Table 2.

EBV targets for the development of NPC immunotherapy and therapeutic vaccine in the past 10 years.

CTL specificity	Prominent effects	Side effects	References
EBV-specific cytotoxic T-lymphocytes (CTLs) immunotherapy
LMP1 & LMP2	Majority of pulmonary lesions were no longer evident in patients with recurrent NPC although primary tumour did not regress	Side effects such as fatigue, weakness, arthralgia, pain, haemoptysis, and epistaxis	[15]
	Highly efficient on patients with relapsed/refractory NPC (62% remains disease-free up to 75 months) particularly with locoregional disease	No long-term toxicity was reported	[51]
	6 out of 11 NPC patients, in whom conventional treatment has failed, showed either tumour regression or disease stabilization lasting more than 4 months	Four patients developed grade 3 neutropenia. Two patients suffered grade 2 thrombocytopenia. One patient suffered grade 2 anaemia. Mild toxic effects such as fatigue and nausea were observed in 6 patients	[52]
LMP1 & LMP2, EBNA1	Refractory NPC patients showed a median survival of 478 days, while patients with no or minimal residual disease remain alive	10 out of 30 patients suffered grade 1 adverse events; 6 out of 30 suffered grade 2 adverse events and 2 out of 30 suffered grade 3	[53]
	The median overall survival increased from 220 to 530 days compared with patients who did not receive the therapy	Few patients have been reported to have flu-like symptoms, malaise, dry cough, and low blood pressure	[54]
LMPs, EBNAs, BZLF1, BRKF1, BRMF1	Combination treatment of gemcitabine and carboplatin (GC) and CTL resulted in improved survival outcomes	Most of the reported side effects were grade 1. Mild toxic effects such as rash, fever, and fatigue were seen	[55]
LMP2, EBNAs, lytic proteins (BZLF1, BRLF1, BMLF1)	Patients with recurrent NPC produced higher number of autologous CTLs following CD45 mAbs	Grade 1 and 2 nonhematologic toxicities were observed among patients, including fever, abdominal pain, hypotension, and nausea. Transient neutropenia was also observed	[49]
EBV-based therapeutic vaccine
Truncated LMP1 & full-length LMP2	Induced delayed type hypersensitivity (DTH) responses in 9 out of 12 patients	Mild nonhematological toxic effects such as fever, fatigue, and skin rash were observed in 9 patients. Total of 15 patients suffered grade 1/2 or 3 anaemia	[56]
LMP2 & EBNA1	Increased the T-cell responses in 15 of 18 patients	Reported negative reactions at injection sites. Flu-like symptoms, fatigue, arthralgia, myalgia, headache/dizziness, and hepatotoxicity were observed	[20]
	Increased immunity and induced differentiation and functional diversification of responsive T-cell populations	Grade 1 and 2 injection site reaction was observed in all participants. Nine patients experienced systemic toxicity	[19]