Vaccines against an oncogenic isoform of esr1 and methods of using the same

Abstract

Methods of reducing the likelihood of a cancer or precancer developing resistance to a cancer therapeutic or prevention agent are provided herein. The methods include administering the cancer therapeutic or prevention agent and a vaccine comprising a polynucleotide encoding a polypeptide whose expression or activation is correlated with development of resistance of the cancer or precancer to the cancer therapeutic or prevention agent to a subject. The vaccine may include a polynucleotide encoding an ESR1 polypeptide or a truncation, deletion or substitution mutant thereof. Methods of using the vaccine including the polynucleotide encoding the ESR1 polypeptide to treat a cancer or precancer are also provided.

1 . A vaccine comprising a polynucleotide encoding an ESR1 polypeptide, wherein the ESR1 polypeptide comprises SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 5 or a peptide fragment thereof at least eight amino acids long and comprising a mutation. 
     
     
         2 . (canceled) 
     
     
         3 . (canceled) 
     
     
         4 . (canceled) 
     
     
         5 . The vaccine of  claim 1 , further comprising a HER3 polypeptide or HER2 polypeptide or a mutant form of HER3 or HER2. 
     
     
         6 . The vaccine of  claim 1 , further comprising a vaccine vector comprising the ESR1 polypeptide. 
     
     
         7 . (canceled) 
     
     
         8 . The vaccine of  claim 6 , wherein the vaccine vector is selected from adenovirus, adeno-associated virus (AAV), fowlpox, vaccinia virus, Venezuelen equine encephalitis virus. 
     
     
         9 . (canceled) 
     
     
         10 . The vaccine of  claim 1 , further comprising a checkpoint inhibitor immunomodulatory agent. 
     
     
         11 . The vaccine of  claim 10 , wherein the checkpoint inhibitor immunomodulatory agent is a CTLA-4 or PD1 antagonistic antibody. 
     
     
         12 . A method of treating a cancer or precancer or of reducing the likelihood of the cancer developing resistance to a cancer therapeutic or prevention agent comprising administering the vaccine of  claim 1  to a subject having the cancer or precancer, wherein administration of the vaccine to the subject treats the cancer or precancer, reduces the likelihood of the cancer or precancer developing resistance to the cancer therapeutic or prevention agent or reverses resistance of the cancer or precancer to the cancer therapeutic or prevention agent. 
     
     
         13 . (canceled) 
     
     
         14 . The method of  claim 12 , wherein the vaccine is administered concurrently with, before or after administration of the cancer therapeutic or prevention agent. 
     
     
         15 . The method of  claim 14 , wherein the cancer therapeutic or prevention agent is an agent targeting HER2, HER1, estrogen receptor, EGFR, or IGF1R. 
     
     
         16 . The method of  claim 12 , wherein the vaccine is administered concurrently with, before or after administration of a checkpoint inhibitor immunomodulatory agent. 
     
     
         17 . The method of  claim 16 , wherein the checkpoint inhibitor immunomodulatory agent is a CTLA-4 or PD1 antagonistic antibody. 
     
     
         18 . The method of  claim 12 , wherein the cancer or precancer is selected from a breast, prostate, lung, ovarian, colon, rectal, pancreas, bladder, head and neck or liver cancer or precancer. 
     
     
         19 . The method of  claim 12 , wherein the subject develops an immune response to ESR. 
     
     
         20 . The method of  claim 19 , wherein the immune response comprises an antibody response or a T cell mediated response. 
     
     
         21 . The method of  claim 19 , wherein the immune response includes at least one of antibody-dependent cellular cytotoxicity, polyclonal antibody response, complement dependent cellular cytotoxicity, cellular cytotoxicity, disruption of ligand binding, disruption of dimerization, mimicking ligand binding causing internalization of ESR1, or degradation of ESR. 
     
     
         22 . The method of  claim 19 , wherein the immune response comprises an antibody response directed to at least a portion of SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5. 
     
     
         23 . The method of  claim 19 , wherein the immune response is specific for a T cell epitope or a B cell epitope flanking or encompassing the mutation at position 537 of SEQ ID NO: 1, at position 538 of SEQ ID NO:3 or at position 303 of SEQ ID NO: 5. 
     
     
         24 . The method of  claim 12 , wherein administration of the vaccine results in a reduction of ESR1 expression on cancer or precancer cells after administration of the vaccine as compared to the level of ESR1 on the cells prior to vaccination. 
     
     
         25 . The method of  claim 12 , wherein administration results in decreased tumor growth rate or decreased tumor size after administration as compared to prior to administration. 
     
     
         26 . The method of  claim 12 , wherein the cancer therapeutic or prevention agent is selected from trastuzumab, lapatinib, cetuximab, pertuzumab and erlotanib.