
==== Front
Cureus
Cureus
2168-8184
Cureus
2168-8184
Cureus Palo Alto (CA)

10.7759/cureus.66164
Gastroenterology
Oncology
Combined Immune Therapy Proves Effective in an Advanced Hepatocellular Carcinoma Patient With Poor Liver Reserve: A Case Report
Muacevic Alexander
Adler John R
Nagai Hisashi 12
Chen Hao 3
Karube Ryusuke 4
Koitabashi Yusuke 4
Numata Ouka 4
Yamahara Kenichi 5
1 Human and Environmental Studies, Tokai University, Kanagawa, JPN
2 Oncology, Ginza Phoenix Clinic, Tokyo, JPN
3 Respiratory Medicine, Yokohama City University Hospital, Yokohama, JPN
4 Regenerative Medicine, Ginza Phoenix Clinic, Tokyo, JPN
5 Laboratory of Molecular and Cellular Therapy, Institute for Advanced Medical Sciences, Hyogo Medical University, Hyogo, JPN
Hao Chen chinsmd@gmail.com
5 8 2024
8 2024
16 8 e661645 8 2024
Copyright © 2024, Nagai et al.
2024
Nagai et al.
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License CC-BY 4.0., which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
This article is available from https://www.cureus.com/articles/277474-combined-immune-therapy-proves-effective-in-an-advanced-hepatocellular-carcinoma-patient-with-poor-liver-reserve-a-case-report
There are no effective treatment options for patients with poor performance status and limited liver reserve, classified as Child-Pugh Grade B and C. A 61-year-old man with a prior medical history of hepatitis C virus infection was admitted to the hospital with abdominal distension and significant abdominal ascites. He was diagnosed with stage IVB hepatocellular carcinoma (HCC), characterized by multiple metastases to lymph nodes, lungs, and bones. After receiving combined immune therapy, including dendritic cell therapy targeting WT1 and α-Galactosylceramide, natural killer cells, and Nivolumab, the patient showed significant improvement in HCC and liver reserve function and followed standard treatment. Combined immune therapy is potentially an important option for patients with advanced hepatocellular carcinoma and poor liver reserve function, especially for relatively young patients.

α-galactosylceramide
wt1
natural killer cell
dendritic cell
hepatocellular carcinoma
combined immune therapy
==== Body
pmcIntroduction

The landscape of cancer immunotherapy is constantly evolving with innovative treatments that harness the body's immune system more effectively to combat malignancy. Among these treatments, integrating dendritic cell (DC) vaccines, natural killer (NK) cell therapy, and immune checkpoint inhibitors such as nivolumab presents a promising trifecta of modalities to enhance anti-tumor immune responses [1]. DC vaccines play a central role in inducing a targeted immune response by presenting tumor-specific antigens to T cells, thereby orchestrating an adaptive immune response tailored to the individual's cancer [2]. Wilms' Tumor 1 (WT1) is commonly used to improve the immune profile, potentially contributing to chemotherapy’s long-lasting and sustained effects [3]. Additionally, the usage of α-Galactosylceramide (α-Galcer) will potentially activate the function of natural killer T (NKT) cells [4].

NK and NKT cells complement this by providing a rapid, innate response capable of destroying tumor cells directly through cytotoxic activity [5]. Their function is crucial in targeting cells that might escape the adaptive immune response triggered by the DC vaccine [6]. Adding a third component, nivolumab, an immune checkpoint inhibitor that targets the programmed cell death-1 (PD-1) pathway, further enhances the immune response [7]. Nivolumab works by blocking the inhibitory signals that cancer cells use to suppress immune activity, thereby preventing the 'turning off' of immune cells and enhancing the body’s ability to fight cancer [8]. This checkpoint blockade can potentially restore and amplify innate and adaptive immune responses, making it an ideal complement to DC and NK cell therapies [1]. This case report explores the synergistic potential of combining these therapies in the treatment of advanced hepatocellular carcinoma (HCC), focusing on the biological rationale and clinical outcomes of this multi-modal approach using DC vaccines targeting WT1 and α-Galcer, NK cell therapy, and Nivolumab.

Case presentation

A 61-year-old man with a medical history of hepatitis C virus infection was admitted to the hospital. He presented to the outpatient department with abdominal distension and was admitted emergently due to abundant abdominal ascites of more than 3 liters. Upon examination at the facility, HCC T4N1M1 stage ⅣB (multiple lymph node metastases, multiple lung metastases, and bone metastases) was identified (Figures 1A, 2A). The patient was also in a pronounced state of ascites accumulation due to portal hypertension caused by the tumor. The laboratory findings showed he had a relatively low ratio of lymphocytes, impaired live function, and a high level of tumor markers (Table 1). Given the poor liver reserve, as indicated by a Child-Pugh classification of Grade C, pharmacotherapy proved challenging, leading to the adoption of a palliative care approach.

Table 1 Laboratory findings of the patients before and after the treatment.

WBC: white blood cell; T-Bil: total bilirubin; AST: aspartate aminotransferase; ALT: alanine aminotransferase; CRP: C-reaction protein; PT: prothrombin time; PT-INR: prothrombin time-international normalized ratio; APTT: activated partial thromboplastin time; PIVKA-Ⅱ: protein induced by vitamin K absence-II; AFP: α‐fetoprotein; HBsAg: hepatitis B surface antigen; HCV: hepatitis C virus.

 	Before the treatment	After the treatment	Reference	
WBC	13,600	5,700	3,900～9,700/mL	
Neutrophil	62.5	57.5	37%～72％	
Lymphocytes	10.4	32.2	25%～48％	
Platelets	10.0	6.6	15.3～34.6 ×104//mL	
T-Bil	3.2	1.5	0.4～1.2 mg/dL	
AST	98	74	5～37 U/L	
ALT	60	81	6～43 U/L	
Albumin	2.3	3.0	4.0～5.2 g/dL	
CRP	0.96	0.12	< 0.30 mg/dL	
PT	48.2%	67.9	70～130%	
PT-INR	1.63	1.30	0.85～1.15 s	
APTT	29.6	31.2	24～34 s	
PIVKA-Ⅱ	7283	19	< 40 mAU/mL	
AFP	³70000	315.6	< 10 ng/mL	
HBsAg	Negative	Negative	Negative	
HCV antibody	Positive	Positive	Negative	

One week after the diagnosis, the patient arrived at our clinic in a wheelchair. Given his poor performance status (PS) and the extensive volume of HCC, a relatively intensive immunotherapy plan was designed. Apheresis was conducted the following day, and two weeks later, the DC vaccine (targeting WT1 and α-Galcer) along with Nivolumab was administered weekly for the first four courses, then biweekly for a total of seven courses. Additionally, a combination of NK cell therapy was administered every three weeks, totaling three courses. After the first three courses of combination immune chemotherapy, the patient's PS improved, and his abdominal tension was significantly alleviated. At the end of the sixth course of combined immune therapy, the patient was referred to the previous hospital to reassess the liver reserve, which had improved to Grade A in the Child-Pugh classification. CT scans showed that the size of both primary tumors and metastases was reduced, and abdominal ascites had disappeared, indicating a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1 (Figures 1B, 2B). Tumor markers also decreased significantly after the treatment, with the protein induced by vitamin K absence-II returning to a normal range. The general condition of white blood cells and the ratio of lymphocytes also improved to a normal range. Based on the improvement in liver reserve, standard chemotherapy with Atezolizumab plus Bevacizumab was initiated after the seventh course of combined immune therapy.

Figure 1 Initial status of the patients at administration, as shown by a CT scan of the coronal plane.

CT: computed tomography.

Figure 2 Improved condition after combined immune therapy, as the CT of the transverse plane shows.

CT: computed tomography.

Discussion

This case report illustrates a notable instance where immune combination therapy was highly effective for a patient with HCC. There are no effective treatment options for patients with poor PS and limited liver reserve, a particularly harsh reality for younger individuals [9]. In this case, the use of immune combination therapy not only enhanced anti-tumor effects but also improved PS and liver reserve. Standard treatments were previously considered unsuitable and are now possible. Immune combination therapy may be regarded as an essential option for patients unfit for standard therapies recommended by guidelines.

Traditional chemotherapy agents are recognized for selectively targeting and destroying rapidly proliferating cancer cells. However, it is increasingly understood that their effectiveness also stems from their capacity to boost anticancer immunity [10]. This occurs either through releasing immune-activating molecules from dying tumor cells or indirectly impacting other immune cells. DCs are harvested from the patient and modified ex vivo to promote an immune response aimed at tumor eradication. Numerous strategies are being tested to enhance long-term anti-tumor responses by DCs. Furthermore, combining DC vaccines with other treatments, such as chemotherapy and monoclonal antibodies, could lead to more effective cancer therapies [11]. NK cells are crucial for identifying and attacking various stressed cells, including tumor and virus-infected cells. NK cells perform direct attacks on these targets and contribute to orchestrating and sustaining broader immune responses [12]. Blocking immune checkpoint pathways, which cancer cells use to evade detection as standard body components, is a promising strategy for achieving anti-cancer immunity. Numerous agents are undergoing extensive clinical evaluation, as discussed in several review articles [13].

However, immune combination therapy has several limitations. First, its high cost has hindered widespread clinical usage. Second, the conditions for cell incubation vary with each sample in different cases, influenced by various factors related to the patient's condition. Third, there is no standardized protocol for the interval and dosage of incubated cells across different cancers, even within the same cancer type.

Conclusions

An advanced HCC patient, initially deemed unsuitable for standard treatment, demonstrated remarkable improvement after receiving combined immune therapy, which was subsequently followed by standard treatment. This combined immune therapy represents a potentially significant treatment option for patients with advanced hepatocellular carcinoma and poor liver reserve function. It is particularly promising for relatively young patients, offering hope and improved outcomes where conventional treatments might not be viable.

Disclosures

Author Contributions

Human subjects: Consent was obtained or waived by all participants in this study.

Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following:

Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work.

Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.

Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

Concept and design:  Hao Chen, Hisashi Nagai, Yusuke Koitabashi, Kenichi Yamahara, Ouka Numata, Ryusuke Karube

Acquisition, analysis, or interpretation of data:  Hao Chen, Hisashi Nagai, Yusuke Koitabashi, Kenichi Yamahara, Ouka Numata, Ryusuke Karube

Drafting of the manuscript:  Hao Chen, Yusuke Koitabashi, Kenichi Yamahara, Ouka Numata

Critical review of the manuscript for important intellectual content:  Hao Chen, Hisashi Nagai, Yusuke Koitabashi, Kenichi Yamahara, Ouka Numata, Ryusuke Karube
==== Refs
References

1 Late-stage ovarian cancer with systemic multiple metastases shows marked shrinkage using a combination of Wilms' tumor antigen 1 (WT1) dendritic cell vaccine, natural killer (NK) cell therapy, and Nivolumab Cureus Nagai H Karube R 0 16 2024
2 Dendritic cell-based cancer immunotherapy for colorectal cancer World J Gastroenterol Kajihara M Takakura K Kanai T 4275 4286 22 2016 27158196
3 WT1 dendritic cell vaccine therapy improves immune profile and prolongs progression-free survival in end-stage lung cancer Cureus Nagai H Karube R 0 15 2023
4 NKT-licensed in vivo dendritic cell-based immunotherapy as cellular immunodrugs for cancer treatment Crit Rev Oncog Fujii SI Shimizu K 45 61 29 2024 38421713
5 NK, NKT and invariant-NKT cells in tumor draining lymph nodes of patients with breast cancer Iran J Immunol Rezaeifard S Safaei A Talei A Faghih Z Erfani N 291 298 16 2019 https://pubmed.ncbi.nlm.nih.gov/31885006/ 31885006
6 Breakthroughs in cancer immunotherapy: an overview of T cell, NK cell, Mφ, and DC-based treatments Int J Mol Sci Lee S Kim TD 17634 24 2023 38139461
7 PD-1/PD-L1 immune checkpoint: potential target for cancer therapy J Cell Physiol Dermani FK Samadi P Rahmani G Kohlan AK Najafi R 1313 1325 234 2019 30191996
8 Nivolumab plus ipilimumab combination therapy in cancer: current evidence to date Int Immunopharmacol Nikoo M Rabiee F Mohebbi H 109881 117 2023 37012882
9 AGA Clinical Practice Guideline on systemic therapy for hepatocellular carcinoma Gastroenterology Su GL Altayar O O'Shea R 920 934 162 2022 35210014
10 Immunostimulation with chemotherapy in the era of immune checkpoint inhibitors Nat Rev Clin Oncol Galluzzi L Humeau J Buqué A Zitvogel L Kroemer G 725 741 17 2020 32760014
11 Dendritic cell therapy in cancer treatment; the state-of-the-art Life Sci Sadeghzadeh M Bornehdeli S Mohahammadrezakhani H 117580 254 2020 32205087
12 Natural killer cell therapies Nature Vivier E Rebuffet L Narni-Mancinelli E Cornen S Igarashi RY Fantin VR 727 736 626 2024 38383621
13 Immune checkpoint inhibitors: basics and challenges Curr Med Chem Li B Chan HL Chen P 3009 3025 26 2019 28782469
