein linked to a second protein, wherein said first protein comprises a diphtheria toxin or a receptor-binding domain of diphtheria toxin, and said second protein comprises a non-human antigenic polypeptide, optionally a non-human antigenic polypeptide that is not a diphtheria toxin; or   present in a composition that also comprises an immunomodulatory polypeptide, or a nucleic acid encoding said immunomodulatory polypeptide, that converts at least partially an immuno-tolerant tumor microenvironment (TME) into an immuno-sensitive TME, optionally wherein said immunomodulatory polypeptide comprises GM-CSF, CCR5, XCL1 or CCL20.   
     
     
         15 - 17 . (canceled) 
     
     
         18 . The composition of  claim 1 , wherein:
 said first part and said second part are for separate, sequential, simultaneous, concurrent or chronologically staggered administration;   said first part is for use in a vaccination step and said second part is for use in a tumor-marking step, optionally wherein:   the tumor marking-step comprises administering the second part into the tumor or proximal to the tumor; and/or   the vaccination step comprises administering the first part via a route selected from the group consisting of intramuscular, intradermal, subcutaneous, intravenous, intraarterial, intraperitoneal, delivery to the interstitial space of a tissue, and delivery to a non-tumor tissue.   
     
     
         19 . (canceled) 
     
     
         20 . A non-tumor antigen, or a nucleic acid sequence encoding said non-tumor antigen, for use in eliciting or directing an immune response against a tumor in a subject; wherein said non-tumor antigen or said nucleic acid is prepared for intratumoral delivery; and wherein said subject is vaccinated with an immunogenic composition comprising said non-tumor antigen as an immunogen, or comprising a nucleic acid encoding said immunogen, and optionally one or more pharmaceutically-acceptable carriers, adjuvants, excipients and/or diluents. 
     
     
         21 . The non-tumor antigen of  claim 20 , wherein:
 said non-tumor antigen, or said nucleic acid sequence marks the tumor as a target for an immune response following intratumoral delivery;   following intratumoral delivery of said non-tumor antigen or nucleic acid sequence encoding said non-tumor antigen, an immune response is specifically directed against said tumor.   
     
     
         22 . (canceled) 
     
     
         23 . A cell having a dendritic phenotype comprising a non-tumor antigen, or a nucleic acid sequence encoding said non-tumor antigen, for use in marking a tumor as a target for an immune response in a subject, wherein said cell having a dendritic phenotype is for intratumoral administration. 
     
     
         24 . A fusion protein or a protein-protein conjugate comprising a first protein linked to a second protein, wherein said first protein comprises a diphtheria toxin or a receptor-binding domain of diphtheria toxin, and said second protein comprises a non-tumor antigen polypeptide. 
     
     
         25 . The fusion protein or conjugate according to  claim 24 , wherein said first protein consists of said receptor-binding domain of diphtheria toxin. 
     
     
         26 . The fusion protein or conjugate according to  claim 24 , wherein said non-tumor antigen polypeptide is selected from the group consisting of a microbial polypeptide, a synthetic polypeptide, keyhole limpet hemocyanin (KLH), beta-galactosidase and green fluorescent protein (GFP), said non-tumor antigen is selected from the group consisting of enhanced green fluorescent protein (eGFP), luciferase, diphtheria toxin, CRM-197, hepatitis A virus VP3,  Clostridium tetani  toxin,  Bordetella pertussis  toxin,  Haemophilus influenzae  protein D, poliovirus Vp1, measles virus hemagglutinin, mumps virus nucleoprotein, rubella virus E1, rubella virus E2, varicella zoster virus IE62, HPV16 E6, HPV16 E7, HPV18 E6, HPV18 E7, Spr96/2021, PV7, PV13,  Neisseria  NHBA,  Neisseria meningitides  fHbp,  Neisseria meningitides  nadA, rotaviruses VP6, rotavirus VP8, and  Corynebacterium diphtheria  toxin. 
     
     
         27 . A nucleic acid encoding the fusion protein of  claim 24 . 
     
     
         28 . The fusion protein or conjugate of  claim 24 , for use as a medicament, optionally for use in a method of eliciting or directing an immune response against a tumor in a subject. 
     
     
         29 . The fusion protein or conjugate of  claim 28 , wherein said subject is vaccinated with an immunogenic composition comprising said fusion protein or conjugate or said second protein as an immunogen, or comprising a nucleic acid encoding said immunogen, and optionally one or more pharmaceutically-acceptable carriers, adjuvants, excipients and/or diluents. 
     
     
         30 . A method for eliciting an immune response against a subject suffering from a tumor, comprising the steps of:
 administering to a subject suffering from a tumor a pharmaceutically effective amount of a non-tumor antigen polypeptide, or a nucleic acid encoding said polypeptide, prepared for intratumoral delivery; and   administering to said subject a pharmaceutically effective amount of an immunogenic composition comprising said polypeptide as an immunogen, or comprising a nucleic acid encoding said immunogen, and optionally one or more pharmaceutically-acceptable carriers, adjuvants, excipients and/or diluents.   
     
     
         31 - 32 . (canceled) 
     
     
         33 . A method for treating a subject suffering from a tumor, comprising the step of:
 administering to a subject suffering from a tumor a pharmaceutically effective amount of the composition of  claim 1 , wherein said composition is simultaneously, separately or sequentially administered.   
     
     
         34 . The composition of  claim 1 , wherein the first part comprises a cell having a dendritic phenotype comprising the non-tumor antigen or a nucleic acid encoding the non-tumor antigen, optionally wherein the dendritic phenotype cell is a CD34-positive, CD1a-positive, and CD83-positive mature dendritic phenotype cell and/or the dendritic phenotype cell is derived from DCOne. 
     
     
         35 . The composition of  claim 1 , wherein the second part comprises a cell having a dendritic phenotype comprising the non-tumor antigen or a nucleic acid encoding the non-tumor antigen, optionally wherein the dendritic phenotype cell is a CD34-positive, CD1a-positive, and CD83-positive mature dendritic phenotype cell and/or the dendritic phenotype cell is derived from DCOne.