Denner, Joachim

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Translational Oncology 14 (2021) 101041 Contents lists available at ScienceDirect Translational Oncology journal homepage: www.elsevier.com/locate/tranon Letters to the Editor Comment on: Endogenous retroviruses expressed in human tumours cannot be used as targets for anti-tumour vaccines  h  I  (  t  m  e  s  o  I  h f  a  a  o  m  b  t  t  i  a s  p  c  o  c  w T  a  C  e  o  h  i  f a  m  w  t t  t  sCDF   R            hR1(In my short communication “Endogenous retroviruses expressed inuman tumours cannot be used as targets for anti-tumour vaccines ” [1] , indicated possible risk factors when human endogenous retrovirusesHERVs), which are highly expressed in some human tumours and inhe placenta, will be used as targets for tumour vaccination and im-unotherapy. The main risk factors are expression of HERVs on humanmbryonic stem cells (ESC), and on immune and other cells. Expres-ion on human ESC is well-documented [2] , expression on immune andther cells is documented at least after infections (for review see [3] ).nteraction of the vaccine or therapy with these normal cells may bearmful. In the accompanying comment, Holst and co-workers deny these riskactors [4] , partially not recognising the virological background. For ex-mple, in one of their studies in a mouse model [5] , they immunisedgainst the melanoma associated retrovirus (MelARV) using an aden-viral vector and prevented colorectal tumor growth and progression inice. However, MelARV is not an endogenous retrovirus, it is a recom-inant virus not present in the murine genome. It is also not surprisinghat immunisation against proteins of HERV-K, artificially expressed onhe surface of mouse tumour cells, successfully reduced tumour growthn the mouse [6] . The HERV- proteins are not expressed on mouse ESCnd mouse immune cells. In the human system, the authors claim that “existing HERV-K-pecific T cell responses induced in human breast and ovarian cancersoints towards a favorable safety profile ” [4] . However, in these studiesytotoxic T cells killing HERV-K-expressing tumour cells were inducednly in vitro , but not in vivo , in the patient [7 , 8] . These HERV-K-specificytotoxic cells did not kill normal cells, but there were no investigationshether human ESC were among these normal cells. Further, the authors compare HERV antigens with fetal antigens.hey argue, that clinical vaccine trials in phase 3 for the fetalntigen melanoma-associated antigen A3 (MAGE-A3) and a specificAR(chimeric antigen receptor)-T cell therapy targeting the New Yorksophageal squamous cell cancer-1 (NY-ESO-1) were performed with-ut specific safety signals. The truth is, that the study using MAGE-A3ad been stopped [9] . Whereas the cancer testis antigen MAGE-A3 isndeed expressed on human ESCs [10] , I was unable to find such dataor NY-ESO-1. The authors claim that I ignore the fact that immune responsesgainst antigens expressed on dendritic cells are a natural part of tu-or immune responses, but I don´t do this and this has nothing to doDOI of original article: 10.1016/j.tranon.2021.101040 ttps://doi.org/10.1016/j.tranon.2021.101041 eceived 4 February 2021; Accepted 5 February 2021 936-5233/© 2021 The Authors. Published by Elsevier Inc. This is an open access ar http://creativecommons.org/licenses/by-nc-nd/4.0/ ) ith a potential harmful effect of vaccination against HERVs as tumourreatment. In conclusion, there is no evidence for an effective and safe applica-ion of HERVs as targets for tumour vaccination and I repeat my sen-ence, that “anti-retroviral vaccines should not be used without furtherafety investigations in this field ” [1] . Redit authors statement Joachim Denner: Conceptualisation, writing eclaration of Competing Interest The author declares an absence of competing or financial interests. unding No funding was received for this publication. Joachim Denner ∗ Institute of Virology, Free University Berlin, Robert von Ostertag-Strasse7-13, 14163 Berlin, Germany∗ Corresponding author. E-mail address: Joachim.Denner@fu-berlin.deeferences [1] J. Denner , Endogenous retroviruses expressed in human tumours cannot be used astargets for anti-tumour vaccines, Transl Oncol 14 (1) (2021) 2020–2021 . [2] N.V. Fuchs , S. Loewer , G.Q. Daley , et al. , Human endogenous retrovirus K (HML-2)RNA and protein expression is a marker for human embryonic and induced pluripo-tent stem cells, Retrovirology 10 (1) (2013) 115 . [3] V. Gröger , A. Emmer , M.S. Staege , H. Cynis , Endogenous Retroviruses in NervousSystem Disorders, Pharmaceuticals 14 (2021) 70 . [4] A-.V. Bermejo , T.K. Nielsen , P. Holst , Comment on: Endogenous retroviruses ex-pressed in human tumours cannot be used as targets for anti-tumour vaccines, Transl.Oncol. (2021) . [5] L. Neukirch , T.K. Nielsen , H. Laursen , J. Daradoumis , C. Thirion , P.J. Holst , Ade-novirus based viruslike-vaccines targeting endogenous retroviruses can eliminategrowing colorectal cancers in mice, Oncotarget 10 (14) (2019) 1458–1472 . [6] B. Kraus , K. Fischer , S.M. Büchner , et al. , Vaccination directed against the humanendogenous retrovirus-K envelope protein inhibits tumor growth in a murine modelsystem, PLoS One 8 (8) (2013) e72756 . [7] K. Rycaj , J.B. Plummer , B. Yin , et al. , Cytotoxicity of human endogenous retrovirusK-specific T cells toward autologous ovarian cancer cells, Clin Cancer Res 21 (2)(2015) 471–483 . ticle under the CC BY-NC-ND license Letters to the Editor Translational Oncology 14 (2021) 101041      [  Expression patterns of cancer-testis antigens in human embryonic stem cells and their cell derivatives indicate lineage tracks, Stem Cells Int 2011 (2011) 795239 . [8] F. Wang-Johanning , L. Radvanyi , K. Rycaj , et al. , Human endogenous retrovirus Ktriggers an antigen-specific immune response in breast cancer patients, Cancer Res68 (14) (2008) 5869–5877 . [9] J.F. Vansteenkiste , B.C. Cho , T. Vanakesa , et al. , Efficacy of the MAGE-A3 cancer im-munotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive2 nonsmall-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-con-trolled, phase 3 trial, Lancet Oncol 17 (6) (2016) 822–835 . 10] N. Lifantseva , A. Koltsova , T. Krylova , T. Yakovleva , G. Poljanskaya , O. Gordeeva ,

Comment on: Endogenous retroviruses expressed in human tumours cannot be used as targets for anti-tumour vaccines

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Comment on: Endogenous retroviruses expressed in human tumours cannot be used as targets for anti-tumour vaccines

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