Case Report: Simultaneous Hyperprogression and Fulminant Myocarditis in a Patient With Advanced Melanoma Following Treatment With Immune Checkpoint Inhibitor Therapy

Abstract

We report here a patient with stage IV mucosal melanoma treated with dual immune checkpoint inhibitor (ICI) therapy (Nivolumab/Ipilimumab) who experienced rapid disease progression and metastatic spread within three weeks of first infusion. Surprisingly, this patient also developed fulminant myocarditis within the same time frame. Immunohistochemical staining of the primary tumor and a metastatic omental lesion revealed robust CD8+ PD-1+ T cell infiltration after ICI treatment, as would be expected following immune activation. However, the CD8+ T cell infiltrate was largely negative for both Granzyme B and TIA-1, suggesting these T cells were not capable of effective tumor lysis. We discuss the possibility that heightened pro-inflammatory T cell activity (rather than tumor-directed cytolytic activity) was induced by anti-PD-1 and anti-CTLA-4, which could have provoked both rapid tumor resistance mechanisms and myocarditis. This case highlights the fact that the mere presence of tumor infiltrating lymphocytes (TILs) does not necessarily correlate to ICI response and that additional functional markers are necessary to differentiate between inflammatory and cytolytic CD8+ TILs.

Immune-related myocarditis in two patients receiving camrelizumab therapy and document analysis

“…Some patients have mild clinical symptoms, and some develop fulminant myocarditis which usually manifests as refractory shock or fatal arrhythmia, with a high fatality rate. 8,17 The 2 patients we included both developed dyspnea shortly after using ICI. Case 1 has severe heart failure, and case 2 has relatively mild dyspnea.…”

Myocarditis Induced by Immunotherapy in Metastatic Melanoma—Review of Literature and Current Guidelines

“…Some authors suggest that myocarditis is associated with response to therapy [ 68 ]. However, a case of myocarditis with concomitant hyper-progression was also described [ 69 ]. It is worth taking into account that not all cardiac and non-cardiac manifestations occurring under ICI therapy are drug-related adverse events, therefore differential diagnoses must be considered in order to avoid unnecessary cessation of ICI treatment, which may have a major impact on overall patient prognosis [ 70 ].…”

Mechanism underlying the immune checkpoint inhibitor-induced hyper-progressive state of cancer

“…A clinical study of head and neck squamous cell carcinoma also suggested that previous local irradiation was an important predictor of HPD [31] . In addition to being associated with radiotherapy, AKT1 E17K mutation [32] and PI3K/AKT pathway [33] were also related to HPD. Interestingly, after immunohistochemical staining of the primary tumor and metastases samples with HPD, Barham et al [34] showed that the tumor infiltrating lymphocyte (TIL) number was not necessarily correlated with ICI response, as levels of granzyme B and TIA-1 of infiltrated CD8 + T cells were mostly negative, indicating that these were inflammatory T cells which cause tumor drug resistance and myocarditis.…”

“…Interestingly, after immunohistochemical staining of the primary tumor and metastases samples with HPD, Barham et al . [ 34 ] showed that the tumor infiltrating lymphocyte (TIL) number was not necessarily correlated with ICI response, as levels of granzyme B and TIA-1 of infiltrated CD8 + T cells were mostly negative, indicating that these were inflammatory T cells which cause tumor drug resistance and myocarditis. They cannot effectively dissolve the tumor, so additional functional markers are required to distinguish between inflammatory and cytolytic CD8 + TIL.…”