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 vaccine vector comprising a polynucleotide encoding mutant ESR1 polypeptide or a portion thereof. 
     
     
         2 . The vaccine of  claim 1 , wherein the mutant ESR1 polypeptide comprises SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 5 or portions of any of SEQ ID NO: 1-3 or 5. 
     
     
         3 . The vaccine of  claim 1 , wherein the mutant ESR1 polypeptide consists of at least one of SEQ ID NO: 1, SEQ ID NO:2, SEQ ID NO: 3, or SEQ ID NO: 5. 
     
     
         4 . The vaccine of  claim 1 , wherein the portion of the ESR1 polypeptide comprises a mutation in ESR1. 
     
     
         5 . The vaccine of  claim 1 , further comprising a HER3 polypeptide or HER2 polypeptide or a mutant form of HER3 or HER2. 
     
     
         6 . (canceled) 
     
     
         7 . The vaccine of  claim 1 , wherein the vaccine vector comprises the mutant ESR1 polypeptide. 
     
     
         8 . The vaccine of  claim 7 , wherein the vaccine vector is selected from the group consisting of adenovirus, adeno-associated virus (AAV), fowlpox, vaccinia virus, and Venezuelan 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 . The method of  claim 12 , wherein the cancer comprises a mutation in ESR1. 
     
     
         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 ESR1. 
     
     
         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 ESR1. 
     
     
         22 . (canceled) 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 12 , wherein the cancer therapeutic or prevention agent is selected from trastuzumab, lapatinib, cetuximab, pertuzumab and erlotanib.