NPC, which is highly associated with EBV infection, is endemic in southern China including Hong Kong with an incidence of more than 20.0 per 100,000 [17]. Platinum-based chemotherapy is the standard first-line treatment for recurrent/metastatic NPC. Unfortunately, almost all patients relapse despite an initial response to chemotherapy. ICI alone, or in combination with systemic chemotherapy has established itself as an efficacious first- and second-line treatment in recurrent/metastatic head and neck squamous cell carcinoma. However, its role in recurrent/metastatic NPC is less defined. The phase I KEYNOTE-028 trial revealed an objective response of 26.3% with pembrolizumab [18]. Tumor response was highly correlated with PD-L1 expression in tumor cells.
Meanwhile, TB is also a notifiable and endemic disease in Hong Kong, with the notification rate of 54.0 per 100,000 population in 2019 [19], compared to 2.8 per 100,000 in the United States. It may remain latent for years or even decades. Containment of TB in its latent state is achieved through the surveillance of TB-directed CD4 + and CD8 + T cells [20], which happen to be the targets of ICIs. Indeed, the pathophysiology of TB reactivation following ICI therapy is complex and poorly understood, which involves both innate and acquired immune responses [15]. On one hand, exposure to TB leads to increased PD-1 and PD-L1 expression on natural killer (NK) cells of the innate system, resulting in release of interferon-γ (IFNγ) and cell lysis. Subsequent binding of PD-1 to PD-L1 and PD-L2 might inhibit further activation of NK cells, which prevents further tissue damage brought by inflammation. On the other hand, TB can also use the acquired immune response to avoid the host immune response by preventing IFNγ release and inhibiting CD8 + cell cytotoxicity via increased PD-1 expression. PD-1/PD-L1 inhibition by ICI, was shown in vitro to enhance CD8 + cell cytotoxicity against IFNγ-activated macrophages, leading to TB reactivation.
There have been some reports of TB reactivation following ICI therapy [3,4,5,6,7,8,9,10,11,12,13,14,15]. Intriguingly, patients in these reports who developed TB reactivation were those whose tumors also responded well to ICIs. It is postulated that TB reactivation which symbolizes an exaggerated immune response in the host might also predict a favorable tumor response to ICI therapy, though further studies are warranted to confirm such correlation.
A recent retrospective review using the US Food and Drug Administration Adverse Events Reporting System revealed that TB infection was only seen in 0.1% of patients after PD-1/PD-L1 therapy [16]. That said, the incidence would be much higher in TB-endemic regions. While international and local guidelines on screening TB before initiation of biological agents including anti-tumor necrosis factor-α (TNFα) for several chronic inflammatory diseases like rheumatoid arthritis have been published [21, 22], consensus on routine screening for TB before ICI therapy for cancer patients is still lacking. Chest radiograph and tuberculin test are recommended screening tools in these guidelines before anti-TNFα therapy. However, they may not be sensitive to diagnose acute/latent TB infection in cancer patients who are often immunocompromised and are also the high-risk groups more susceptible to TB reactivation after ICI therapy [23].
IGRA by detecting IFNγ released by T cells exposed to TB antigens, has been found more sensitive than the traditional methods to diagnose acute and latent TB, even in immunocompromised patients [24, 25]. New generations of IGRA were found even more sensitive than their earlier generations [24, 25]. Hopefully, international recommendations on TB screening with accurate and reliable methods before ICI initiation for cancer patients can be proposed and implemented routinely in TB-endemic regions.
In conclusion, we report the first gastrointestinal TB reactivation following ICI therapy for metastatic NPC. Accurate TB screening methods should be considered for latent TB infection before ICI therapy for cancer patients.