Trial Title:
Valuation of the Safety and Efficacy of Combination of Cryoablation and Dendric Cell/Cytokine-induced Killers Cells Treatment for Advanced Liver Cancers
NCT ID:
NCT05622825
Condition:
Advanced Liver Cancers
Conditions: Official terms:
Liver Neoplasms
Conditions: Keywords:
DC-CIK
Cryoablation
Advanced Liver Cancers
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Not yet recruiting
Study design:
Allocation:
N/A
Intervention model:
Single Group Assignment
Intervention model description:
Patients must receive 2 DC/AT hepatic artery infusion and be treated with cryoablation
technique.
Phase Ⅰ The first 3 subjects were enrolled by Sequential enrollment. The next subject can
be enrolled only after the first subject has completed the return transfusion and the
safety assessment (V7). After the sixth subject completes the safety assessment (V7), the
next nine subjects can be enrolled in phase IIA of the trial to evaluate the efficacy of
the trial. If less than two of the first six subjects have a Common Terminology Criteria
for Adverse Events (CTCAE) v5.0 level 3 or higher adverse event related to the test drug
Phase Ⅱ Phase IIA to evaluate the efficacy and implementation. However, if two of the
first six subjects have a Grade 3 or higher trial drug-related adverse event or one or
more deaths, the trial will be terminated immediately and all cell product
process-related factors in this trial will be fully investigated.
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Biological
Intervention name:
DC-CIK
Description:
To explore the therapeutic effect and safety of cryoablation combined with autologous
DC-CIK (through hepatic artery infusion, HIA) for patients with advanced liver cancers
Arm group label:
cryoablation combined DC-CIK
Summary:
The treatment of liver cancer needs integrated medical strategies, including surgery,
chemotherapy, target therapy, radiotherapy, and immunotherapy. According to the patient's
condition to develop a personalized and best treatment plan. Cryoablation can produce
osmotic shock through repeated freeze-thaw to cause tumor cell necrosis, and release
tumor antigens to activate anti-tumor immune responses. Immune cell therapy is an
emerging field across cancer types in current cancer treatment. This study desired to
combine cryotherapy and cellular immunotherapy to achieve the effect of tumor control. In
recent years, cancer treatment studies have showed that cryoablation combined with immune
cell therapy can play a good auxiliary effect and improve the cancer treatment efficacy
significantly.
This trial study is a single center, single-arm, non-blind open-label human clinical
trial. To explore the therapeutic effect and safety of cryoablation combined with
autologous DC-CIK (through hepatic artery infusion, HAI) for patients with advanced liver
cancers. The DC-CIK biologics are provided by BOHUI Biotech company. Their core
technology (including clinical treatment and cell culture techniques) was transferred
from Dr. Hasumi who is a Japanese clinician and this technical founder.
Detailed description:
The World Health Organization's International Agency for Research on Cancer (IARC) has
released the latest global cancer burden data for 2020, which shows that 19.3 million new
cancer cases happened and nearly 10 million deaths occurred in 2020. Currently, one in
five people of the world will have cancer in their lifetime, and one in eight men and one
in 11 women will die of cancer. According Taiwan Cancer registry introduction from
Ministry of Health and Welfare in 2017, the number of new cancer cases was 111,684, 5,852
more people than in 2015. Liver cancer, in particular, ranks fourth in the cancer
rankings. The main causes of liver cancer are hepatitis B, hepatitis C, or cirrhosis of
the liver caused by alcohol. Other causes include Aspergillus flavus toxin, non-alcoholic
fatty liver disease and liver aspirates etc.
Immune cell therapy is an emerging field in the treatment of advanced liver cancer. Many
types of immune effector cells such as lymphokine-activated killer (LAK) cells, dendritic
cells (DC), tumor infiltrating lymphocyte (TIL) cells, cytokine-induced killer (CIK)
cells, and lymphocyte-activated lymphocyte (LAK) cells are used to treat advanced liver
cancer. CIK cells have been developed for immunotherapy applications. CIK cells such as
CD3+CD56+ cells, CD3+CD56- cells and CD3-CD56+ cells, have the ability to kill tumors
directly by demonstrating the non-restrictive cytolytic effect of MHC, similar to the
function of general T cells. CIK cells bind to LFA-1 ligands on tumor cells through
LFA-1, resulting in tumor cell killing, and then binding of the receptor to its ligand on
NK cells initiates a downstream cell signaling pathway and further activates CIK cells
for tumor cytotoxicity. Finally, CIK cells activate the signaling pathway via Fas-FasL
and induce apoptosis in cancer cells. DCs are differentiated from hematopoietic stem
cells in the bone marrow, often in the form of monocytes, which differentiate into mature
dendritic cells in response to cytokine stimulation. After tumor-associated antigen (TAA)
phagocytosis, antigens are treated by two pathways, the cytosolic pathway and vacuolar
pathway, by which they are processed into peptides and loaded onto the major
histocompatibility complex class I(MHC I). Then the TAA-MHC I complex is delivered to the
DC surface. When DC-presenting TAAs migrate and reach the lymph nodes, they are able of
priming T cells and prompting anti-tumor immunity. Dendritic cells are efficient
activators of naïve T cells and are potent APCs. They play a central role in
immune-mediated cancer elimination through antigen presentation and T-cell priming. More
recently, they have been combined to form DC-CIK cell therapy, which is a combination
immunotherapy where DC and CIK cells are cultured together. In terms of therapeutic
mechanism, dendritic cells are specialized antigen-presenting cells, and mature dendritic
cells can present tumor antigens via the MHC-I pathway to effectively counteract the
immune escape mechanism of tumor cells. The specific tumor-killing effect of CIK is
further enhanced. Many studies have shown that treating cancer patients with DC-CIK cells
significantly prolong the survival time and enhance the immune function of the patient.
Recent trends in cancer treatment have confirmed that when cryoablation of tumors is
combined with immune cell therapy, it can have a good complementary effect and
significantly improve the efficacy of cancer treatment. It is believed that cryotherapy
causes necrosis of tumor cells through the physical changes of osmotic shock produced by
repeated freezing and thawing, which in turn releases tumor antigens and activates
anti-tumor immune responses. A retrospective study conducted in 2013 in patients with
stage IV lung cancer investigated the efficacy of cryoablation combined with immune cell
DC-CIK and showed that cryoablation with DC-CIK significantly prolonged the overall
survival (OS) of patients. The results of the 2017 clinical trial showed that
cryoablation with NK cell therapy improved the clinical response rate and disease control
rate (DCR) of patients with advanced lung cancer, with the proportion of patients with PR
(63.3% vs. 43.3%, P<0.01) and disease control rate ( The results of the clinical trial in
advanced hepatocellular carcinoma showed that among 61 patients admitted from 2015 to
2017, cryoablation with NK immunotherapy significantly prolonged the progression free
survival (PFS) of patients (9.5%). (PFS) (9.1 months vs. 7.6 months, P=0.0107), response
rate (60% vs. 46.1%, P<0.05) and disease control rate (85.7% vs. 69.2%, P<0.05).
The trial was designed as a single-arm, uncontrolled, open-label, non-random assignment
design. The efficacy and safety of hepatic artery infusion with autologous DC-CIK immune
cells before and after ablation of liver tumors using cryoablation technique in patients
with advanced liver cancer was investigated. The DC-CIK immune cell therapy technology
was developed in collaboration with Bohui Biotech, and the core cell technology was
transferred from Dr. Hasumi autologous immune cell therapy in Japan. The program will
track the changes in tumor size and tumor index before and after treatment, and conduct
safety assessment to evaluate the safety and efficacy of this trial treatment.
During the clinical trial, peripheral blood will be collected from patients for
exploratory index analysis to complement the clinical evaluation results. According to
the results of the clinical study in 2013, patients with stage IV solid cancer who had
failed standard treatment had increased CD8+CD56+ cell populations after autologous
immune cell therapy by Dr. Hasumi in Japan and continued to be followed up until one year
later. In 2019, a study also showed that disease control was lower in the group of
patients with liver cancer with high free DNA concentrations treated with sorafenib than
in the group with low free DNA concentrations. The whole-genome sequencing of cell-free
DNA (cfDNA) to obtain copy number alteration (CNA) profiles can be used as predictors of
sorafenib treatment outcome. Therefore, in this clinical trial, blood samples were taken
from patients before and after treatment, and the distribution of immune cell populations
and changes in cell-free DNA (cfDNA) in blood were analyzed separately by separating the
buffy coat and plasma using a density gradient centrifuge, and using the Qubit 2.0
Fluorometer. The qubit dsDNA High Sensitivity assay kit (Life Technology, Carlsbad, CA,
USA) was used to quantify the amount of free DNA and to detect the copy number of free
DNA, and to analyze the free DNA to find out the biomarkers that can be used for
treatment effect tracking.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Patients aged between 20 and 80 years old.
2. Patients with advanced stage hepatocellular carcinoma or advanced stage hepatic
metastasis derived from extrahepatic primary carcinoma, who are judged as advanced
stage by clinical criteria (The Eighth Edition AJCC Cancer Staging Manual) through
pathology and imaging reports.
3. Patients who have been evaluated by a physician for benefits and risks and are no
longer considered suitable for previous third-line therapies will be included in
this trial.
4. There is at least one target lesion larger than 1.0 cm that can be measured by MRI
or CT and is appropriately located for cryoablation by imaging.
5. Child-Pugh class (A or B).
6. Adequate bone marrow function (white blood cell count > 2x109/L, platelet count >
5x1010/L).
7. coagulation function: prothrombin time (PT), activated partial thromboplastin time
(APTT) ≤ 1.5 times the upper limit of normal
8. renal function: blood creatinine concentration (creatinine) < 1.5 mg/dL .
9. Karnofsky Performance Status (KPS) score70 -10.
10. maximum tumor diameter ≤ 5 cm
11. number of tumors ≤ 5
12. Survival period greater than 3 months as predicted by the physician.
Exclusion Criteria:
1. Tumor size >5 cm in diameter or tumor number >5.
2. not suitable for cytarabine or cryoablation as determined by the trial physician.
3. Blood screening for any of the following viral infections: human immunodeficiency
virus, human T-lymphotropic virus, syphilis, hepatitis B virus, hepatitis C virus,
cytomegalovirus IgM antibody positive, etc.
4. Previous treatment prior to screening: Chemotherapy or radiation therapy must be
completed before 3 weeks of screening to avoid systemic immune responses interfering
with the immune cell therapy. If participating in clinical trials of other biologic
agents or immunotherapy, at least 4 weeks of screening is required.
5. Patient is acutely or chronically infected or in acute cytomegalovirus attack at the
time of screening.
6. Patients with level 3 hypertension, or patients with severe coronary disease.
7. patients with autoimmune disease.
8. patients who are pregnant, breastfeeding, or unable to use effective contraception.
Gender:
All
Minimum age:
20 Years
Maximum age:
80 Years
Healthy volunteers:
No
Start date:
January 2023
Completion date:
December 2024
Lead sponsor:
Agency:
National Taiwan University Hospital
Agency class:
Other
Source:
National Taiwan University Hospital
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05622825
