title: A cancer immunotherapy approach targeting mutant isocitrate dehydrogenase 1
creator: Schumacher, Theresa
subject: 500
subject: 500 Natural sciences and mathematics
subject: 570
subject: 570 Life sciences
description: Point mutations in the isocitrate dehydrogenase (IDH) genes  are  an  early,  if  not  the  earliest  event  during  the  development  of  gliomas  and  other  tumors,  such  as  acute  myeloid  leukemia  (AML).  Among  grade  II  and  grade  III  gliomas,  more  than  80  %  carry  an  IDH  mutation.  In  these  entities,  mutations  almost  exclusively  affect  the  catalytically  critical  arginine  residue  of  the  cytoplasmic  IDH1,  leading  to  the  amino  acid  exchange  to  histidine  (R132H).  This  and  other  IDH  mutations  result  in  a  neomorphic  enzyme  function  and  the  production  of  the  oncometabolite  2-­‐hydroxyglutarate  (2-­‐HG)  and  thus  genome-­‐wide  hypermethylation  and  malignant  transformation.  The  work  at  hand  demonstrates  the  suitability  of  IDH1R132H  as  a  target  for  immunotherapy  in  an  MHC-­‐humanized  mouse  model,  A2.DR1.  Peptides  encompassing  the  mutated  region  bound  MHC  class  II  in  vitro  and  induced  a  mutation-­‐specific  CD4+  T  helper  (Th)  response  in  vivo,  whose  antigen-­‐specificity  persisted  in  a  specific  T  cell  line  and  clone  and  which  was  accompanied  by  IDH1R132H-­‐specific  antibody  production.  To  detect  IDH1R132H-­‐specific  IgG  in  mouse  and  human  serum,  a  peptide-­‐coated  ELISA  was  established.  Several  tested  patients  with  IDH1R132H+  gliomas  showed  spontaneous  IDH1R132H-­‐specific  antibody  and  CD4+  Th1  cell  responses.  Preventive  and  therapeutic  IDH1R132H  peptide  vaccination  of  A2.DR1  mice  bearing  syngeneic  IDH1R132H+  sarcomas  resulted  in  an  effective  mutation-­‐specific  antitumor  immune  response  capable  of  controlling  tumor  growth  in  a  CD4+  T  and  B  cell-­‐  dependent  manner.  Functionality  of  the  vaccine  was  evidenced  by  loss  of  IDH1R132H  expression  in  IDH1-­‐transduced  sarcomas  and  infiltration  of  IDH1R132H-­‐specific  CD4+  T  cells  into  the  tumor  bulk.  Compared  to  therapeutic  MHC  II-­‐mediated  peptide  vaccination  against  the  well-­‐established  cancer  testis  antigen  1  (CTAG1B,  NY-­‐ESO-­‐1),  IDH1R132H  is  a  relevant  neoantigen  of  comparable  efficacy.  Given  the  IDH1R132H-­‐mediated  accumulation  of  2-­‐HG,  the  effect  of  this  metabolite  on  human  T  cells  is  of  potential  relevance  during  IDH1R132H-­‐targeted  immunotherapy.  However,  neither  human  peripheral  CD4+  nor  CD8+  T  cell  functions  from  healthy  subjects  were  affected  by  2-­‐HG.  In  conclusion,  IDH1R132H  represents  a  potentially  clinically  meaningful  tumor-­‐specific  neoantigen.  Conceptually,  patients  with  low-­‐grade  and  anaplastic  gliomas  with  a  high  II  prevalence  of  the  IDH1R132H  mutation  represent  a  patient  population,  which  may  particularly  benefit  from  a  tumor  vaccine,  as  there  is  currently  no  therapy  preventing  recurrence  in  this  relatively  young  and  immunologically  competent  patient  population.  Moreover,  patient  groups  with  other  IDH1R132H-­‐mutated  tumors  might  potentially  also  benefit  from  such  a vaccine.
date: 2014
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/16805/1/Dissertation%20Schumacher%20Theresa.pdf
identifier: DOI:10.11588/heidok.00016805
identifier: urn:nbn:de:bsz:16-heidok-168052
identifier:   Schumacher, Theresa  (2014) A cancer immunotherapy approach targeting mutant isocitrate dehydrogenase 1.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/16805/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng