Study of Adoptive Transfer of Invariant Natural Killer T Cells Combined With TAE/TACE to Treat Unresectable Hepatocellular Carcinoma (HCC): Phase II Clinical Trial
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Sponsor: Beijing YouAn Hospital

Study of Adoptive Transfer of Invariant Natural Killer T Cells 
Combined With TAE/TACE to Treat Unresectable Hepatocellular 
Carcinoma (HCC): Phase II Clinical Trial  
 
NCT04011033  
October 1, 2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

1. Background and Aims 
Hepatocellular carcinoma (HCC) is the fifth most common cancer and a leading 
cause of cancer-related death among males and females of all ages 1. It was estimated 
that in 2018, there were 840 thousand new liver cancer cases and 780 thousand liver 
cancer-related deaths in the world 1. Of importance, unresectable HCC accounts for 
more than 70%~80% of the cases, limiting the possibility of achieving a cure in many 
patients 2, 3. Currently, the prognosis of HCC is poor, with a 5-year survival of about 
18% even in developed countries 4. 
Transarterial embolization (TAE) or transarterial chemoembolization (TACE) is 
a standard therapy for intermediate-stage HCC, which is accepted as a routine practice 
worldwide 5, 6. Nevertheless, different clinical characteristics of HCC, such as liver 
function and tumor load (different size, number, and location), will lead to different 
responses to TA(C)E treatment and different survival times. Furthermore, repeated 
TACE procedures could gradually lead to TACE refractoriness, and some patients 
even show TACE failure 7. According to the Japanese Society of Hepatology (JSH) 
guidelines 8, TA(C)E failure is defined as an insufficient response after ≥2 consecutive 
TA(C)E procedures, as revealed by the response evaluation using computed 
tomography (CT) or magnetic resonance imaging (MRI) after 1~3 months. The 
median tumor doubling time after an initial response of HCC to TACE is 46 days, 
and >90% of the recurrent nodules have a doubling time of <3 months 9. The 
recurrence rate of intrahepatic lesions after TA(C)E is 37% and 61% at 6 and 12 
months, respectively 10. Therefore, patients with HCC failed to respond to TACE, 

under which circumstance is defined as TACE refractoriness, should switch to or 
combine with systemic therapy as soon as possible because repeated TACE is no 
longer beneficial for such patients 9. 
The Asia-Pacific region has the highest incidence of HCC, with >50% of all the 
cases in the world 1. In addition, >80% of HCC cases in China occur due to viral 
hepatitis and cirrhosis 11, 12. Of note, pancytopenia is a common clinical manifestation 
of liver cirrhosis 13, 14. Therefore, the number and frequency of peripheral blood 
lymphocytes in many patients with HCC are lower than in the normal population 15. 
Furthermore, the decline of immune system function is the basis of the occurrence, 
development, recurrence, and metastasis of various tumors, including the decrease in 
anti-tumor killing and immune monitoring functions 16. TA(C)E can induce tumor 
necrosis, and ischemia-reperfusion injury can induce further tumor cell damage. 
TA(C)E is considered to improve tumor immunogenicity by releasing antigens and 
stimulating cytotoxic lymphocytes (CTL) recruitment in tumors 17. After reperfusion, 
natural killer T (NKT) cells are activated rapidly by CD1d 18. Invariant NKT (iNKT) 
cells are enriched in the human liver, and they express a limited T-cell receptor (TCR) 
β spectrum and unique TCR α rearrangement (Vα24-Jα 18 in humans and Vα14-Jα18 
in mice) 19. Clinical trials have shown that activated iNKT cells can rejuvenate 
depleted CD8+ T cells and natural killer (NK) cells 20-24. Some of these trials activated 
iNKT with aGalcer-loaded monocytic dendritic cell vaccines and others adoptively 
transferred iNKT cells. These activated or reactivated lymphocytes can help remove 
residual cancer cells and prevent tumor recurrence and metastasis. Therefore, TA(C)E 

combined with adoptive iNKT therapy might be an option for the treatment of HCC. 
In our previous phase I trial 25, the adoptive transfer therapy of autologous iNKT 
cells in patients with recurrent or refractory Barcelona Clinic Liver Cancer (BCLC) 
B/C liver cancer demonstrated a partial clinical response and objective immune 
response, with very slight side effects. Therefore, we will conduct a multicenter, 
randomized, open trial in BCLC B/C stage patients with HCC after failure to TACE to 
explore the efficacy and safety of TAE combined with adoptive autologous iNKT cell 
therapy compared with TAE alone. 
2. Study Design and Participants 
This randomized, multicenter, open-labeled phase II trial will be conducted at 
Beijing YouAn Hospital of Capital Medical University, Beijing Shijitan Hospital of 
Capital Medical University, and Beijing Ditan Hospital of Capital Medical University 
between March 2018 and March 2020. This study will be performed according to the 
guidelines of the Helsinki Declaration.  
3. Criteria 
Inclusion Criteria: 
1) 18-80 years of age, 2) TACE failure/refractory BCLC B HCC confirmed by 
CT, MRI, and/or histopathology, 3) life expectancy of at least 12 weeks, 4) 
Child-Pugh A/B，5) adequate hematological and renal functions, including white 
blood cell (WBC) count >3.0×109/L, lymphocyte count >0.8×109/L, platelet 
count >50×109/L, hemoglobin concentration >85 g/L, and serum creatinine 

concentration of <1.5-times the upper limit of normal value (ULN), and 6) previous 
treatment terminated at least 4 weeks before entry to this study.  
Exclusion Criteria: 
1) Known history of the human immunodeficiency virus (HIV) or syphilis 
infection, 2) clinically serious infections, 3) history of stem cell transplant or organ 
allograft, 4) history of severe hypertension or cardiac disease, 5) known central 
nervous system (CNS) tumor, 6) autoimmune disease requiring systemic therapy with 
immunosuppressive agents, 7) history of allergy to immunotherapy or related drugs, 8) 
pregnancy or lactation, or 9) deemed not suitable for cellular immunotherapy by the 
investigators. 
Research Suspension / Termination Criteria: 
1) the patient withdrew his informed consent and asked to withdraw, 2) CT/MRI 
examination confirmed the occurrence of PD, according to the imRECIST, 3) unable 
to tolerate AEs, or serious adverse events (SAE), abnormal laboratory tests or 
concurrent diseases, etc, and the researchers judged that it is not in the best interests 
of patients to continue to participate in the study, 4) the study and treatment of 
patients was significantly delayed for any reason, which exceeded the scheduled 
treatment time ≥ 8 weeks from the time of the last administration, 5) other situations 
in which the researchers believe that it is necessary to stop treatment, 6) pregnancy 
occurred in the patient, 7) use new antineoplastic therapy, 8) the sponsor terminates 
the study. 
Elimination Criteria: 

1) the use of research drugs is not consistent with the clinical regimen, and has a 
significant impact on the evaluation of efficacy and safety, 2) those without any 
record, 3) those who did not take research drugs. 
TACE Failure Criteria:  
1) Intrahepatic lesion [i, two or more consecutive ineffective responses seen 
within the treated tumors (viable lesion >50%), even after changing the 
chemotherapeutic agents and/or reanalysis of the feeding artery, on response 
evaluation CT/MRI after 1–3 months following adequately performed selective TACE. 
ii, two or more consecutive progressions in the liver (including an increase in the 
number of tumors compared to that before the previous TACE procedure), even after 
changing the chemotherapeutic agents and/or reanalysis of the feeding artery, on 
response evaluation CT/MRI after 1–3 months following adequately performed 
selective TACE]. 2) Continuous elevation of tumor markers right after TACE, even 
though transient minor reduction is observed. 3) Appearance of vascular invasion. 4) 
Appearance of extrahepatic spread. 
4. Endpoints and Definitions 
The primary endpoint is the PFS, i.e., the time from enrollment to disease 
progression according to the modified RECIST (mRECIST) guideline in trial 
immunotherapeutics, or death from any cause, whichever occurred first. Secondary 
endpoints include overall survival (OS), objective response rate (ORR), disease 
control rate (DCR), quality of life (QoL), and safety. Patients without any 
post-baseline tumor assessment are considered non-responders. Objective responses 

will be confirmed at least 28 days after the initial documentation of the response. 
Progression-Free Survival: Time from the date of enrollment to the date of first 
documentation of tumor progression. 
Progression was defined using Modified RECIST (mRECIST): an increase of at 
least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as 
reference the smallest sum of the diameters of viable (enhancing) target lesions 
recorded since treatment started. 
Overall survival: time from the date of enrollment to the date of death from any 
cause. 
Objective response rate: including complete response (CR) and partial response 
(PR) evaluated by imaging according to mRECIST for target lesions and assessed by 
MRI/CT. Complete Response (CR), disappearance of any intratumoral arterial 
enhancement in all target lesions. Partial Response (PR), at least a 30% decrease in 
the sum of diameters of viable (enhancement in the arterial phase) target lesions, 
taking as reference the baseline sum of the diameters of target lesions. Objective 
Response Rate = CR + PR. 
Disease Control Rate: including complete response (CR), partial response (PR), 
and disease stabilization (SD), evaluated by imaging according to mRECIST for 
target lesions and assessed by MRI/CT. Complete Response (CR), disappearance of 
any intratumoral arterial enhancement in all target lesions. Partial Response (PR), at 
least a 30% decrease in the sum of diameters of viable (enhancement in the arterial 
phase) target lesions, taking as reference the baseline sum of the diameters of target 

lesions. Stable disease (SD), any cases that do not qualify for either partial response or 
progressive disease. Disease Control Rate = CR + PR + SD. 
The Quality of Life (QoL) will be assessed according to the EORTC (EORTC: 
the European Organization for Research and Treatment of Cancer) QLQ-C30 scale 
between the TAE-iNKT and TAE group. And the time to deterioration of QoL, as 
reported by the patient, with deterioration defined as a decrease from baseline of 10 
points or more on the EORTC QLQ–C30 maintained for two consecutive 
assessments. 
Safety and side-effect profiles will be assessed based on the nature, frequency, 
and severity of adverse events, according to the National Cancer Institute (NCI) 
Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.3. Common 
Adverse events (AEs) occurring on or after the first treatment day through the end of 
this trial will be recorded according to NCI-CTCAE 4.03.  
5. Drugs for research 
Name of Drug 
iNKT cells 
Production of iNKT Cells 
1) Isolate PBMCs by leukapheresis using a COM.TEC apheresis system and 
Lymphoprep density gradient medium.  
2) Resuspend PBMCs in Corning serum-free cell medium KBM581 and 
stimulate with 100 ng/mL α-GalCer and 100 U/mL animal-free recombinant human 

interleukin-2 for 48 hours; the rhIL-2 was replenished every other day.  
3) 
Stimulate 
PBMCs 
with 
1,000 
IU/mL 
granulocyte-macrophage 
colony-stimulating factor and IL-4 for 1 week, and obtain mature, monocyte-derived 
DCs. 
4) Sort iNKT cells by using anti-iNKT microbeads according to the 
manufacturer’s protocol on day 7.  
5) Co-culture the sorted iNKT cells with mature DCs for 14 days, and collect 
cells for infusion on day 21. An aliquot of cells was used for immunophenotyping and 
functional testing.  
6) Determine the frequency of iNKT cells in T cells by using a FACSCanto II 
cytometer.  
7) The criteria for iNKT cell administration include a negative bacterial culture, a 
negative mycoplasma test result, and an endotoxin level < 0.05 units/mL. 
Production Standards 
Inspection item 
Statutory (Pharmacopoeia) 
standard 
Internal quality control 
standard 
Color 
--- 
Colorless or innocent 
Character 
--- 
Transparent suspension 
Identification 
Flow cytometry 
Cellular 
immunophenotype 
Rate of 
survival cell 
≥95% 
≥95% 
Quantity 
(survival cell) 
--- 
Day7：≥5*107； 
Day 21：≥1*108 
Microbial limit 
test 
Aseptic, (bacteria and mold 
shall not be detected). 
Aseptic, (bacteria and mold 
shall not be detected). 

Mycoplasma (not allowed to 
be detected). 
Endotoxin≤2EU/ml 
Mycoplasma (not allowed to be 
detected). 
Endotoxin≤2EU/ml 
Proportion  
90% 
90% 
Dose and Administration 
Intravenous infusion. From the date of cell collection, the cells will be infused on 
the 7th and 21st day of each month as a course of treatment for a total of three courses, 
the reinfusion dose is determined according to the patient's body surface area, which 
was about 108~109cells/m2.  
Drug Combination 
Human IL-2 (25,000 IU/kg per day) will be administered (subcutaneous injection) 
once every other day for 1 week after iNKT cell infusion. 
6. Interventions 
The patients will be randomized 1:1 using a random number table to receive TAE 
treatment vs. the combination treatment of TAE and adoptive autologous iNKT cell 
infusion (TAE-iNKT). The patients in the TAE and TAE-iNKT groups will undergo 
TAE at weeks 0 and 4 after enrollment. TAE will be performed at the local hospitals.  
In the TAE-iNKT group, iNKT cells will be administered at 1st, 3th, 5th, 7th, 9th, 
11th weeks after enrollment. After iNKT cell infusion, a subcutaneous injection of 
interleukin (IL)-2 (25,000 IU/kg) will be administered once every other day for 1 
week. 
All target and non-target lesions will be assessed by chest, abdomen, and pelvis 
CT or MRI at baseline and every 4 weeks until week 16, and then every 8 weeks until 

radiological progression. At the same time points, routine blood tests, tumor 
biomarkers, α-fetoprotein (AFP), and quality of life (QoL) will be measured. 
After the end of treatment, the survival follow-up of the subjects will continue to 
be conducted every 3 months, while those who end treatment for reasons other than 
disease progression will undergo regular tumor imaging evaluation as much as 
possible after treatment, and survival follow-up must be carried out. 
The details of follow-up are shown in the table below: 
Project / time 
Screening/ 
baseline period
（-14d～0w） 
The first 
cycle 
3W±7d 
The second 
cycle 
6w±7d 
Odd 
cycle 
±7d 
Even 
cycle 
±7d 
Out-of- 
group 
follow-up 
±7d 
Sign the informed 
consent form 
× 
 
 
 
 
 
Medical history 
× 
 
 
 
 
 
Inclusion / exclusion 
criteria 
× 
 
 
 
 
 
Physical 
examination and 
vital signs 
× 
× 
× 
× 
× 
× 
Blood routine 
× 
× 
× 
× 
× 
× 
Urine routine 
× 
× 
× 
× 
× 
× 
Biochemistry (liver 
and kidney function, 
blood glucose, blood 
lipid) 
× 
× 
× 
× 
× 
× 
Myocardial enzyme 
× 
× 
× 
× 
× 
× 
Thyroid function 
× 
× 
× 
× 
× 
× 
Five items of 
hepatitis B 
× 
 
 
 
 
 
Hepatitis C antibody 
× 
 
 
 
 
 
HBV-DNA/HCV 
RNA quantification 
× 
 
× 
× 
× 
Syphilis antibody 
× 
 
 
 
 
 
HIV antibody 
× 
 
 
 
 
 
Digestive tumor 
markers, AFP 
× 
× 
× 
× 
× 
× 
Coagulation 
× 
× 
× 
× 
× 
× 

Autoantibody 
× 
 
 
 
 
 
T cell subsets 
× 
× 
× 
× 
× 
× 
Detection of cell 
suspension (bacteria, 
fungi, endotoxin) 
× 
× 
× 
× 
× 
 
Electrocardiogram 
× 
 
× 
 
× 
× 
Colour Sonography 
× 
 
 
 
 
× 
Liver enhanced MR 
or CT 
× 
 
× 
 
× 
× 
Imaging data of 
other organs 
× 
 
× 
 
× 
× 
Pathological 
examination of 
tumor 
× 
 
 
 
 
 
Drug combination 
× 
× 
× 
× 
× 
× 
Adverse events 
× 
× 
× 
× 
× 
× 
 
The Implementation of TAE 
1) Select catheterization of the feeding artery by using a microcatheter.  
2) Perform abdominal and hepatic arteriography. 
3) Embolization with Gelfoam until near stasis of the arterial flow.  
4) Determine the dose of iodized oil by the tumor size or based on whether the 
portal vein had a tumor thrombosis.  
5) Inject the emulsion of iodized oil until the accumulation of the emulsion in the 
tumor and the visualization of the portal vein branches near the tumor. (If there was a 
significant arterioportal shunt, embolization with Gelfoam was first performed to 
occlude the shunt, after which the iodized oil emulsion was infused, and embolization 
with Gelfoam was performed.) 
7. Statistical Analysis  

The trial was designed to use a 2-sided 5% type I error and had 80% power to 
detect an improvement in PFS from 1.5 months in the TAE group to 4.5 months in the 
TAE-iNKT group, corresponding to a hazard ratio (HR) of 0.33 in terms of median 
PFS. In consideration of these assumptions, the trial design was powered for 60 
patients to be randomly assigned in each group as the intention-to-treat population 
(allocation ratio of 1:1, n=30 patients in each group), and allowing for a drop-out rate 
of 20%. Sample size estimation was performed using PASS 11.  
Continuous variables will be expressed as the median and IQR, and will be 
compared using t tests or Mann-Whitney tests. Categorical variables will be presented 
as the frequency and percentage, and will be compared using Fisher’s exact tests. 
Survival and time to QoL deterioration will be estimated using the Kaplan-Meier 
method, and their 95% CIs will be calculated using the Brookmeyer and Crowley 
method. Survival differences will be compared using log-rank tests. Peripheral blood 
cells will be analyzed using Sidak’s multiple comparison test. The overall two-sided 
significance level of P< .05 will be split into a two-sided significance level of P< .01 
for tests of PFS, OS, ORR, DCR, and QoL according to the Bonferroni method 
(dividing the available total α (typically 0.05) equally among the chosen endpoints). If 
the PFS and/or all secondary endpoints are statistically significant at a two-sided 
significance level of 0.01, the curative effect of TAE-iNKT will be deemed better than 
that of TAE alone. All statistical analyses will be conducted using SAS software 
version 9.4 (SAS Institute). 
8. Data Management. 

Designated and trained staff act as data managers, responsible for the data 
management of this study, complete data collection, input, quality inspection and 
make data security monitoring plan in accordance with the requirements of GCP. 
When the following conditions are met, the data can be locked: all data have been 
entered into the database; all questions have been solved; the researcher has 
completed the signature; the analytical population has been defined and judged. After 
the database is locked, if the project team evaluates that it needs to be unlocked, it can 
reopen the lock. The process of unlocking the database should include notifying the 
project team, clearly defining which data errors will be changed, the reason for the 
change, and the date of the change, and signed by key researchers, data managers, and 
statistical analysts. The re-locking of the database should follow the same notification 
/ approval process as the database lock for the first time. 
9. Handling of Adverse Events during and after the Study. 
Researchers should follow up, observe and record the outcome of all adverse 
events, and follow patients who drop out of the study because of adverse events until 
the adverse events are completely relieved. Researchers must determine whether 
adverse events are related to research drugs and provide evidence to support this 
judgment. 
In all clinical or laboratory examinations, abnormal items of clinical significance 
should be filled in the form of adverse events and followed up at least once a week 
until normal or reached the baseline level. 

Measures to Deal with Expected Adverse Events 
1) Fever: patients may have different degrees of fever, doctors will give 
symptomatic antipyretic treatment. 
2) Allergic reaction: a small number of patients may have allergic reaction, such 
as skin pruritus, urticaria, chest tightness and so on. 
3) Digestive tract symptoms: patients may have digestive tract symptoms of 
nausea, vomiting and various stomach discomfort, and doctors will give gastric 
mucosal protective agents, acid suppressants, gastric motility drugs or antiemetic 
drugs according to the situation. 
If any serious adverse event occurs in the course of clinical research, the 
researcher shall report the serious adverse event to the ethics committee of the 
research unit and the applicant unit of clinical research within 24 hours of knowing 
the serious adverse event. At the same time, researchers must fill in the form of 
serious adverse events and record the time, severity, duration, measures taken and 
outcome of serious adverse events.  
10. Follow-up and Medical Measures after the End of the Study. 
After the completion of this study, the subjects may still have the end events of 
the disease itself, such as the progression of liver cancer and the deterioration of liver 
function. We will closely observe and follow up, communicate with patients in time, 
and put forward objective medical suggestions. Therefore, the regular return visit of 
the subjects will be very important, because it will help to detect the progress of these 

diseases in the early stage, so that the clinical follow-up doctors can take timely and 
effective treatment measures to improve the prognosis. 
11. Data Preservation. 
The original data of the examination results (including the test sheet) are owned 
by the researchers. The CRF shall be in triplicate, one copy shall be retained by the 
bidding unit, one copy by the participating unit and one copy by the statistical unit. 
Demographic data, related medical history, physical examination, a series of 
laboratory tests and combined medication and adverse events take the CRF table and 
hospital case system data as the original data, in which the part related to the privacy 
of the subjects is only reflected in the original medical records. 
Researchers should properly preserve research documents in accordance with 
relevant requirements. Important documents should be kept until 5 years after the end 
of the clinical study. 
 
12. References 
 
1. 
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: 
GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A 
Cancer Journal for Clinicians. 2018;68(6):394-424. doi:https://doi.org/10.3322/caac.21492 
2. 
Lafaro KJ, Demirjian AN, Pawlik TM. Epidemiology of Hepatocellular Carcinoma. Surgical 
Oncology Clinics. 2015;24(1):1-17. doi:10.1016/j.soc.2014.09.001 
3. 
Jelic S, Sotiropoulos GC. Hepatocellular carcinoma: ESMO Clinical Practice Guidelines for 
diagnosis, 
treatment 
and 
follow-up. 
Annals 
of 
Oncology. 
2010;21:v59-v64. 
doi:10.1093/annonc/mdq166 
4. 
Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of 
Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for 
Clinicians. 2021;71(3):209-249. doi:https://doi.org/10.3322/caac.21660 
5. 
Kokudo N, Takemura N, Hasegawa K, et al. Clinical practice guidelines for hepatocellular 

carcinoma: The Japan Society of Hepatology 2017 (4th JSH-HCC guidelines) 2019 update. Hepatology 
Research. 2019;49(10):1109-1113. doi:https://doi.org/10.1111/hepr.13411 
6. 
Chang PY, Huang CC, Hung CH, et al. Multidisciplinary Taiwan Consensus Recommendations 
for the Use of DEBDOX-TACE in Hepatocellular Carcinoma Treatment. Liver Cancer. Oct 
2018;7(4):312-322. doi:10.1159/000487608 
7. 
Takayasu K, Arii S, Ikai I, et al. Prospective Cohort Study of Transarterial Chemoembolization for 
Unresectable Hepatocellular Carcinoma in 8510 Patients. Gastroenterology. 2006;131(2):461-469. 
doi:10.1053/j.gastro.2006.05.021 
8. 
Kudo M, Matsui O, Izumi N, et al. Transarterial Chemoembolization Failure/Refractoriness: 
JSH-LCSGJ 
Criteria 
2014 
Update. 
Oncology. 
2014;87(suppl 
1)(Suppl. 
1):22-31. 
doi:10.1159/000368142 
9. 
Woo HY, Jang JW, Choi JY, et al. Tumor doubling time after initial response to transarterial 
chemoembolization 
in 
patients 
with 
hepatocellular 
carcinoma. 
Scandinavian 
Journal 
of 
Gastroenterology. 2010/03/01 2010;45(3):332-339. doi:10.3109/00365520903456573 
10. Terzi E, Golfieri R, Piscaglia F, et al. Response rate and clinical outcome of HCC after first and 
repeated 
cTACE 
performed 
&#x201c;on 
demand&#x201d. 
Journal 
of 
Hepatology. 
2012;57(6):1258-1267. doi:10.1016/j.jhep.2012.07.025 
11. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of 
hepatocellular carcinoma: trends, risk, prevention and management. Nature Reviews Gastroenterology 
& Hepatology. 2019/10/01 2019;16(10):589-604. doi:10.1038/s41575-019-0186-y 
12. Ding C, Fu X, Zhou Y, et al. Disease burden of liver cancer in China from 1997 to 2016: an 
observational study based on the Global Burden of Diseases. BMJ Open. 2019;9(4):e025613. 
doi:10.1136/bmjopen-2018-025613 
13. Lv Y, Yee Lau W, Wu H, et al. Causes of peripheral cytopenia in hepatitic cirrhosis and portal 
hypertensive 
splenomegaly. 
Experimental 
Biology 
and 
Medicine. 
2017;242(7):744-749. 
doi:10.1177/1535370217693113 
14. Afdhal NH, Giannini EG, Tayyab G, et al. Eltrombopag before Procedures in Patients with 
Cirrhosis and Thrombocytopenia. New England Journal of Medicine. 2012;367(8):716-724. 
doi:10.1056/NEJMoa1110709 
15. Taussig MD, Irene Koran ME, Mouli SK, et al. Neutrophil to lymphocyte ratio predicts disease 
progression following intra-arterial therapy of hepatocellular carcinoma. HPB. 2017;19(5):458-464. 
doi:10.1016/j.hpb.2017.01.013 
16. Miller Jacques FAP, Sadelain M. The Journey from Discoveries in Fundamental Immunology to 
Cancer Immunotherapy. Cancer Cell. 2015;27(4):439-449. doi:10.1016/j.ccell.2015.03.007 
17. Girardi E, Zajonc DM. Molecular basis of lipid antigen presentation by CD1d and recognition by 
natural 
killer 
T 
cells. 
Immunological 
Reviews. 
2012;250(1):167-179. 
doi:https://doi.org/10.1111/j.1600-065X.2012.01166.x 
18. Nair S, Dhodapkar MV. Natural Killer T Cells in Cancer Immunotherapy. Review. Frontiers in 
Immunology. 2017-September-22 2017;8(1178)doi:10.3389/fimmu.2017.01178 
19. Salio M, Silk JD, Jones EY, Cerundolo V. Biology of CD1- and MR1-Restricted T Cells. Annual 
Review of Immunology. 2014;32(1):323-366. doi:10.1146/annurev-immunol-032713-120243 
20. Motohashi S, Ishikawa A, Ishikawa E, et al. A Phase I Study of &lt;em&gt;In vitro&lt;/em&gt; 
Expanded Natural Killer T Cells in Patients with Advanced and Recurrent Non–Small Cell Lung 
Cancer. Clinical Cancer Research. 2006;12(20):6079. doi:10.1158/1078-0432.CCR-06-0114 

21. Kunii N, Horiguchi S, Motohashi S, et al. Combination therapy of in vitro-expanded natural killer 
T cells and α-galactosylceramide-pulsed antigen-presenting cells in patients with recurrent head and 
neck 
carcinoma. 
Cancer 
Science. 
2009;100(6):1092-1098. 
doi:https://doi.org/10.1111/j.1349-7006.2009.01135.x 
22. Yamasaki K, Horiguchi S, Kurosaki M, et al. Induction of NKT cell-specific immune responses in 
cancer tissues after NKT cell-targeted adoptive immunotherapy. Clinical Immunology. 2011/03/01/ 
2011;138(3):255-265. doi:https://doi.org/10.1016/j.clim.2010.11.014 
23. Exley MA, Friedlander P, Alatrakchi N, et al. Adoptive Transfer of Invariant NKT Cells as 
Immunotherapy for Advanced Melanoma: A Phase I Clinical Trial. Clinical Cancer Research. 
2017;23(14):3510. doi:10.1158/1078-0432.CCR-16-0600 
24. Toyoda T, Kamata T, Tanaka K, et al. Phase II study of α-galactosylceramide-pulsed 
antigen-presenting cells in patients with advanced or recurrent non-small cell lung cancer. Journal for 
ImmunoTherapy of Cancer. 2020;8(1):e000316. doi:10.1136/jitc-2019-000316 
25. Gao Y, Guo J, Bao X, et al. Adoptive Transfer of Autologous Invariant Natural Killer T Cells as 
Immunotherapy for Advanced Hepatocellular Carcinoma: A Phase I Clinical Trial. The Oncologist. 
2021;26(11):e1919-e1930. doi:https://doi.org/10.1002/onco.13899