Letter to the Editor| Volume 153, P72-73, August 2021

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Could controlling occult cytomegalovirus reactivation with prophylactic valganciclovir prevent immune checkpoint blockade–Related complications?

      A recent article in Nature Communications makes provocative claims about the immunopathogenesis of hepatitis in a subset of patients receiving combined immune checkpoint blockade [
      • Hutchinson J.A.
      • Kronenberg K.
      • Riquelme P.
      • Wenzel J.J.
      • Glehr G.
      • Schilling H.L.
      • et al.
      Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis.
      ]. The central tenet of this report is cytomegalovirus (CMV)-specific memory T cell responses are primarily responsible for liver inflammation in certain patients with advanced melanoma receiving αPD-1 and αCTLA-4 therapy. This conclusion stems from the discovery that elevated CD4+ effector memory T cell (TEM) frequency in the blood is strongly associated with CMV serostatus and hepatitis risk. The authors speculate that patients with metastatic melanoma are peculiarly susceptible to chronic or recurrent CMV reactivation, which drives expansion of virus-specific CD4+ TEM cells long before starting immunotherapy. They further claim that these expanded CD4+ TEM cells make exaggerated responses against CMV in the liver after anti–PD-1 and anti–CTLA-4 treatment, which lead to hepatitis. This mechanism is surprising in many respects, not least, because there is no recognised association between metastatic melanoma and CMV disease. Nevertheless, Hutchinson et al. claimed that valganciclovir treatment led to clinical improvements in two patients with steroid-refractory hepatitis. However, it has to be taken into account that valganciclovir was given in combination with immunosuppressive drugs. Furthermore, their results suggest that prophylactic valganciclovir given to four patients with elevated CD4+ TEM cells at the start of immunotherapy prevented hepatitis.
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        • Hutchinson J.A.
        • Kronenberg K.
        • Riquelme P.
        • Wenzel J.J.
        • Glehr G.
        • Schilling H.L.
        • et al.
        Virus-specific memory T cell responses unmasked by immune checkpoint blockade cause hepatitis.
        Nat Commun. 2021; 12: 1439
        • Zimmer L.
        • Livingstone E.
        • Hassel J.C.
        • Fluck M.
        • Eigentler T.
        • Loquai C.
        • et al.
        Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial.
        Lancet. 2020; 395: 1558-1568
        • Franklin C.
        • Rooms I.
        • Fiedler M.
        • Reis H.
        • Milsch L.
        • Herz S.
        • et al.
        Cytomegalovirus reactivation in patients with refractory checkpoint inhibitor-induced colitis.
        Eur J Canc. 2017; 86: 248-256
        • Kim H.
        • Ha S.Y.
        • Kim J.
        • Kang M.
        • Lee J.
        Severe cytomegalovirus gastritis after pembrolizumab in a patient with melanoma.
        Curr Oncol. 2020; 27: 436-439
        • Lin X.
        • Lu T.
        • Li S.
        • Xie X.
        • Chen X.
        • Jiang J.
        • et al.
        Cytomegalovirus infection as an underestimated trigger for checkpoint inhibitor-related pneumonitis in lung cancer: a retrospective study.
        Clin Transl Oncol. 2021; 23: 389-396
        • Uslu U.
        • Agaimy A.
        • Hundorfean G.
        • Harrer T.
        • Schuler G.
        • Heinzerling L.
        Autoimmune colitis and subsequent CMV-induced hepatitis after treatment with ipilimumab.
        J Immunother. 2015; 38: 212-215
        • Caselli E.
        • Zatelli M.C.
        • Rizzo R.
        • Benedetti S.
        • Martorelli D.
        • Trasforini G.
        • et al.
        Virologic and immunologic evidence supporting an association between HHV-6 and Hashimoto’s thyroiditis.
        PLoS Pathog. 2012; 8e1002951
        • Johnson D.B.
        • McDonnell W.J.
        • Gonzalez-Ericsson P.I.
        • et al.
        A case report of clonal EBV-like memory CD4+ T cell activation in fatal checkpoint inhibitor-induced encephalitis.
        Nat Med. 2019; 25: 1243-1250