Letter to the Editor: Could Immunogenicity of Kaposi Sarcoma Be More Linked to Viral Antigens Than to the Tumor Mutational Burden?

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Julie Delyon Hôpital Saint-Louis, Paris Diderot University, Paris, France, Email: julie.delyon@aphp.fr

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Dimitri Arangalage Hôpital Bichat, Paris Diderot University, Paris, France

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Barouyr Baroudjian Hôpital Saint-Louis, Paris, France

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Celeste Lebbe Hôpital Saint-Louis, Paris Diderot University, Paris, France

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Re: James Saller, Christine M. Walko, Sherri Z. Millis, et al. Response to Checkpoint Inhibitor Therapy in Advanced Classic Kaposi Sarcoma: A Case Report and Immunogenomic Study. J Natl Compr Canc Netw 2018;16(7):797–800.

We read with great interest the article by Saller et al,1 which extends the observations of our previous report of 2 cases of classic Kaposi sarcoma (KS) successfully treated with PD-1 blockade.2

Although both of our patients similarly experienced durable partial responses to PD-1 inhibition, it is of paramount importance to keep in mind that up to 15% of patients may experience severe immune-related adverse events (irAEs), most often requiring the administration of high doses of steroids and/or immunosuppressive treatments. Although these treatments are essential for the management of irAEs, they are also associated with KS promotion, including classic KS.3 Therefore, the benefits of immune checkpoint inhibition (ICI) may be overshadowed. Indeed, one of our patients developed severe immune-related myocarditis, resulting in acute pulmonary edema and cardiogenic shock, with a left ventricular ejection fraction reduction to 25%, requiring several days of noninvasive ventilation and inotropic support. The myocarditis was successfully treated with high doses of intravenous methylprednisolone and immunoglobulin therapy, followed by 6 weeks of systemic corticosteroids. However, KS subsequently relapsed within 5 months with major bone involvement, leading to the reinstitution of chemotherapy.

We agree that a high tumor mutational burden (TMB) is generally associated with an increased tumor response to ICI. However, other markers have recently been unveiled, such as PD-L1 amplification4 and, most importantly, immunogenicity of virus-associated antigens in virus-associated tumors. It is worth emphasizing that in Merkel cell polyomavirus (MCPyV)–associated Merkel cell carcinoma (MCC), which represents up to 80% of cases in the United States and Europe, TMB has been shown to be low (12.5 mutations per exome), whereas the benefit from ICI is at least as good as in MCPyV-negative, UV-induced MCC, which carries a high TMB (1,121 mutations per exome).5 It is now known that all KS are associated with HHV-8 infection. Cytogenetic and comparative genomic hybridization studies have revealed few abnormalities in early KS, such as clonal loss of chromosome Y, whereas additional chromosomal aberrations can be detected in more advanced stages of the disease.6 Therefore, we hypothesize that the strong response to PD-1 inhibition observed in KS may probably be driven more by immunogenic viral antigens than by the TMB.

Further studies are warranted to confirm these results and decipher the importance of immunogenic viral antigens and/or TMB. The hope is that results of an ongoing French multicentric study will provide further insight into the benefit of PD-1 inhibition in classic/endemic KS (ClinicalTrials.gov identifier: NCT03469804).

Call for Correspondence

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References

  • 1.

    Saller J, Walko CM, Millis SZ et al.. Response to checkpoint inhibitor therapy in advanced classic Kaposi sarcoma: a case report and immunogenomic study. J Natl Compr Canc Netw 2018;16:797800.

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    • Search Google Scholar
    • Export Citation
  • 2.

    Delyon J, Bizot A, Battistella M et al.. PD-1 blockade with nivolumab in endemic Kaposi sarcoma. Ann Oncol 2018;29:10671069.

  • 3.

    Anderson LA, Lauria C, Romano N et al.. Risk factors for classical Kaposi sarcoma in a population-based case-control study in Sicily. Cancer Epidemiol Biomarkers Prev 2008;17:34353443.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Goodman AM, Piccioni D, Kato S et al.. Prevalence of PDL1 amplification and preliminary response to immune checkpoint blockade in solid tumors. JAMA Oncol 2018;4:12371244.

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    • Search Google Scholar
    • Export Citation
  • 5.

    Nghiem PT, Bhatia S, Lipson EJ et al.. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med 2016;374:25422552.

  • 6.

    Sun Z, Xiao B, Jha HC et al.. Kaposi's sarcoma-associated herpesvirus-encoded LANA can induce chromosomal instability through targeted degradation of the mitotic checkpoint kinase bub1. J Virol 2014;88:73677378.

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    • Search Google Scholar
    • Export Citation
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  • 1.

    Saller J, Walko CM, Millis SZ et al.. Response to checkpoint inhibitor therapy in advanced classic Kaposi sarcoma: a case report and immunogenomic study. J Natl Compr Canc Netw 2018;16:797800.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Delyon J, Bizot A, Battistella M et al.. PD-1 blockade with nivolumab in endemic Kaposi sarcoma. Ann Oncol 2018;29:10671069.

  • 3.

    Anderson LA, Lauria C, Romano N et al.. Risk factors for classical Kaposi sarcoma in a population-based case-control study in Sicily. Cancer Epidemiol Biomarkers Prev 2008;17:34353443.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Goodman AM, Piccioni D, Kato S et al.. Prevalence of PDL1 amplification and preliminary response to immune checkpoint blockade in solid tumors. JAMA Oncol 2018;4:12371244.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 5.

    Nghiem PT, Bhatia S, Lipson EJ et al.. PD-1 blockade with pembrolizumab in advanced Merkel-cell carcinoma. N Engl J Med 2016;374:25422552.

  • 6.

    Sun Z, Xiao B, Jha HC et al.. Kaposi's sarcoma-associated herpesvirus-encoded LANA can induce chromosomal instability through targeted degradation of the mitotic checkpoint kinase bub1. J Virol 2014;88:73677378.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 1.

    Saller J, Walko CM, Millis SZ et al.. Response to checkpoint inhibitor therapy in advanced classic Kaposi sarcoma: a case report and immunogenomic study. J Natl Compr Canc Netw 2018;16:797800.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2.

    Delyon J, Bizot A, Battistella M et al.. PD-1 blockade with nivolumab in endemic Kaposi sarcoma. Ann Oncol 2018;29:10671069.

  • 3.

    Stevanovic S, Pasetto A, Helman SR et al.. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science 2017;356:200205.

    • PubMed
    • Search Google Scholar
    • Export Citation
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