Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report

Abstract

Effective treatment or prevention of immune side effects associated with checkpoint inhibitor therapy of cancer is an important goal in this new era of immunotherapy. Hepatitis due to immunotherapy with antibodies against PD-1 is uncommon and generally of low severity. We present an unusually severe case arising in a melanoma patient after more than 6 months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4+ T cells were profoundly depleted by ATG, while CD8+ T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4+ T cell phenotype were stably present in the patient before disease onset. These included a population of CCR4−CCR6− effector/memory CD4+ T cells expressing intermediate levels of the Th1-related chemokine receptor CXCR3 and abnormally high multi-drug resistance type 1 transporter (MDR1) activity as assessed by a rhodamine 123 excretion assay. Expression of MDR1 has been implicated in steroid resistance and may have contributed to the severity and lack of a sustained steroid response in this patient. The number of CD4+ rhodamine 123-excreting cells was reduced > 3.5-fold after steroid and ATG treatment. This case illustrates the need to consider this form of steroid resistance in patients failing treatment with corticosteroids. It also highlights the need for both better identification of patients at risk and the development of treatments that involve more specific immune suppression.Electronic supplementary materialThe online version of this article (10.1007/s00262-017-2107-7) contains supplementary material, which is available to authorized users.

Combination with SGT-53 overcomes tumor resistance to a checkpoint inhibitor

“…Although rare and generally of low severity, hepatitis due to immunotherapy with anti-PD1 has been reported. 23

10.1080/2162402X.2018.1484982-F0008Figure 8.SGT-53 prevents fatal xenogeneic hypersensitivity following repeated anti-PD1 administration in a syngeneic 4T1 breast cancer model. (A) Survival of BALB/c mice bearing 4T1 tumor after repeated dosing with anti-PD1 antibody alone or in combination with SGT-53.

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The immune checkpoint CD96 defines a distinct lymphocyte phenotype and is highly expressed on tumor‐infiltrating T cells

“…To most accurately compare protein expression levels between PBMC and TD we utilized a CD45‐based barcoding strategy, whereby a given patient's TD and PBMCs were first stained separately with CD45‐Pd104 and CD45‐Pd110, separately then washed and combined for subsequent antibody staining steps. Cells were stained for mass cytometry analyses as described . Briefly, cells were stained with 1.25 μ m Cell‐IDTM Cisplatin in PBS (Fluidigm) 3 min at room temperature and quenched by rapid addition of FCS.…”

“…Cells were stained for mass cytometry analyses as described. 31 Briefly, cells were stained with 1.25 lM Cell-IDTM Cisplatin in PBS (Fluidigm) 3 min at room temperature and quenched by rapid addition of FCS. Cells were then washed twice in FACS buffer and then stained with a fluorophore-conjugated antibody cocktail for 20 min at 4°C.…”

Clinical diagnosis and treatment of immune checkpoint inhibitor‐associated adverse events in the digestive system

“…Tacrolimus may be considered in case of failure after the administration of MMF. It has also been reported that antithymocyte globulin (ATG) can be used to treat severe hepatitis in patients who have failed to respond to corticosteroids . ICI‐related hepatotoxicity usually resolves within four to six weeks with the appropriate treatment.…”