Supplementary Table 1 | Immunotherapies with FDA-approval for cancer treatment
Agent
Class
Indication
FDA
Ipilimumab
Anti-CTLA-4-blocking mAb
Metastatic melanoma
Reference ID: 3417,736
Nivolumab
Anti-PD-1-blocking mAb
Metastatic melanoma, squamous lung cancer
Reference ID: 3677,021
(2nd line)
Pembrolizumab
Anti-PD-1-blocking mAb
Metastatic melanoma
Reference ID: 3621,876
Sipuleucel
Cell-based vaccine
Castration resistant metastatic prostate cancer
SR-1346.02, 28 SEP
(Provenge)
High dose IL-2
2009
Cytokine
Metastatic melanoma, metastatic renal cell
cancer
Abbreviations: CTLA-4, cytotoxic T-lymphocyte protein 4; mAb, monoclonal antibody.
1
Reference ID: 3165,255
Supplementary Table 2 | Clinical trials on cell-based immunotherapies (DCs) in HCC
Reference
Agent
Treatment schedule
Study design
Population
Endpoint
Relevant findings
Chi et al.
Autologous
2 IT injections
Prospective,
14 patients with
Not reported*
RR: 2 PR, 7 SD by WHO criteria;
(2005)S1
immature DCs
2 days after EBRT
single arm,
advanced tumours
increased AFP-specific immune
(8 Gy) separated by
dose finding
suitable for EBRT
responses in 4/10 patients;
21 days
increased NK cell activity in 3/10
patients; no relevant toxicity
Nakamoto
Autologous
1 IA injection
Prospective,
10 patients with HCV-
Not reported*
No difference in RFS compared with
et al.
immature DCs
mixed with
single arm
related tumours in
a historical control group; DC
(2007)S2
pulsed with
Gelfoam, during
TNM stage >II treated
migration to regional lymph nodes
HepG2-derived
selective
with TAE
not observed; ELISPOT response to
tumour lysate
embolization
AFP, hTERT, Her-2/neu and MRP3
increased by 2–20-fold in 6/8
patients; no relevant toxicity
Butterfield
Autologous
3 biweekly ID
Prospective,
16 HLA-A*0201
Safety and
No AFP or tumour responses;
et al.
immature DCs
injections
single arm,
patients with AFP-
immunological
substantial but mostly modest
(2006)S3
pulsed separately
dose finding
expressing TNM stage III
effects*
tetramer responses in 6/10 patients
with 4 AFP
and IV tumours
with concordant ELISPOT responses
peptides
in 5/6; enhanced NK cell
activation; inability to generate
acceptable DCs in 2 patients; no AEs
attributable to vaccination
Tada et al.
Autologous
6 SC injection and
Prospective,
5 patients with early
Safety, feasibility
RR: No tumour response; strong
(2012)S4
mature DCs
topical imiquimod
single arm
and intermediate
and immune
T-cell responses against HCC
pulsed with three
every 2 weeks after
tumours with no prior
activity*
antigens in 5/5 patients
tumour-
TACE
response to TACE
(particularly against AFP and
associated
MAGE-1); no relevant toxicity
proteins AFP,
MAGEA1, GPC3
Mazzolini
Autologous
3 IT injections on
Prospective,
17 patients with
2
P: feasibility and
RR: 0 PR, 1 SD/8 HCC pts; 1/8
et al.
mature DCs
metastatic digestive
safety*
positive DTH with tumour lysate in
(2005)S5
transduced with
tumours (8 patients
S: biological effect
HCC patients; substantial increase
an adenoviral
with advanced HCC)
and antitumour
in tumour infiltration by effector
activity
immune cells in 5 patients with
weeks 0, 3 and 6
single arm
vector encoding
human IL-12
HCC; no relevant toxicity (no DLT)
Qiu et al.
Autologous
2 to 7 IV weekly
Prospective,
9 patients with stage III
(2011)S6
mature DCs
injections (no
single arm
tumours treated by
positive DTH after Tx; prolonged
pulsed with
prespecified
cytoreductive resection
survival compared to a historical
tumour lysate
schedule reported)
followed by RFA,
control group (median 17.1 versus
incubated with
chemotherapy or
10.1 months); increased frequency of
recombinant
interventional Tx
IFN-γ-producing T cells; fever and
Not defined*
bovine α1,3GT,
RR: 3 PR; 0 SD; 8/9 patients had
rash common but not severe
cocultured with
BM-derived CIKs
El Ansary
Autologous
Prospective,
30 patients with
et al.
mature DCs
1 ID injection
randomized
advanced HCC not
reported); increased peripheral CD8+
(2013)S7
pulsed with
(BSC)
amenable to surgery,
T cells; no serious AEs reported
HepG2-derived
Not defined*
RR: 2 PR; 9 SD (criteria not
local ablation or TACE
tumour lysate
Palmer
Autologous
one to six three-
Prospective,
39 patients with
P: tumour response,
RR: 1 PR, 6 SD/25 evaluable
et al.
matured DCs
weekly IV
single arm
advanced HCC not
toxicity
patients; 4 /17 patients had AFP
(2009)S8
pulsed with
injections
amenable to surgery,
S: changes in serum
responses; no relevant toxicity
local ablation or TACE.
AFP and immune
including hepatic toxicity or
response
de novo autoantibody formation
Not reported*
RR: 4 PR, 17 SD/31 patients
HepG2-derived
tumour lysate
Lee et al.
Autologous
Group 1: 5 weekly
Prospective,
31 patients with TNM
(2005)S9
mature DCs
IV injections; group
single arm
stage IV tumours
pulsed with
2: same plus
increased survival in comparison
autologous
monthly injections
with a historical control group; no
tumour lysate
for 2–12 months
relevant toxicity
evaluable; 0/10 DTH responses;
*The method used for sample size calculation was not reported. Abbreviations: α1,3GT, α1,3-galactosyltransferase; AE, adverse events; AFP, α-fetoprotein;
BSC, best supportive care; CIK, cytokine-induced killer cells; DC, dendritic cell; DLT, dose-limiting toxicity; DTH, skin delayed hypersensitivity test; EBRT,
3
external beam radiation therapy; ELISPOT, enzyme-linked immunospot; GPC3, glypican-3; Gy, grey; HCC, hepatocellular carcinoma; Her-2/neu, receptor
tyrosine-protein kinase erbB-2; hTERT, telomerase reverse transcriptase; IA, intra-arterial; ID, intradermal; IT, intrathecal; IV, intravenous; MAGEA1,
melanoma-associated antigen 1; MRP3, canalicular multispecific organic anion transporter 2; NK, natural killer; P, primary endpoint; PR, partial
response; RFA, radiofrequency ablation; RFS, recurrence-free survival; RR, response rate; S, secondary endpoint; SC, subcutaneous; SD, stable disease; TNM,
tumour-node-metastasis; TACE, transarterial chemoembolization; TAE, transarterial embolization; Tx, treatment.
4
Supplementary Table 3 | Clinical trials on cell-based immunotherapies (CIKs) in HCC
Reference
Agent
Treatment schedule
Study design
Population
Endpoint
Relevant findings
Takayama
Autologous
6 IV infusions 2 to
Prospective,
150 patients
P: 3-year RFS and
Increased 3-year RFS (37% versus
et al.
lymphocytes
24 months after
randomized
undergoing R0
TTR
22%) and TTR (median: 2.8 versus
(2000)S10
activated with
resection
resection (76 received
S: disease-specific
1.6 years); no difference in OS; no
CIKs)
survival and OS
relevant toxicity
Clinical effect
No difference in recurrence rates;
rIL-2
Hui et al.
Autologous
3 (group 1) or 6
Prospective,
127 patients with
(2009)S11
lymphocytes
(group 2) IV
randomized
solitary tumours treated
increase in RFS (5-year rate: 23%,
activated with
infusions every
(BSC); sample
by R0 resection (84
19% and 11% in groups 1, 2 and
rIL-2 and rIL-1a
2 weeks after
size
received CIKs)
control); no difference in OS; 5
resection
calculation
patients had DLT (persistent fever)
not reported
Pan et al.
Autologous
At least 4 IV
(2013)S12
lymphocytes
injections every
solitary resected
(5-year OS: 65.9% versus 50.2%);
activated with
2 weeks after
tumours (no selection
multivariate survival analysis
rIL-2 and rIL-1a
resection
criteria for CIK
showed AST, tumour size, tumour
therapy) compared
number, pathological grades and
with a historical
CIK Tx as independent prognostic
Retrospective
204 patients with
OS
cohort
Increased OS in CIK-treated patients
factors
Weng et al.
Autologous
8–10 IV injections
Prospective,
45 patients with
(2008)S13
lymphocytes
given every
randomized
nodular or massive
RFS rate (9% versus 30%); increase
activated with
15 days, starting
(BSC)
HCC (2–13 cm) in
in circulating CD3+, CD4+, and
rIL-2
6–8 weeks after
vascular complete
CD3+CD56+ cells and decreased CD8+
locoregional
response after TACE
T cells; no relevant toxicity
therapy
and RFA Tx
P: TTR and RFS
TTR not reported; reduced 1-year
Ma et al.
Autologous
6 IV infusions
Prospective,
7 patients with small
P: changes in
Increased proportion of CD3+CD8+
(2010)S14
lymphocytes
every 2 weeks
single arm
(1.0–3.5 cm) tumours;
peripheral cell
T cells (36% versus 48.%); increased
activated with
within 3 months
tumour-naive or
subsets and IFN-γ
blood levels of IFN-γ (7.6 versus
rIL-2, and
after RFA
relapsing after prior
levels; tumour
4.7 pg/ml); no recurrence after
therapy
recurrence
7 month follow-up
RetroNectin®
5
(Takara Bio Inc.,
Japan)
Yu et al.
Autologous
2 IV monthly until
Prospective,
132 patients with early
P: OS
Increased OS in CIK-treated patients
(2014)S15
lymphocytes
recurrence (post-
randomized
to advanced tumours
S: PFS
(median 24.9 versus 11.3 months);
activated with
resection),
(BSC)
receiving standard Tx
no difference in recurrence rate or
rIL-2 and rIL-1a
progression (post-
(66 received CIKs)
pattern after resection; no relevant
TACE or BSC) or
toxicity
up to 36 months
Shi et al.
Autologous
3 IV infusions 10
Prospective,
13 patients with mostly
P: Changes in
Increased proportion of CD3+CD8+,
(2004)S16
lymphocytes
to 15 days after
single arm
advanced HBV-related
peripheral
CD3+CD56+ and CD25+ cells and
activated with
apheresis
tumours
lymphocytes subsets
type I and II dendritic cells
rIL-2
Abbreviations: AST, aspartate aminotransferase; BSC, best supportive care; CIK, cytokine-induced killer cells; DLT, dose-limiting toxicity; HCC,
hepatocellular carcinoma; IV, intravenous; OS, overall survival; P, primary endpoint; PFS, progression free survival; R0, negative-margin resection; RFA,
radiofrequency ablation; RFS, recurrence-free survival; S, secondary endpoint; TACE, transarterial chemoembolization; TTR, time to recurrence; Tx,
treatment.
6
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