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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

DC-CIK

Kai-Wen Huang, MD, PhD

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.

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.

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.

Valuation of the Safety and Efficacy of Combination of Cryoablation and Dendric Cell/Cytokine-induced Killers Cells Treatment for Advanced Liver Cancers

Evaluation of the Safety and Efficacy of Combination of Cryoablation and Dendric Cell/Cytokine-induced Killers Cells Treatment for Advanced Liver Cancers

Evaluation of the treatment outcome using computed tomography (CT or PET/CT) or magnetic resonance imaging (MRI) to facilitate comparison of pre- and post-treatment differences. Response Evaluation Criteria in Solid tumor (RECIST criteria) will be used to evaluate the treatment effect of target lesions after treatment. The RECIST criteria will calculate Disease Control Rate.

Pre- and post-treatment Eastern Cooperative Oncology Group (ECOG) measures changes in values. The overall physical health and quality of life is scored on normal, no complaints(0) to dead(5)

Pre- and post-treatment Cancer Quality of Life Questionnaire (EORTC QLQ- C30 Chinese version 3) measures changes in values. The overall physical health and quality of life is scored on a 7-point scale from very poor (0) to very good (7)

National Taiwan University Hospital

Gland and Hormone Related Diseases

Rare Diseases

Pancreatic Neoplasms

Endocrine Gland Neoplasms

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Antineoplastic Agents

Antirheumatic Agents

Anti-Infective Agents

Cyclophosphamide

Hydroxychloroquine

1x10\^9-5x10\^10 in vitro expanded autologous TILs will be infused i.v. to patients with advanced hepatobiliary-pancreatic cancers after NMA lymphodepletion treatment with hydroxychloroquine(600mg,single-dose) and cyclophosphamide.

Adoptive transfer of 1x10\^9-5x10\^10 autologous TILs to patients i.v. in 30-120 minutes.

Tumor Infiltrating Lymphocyte

Clinical GC

Jun Li, Doctor

This study is to investigate the safety and efficacy of tumor infiltrating lymphocyte (TIL) therapy in patients with advanced hepatobiliary-pancreatic cancers. Autologous TILs are expanded from tumor resections or biopsies and infused i.v. into the patient after NMA lymphodepletion treatment with hydroxychloroquine(600mg,single-dose) and cyclophosphamide.

Study on TIL for the Treatment of Advanced Hepatobiliary-Pancreatic Cancers

A Clinical Study on TIL for the Treatment of Advanced Hepatobiliary-Pancreatic Cancers

To characterize the safety profile of GC101 TIL in patients with advanced hepatobiliary-pancreatic cancers as assessed by incidence of adverse events.

Proportion of patients with response per Response Evaluation Criteria in Solid Tumors (RECIST v1.1):

ORR (proportion of patients) = # with CR + # with PR / # with CR + # with PR + # with SD + # with PD.

( Except baseline evaluation within 28 days before TIL infusion，PET/CT scan will be performed at 6 weeks after TIL infusion, and than every 6 weeks for 6 months, and then every 6 months after that for up to 3 years)

Percentage of patients that meet CR, PR and SD criteria set in this study according to RECIST v1.1： DCR (proportion of patients) = # with CR + # with PR + # with SD / # with CR + # with PR + # with SD + # with PD.

The time length between the first confirmed objective response per RECIST 1.1 to the GC101 TIL treatment and the subsequent disease progression per RECIST 1.1

The time length between GC101 TIL infusion and confirmed subsequent disease progression according to RECIST 1.1

The length of time from the date of the start of GC101 TIL treatment that the patients are still alive.

Comparison of patients' quality of life before and after GC101 TIL treatment as assessed by the EORTC QLQ-30 (V3.0).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Valuation of the Safety and Efficacy of Combination of Cryoablation and Dendric Cell/Cytokine-induced Killers Cells Treatment for Advanced Liver Cancers	NCT05622825	Advanced Liver ...	DC-CIK	20 Years - 80 Years	National Taiwan University Hospital
Valuation of the Safety and Efficacy of Combination of Cryoablation and Dendric Cell/Cytokine-induced Killers Cells Treatment for Advanced Liver Cancers	NCT05622825	Advanced Liver ...	DC-CIK	20 Years - 80 Years	National Taiwan University Hospital
Study on TIL for the Treatment of Advanced Hepatobiliary-Pancreatic Cancers	NCT05098197	Advanced Liver ... Tumor Infiltrat... Treatment Side ... Effects of Immu... Advanced Pancre...	Tumor Infiltrat...	18 Years - 75 Years	Shanghai Juncell Therapeutics

Spots Global Cancer Trial Database for advanced liver cancers