Long-term tumor suppression in cholangiocarcinoma using cytokine-induced killer cell therapy and high-dose vitamin C: a case report
Article information
Abstract
This case study explores the effectiveness of autologous cytokine-induced killer (CIK) cell-based immunotherapy in a 49-year-old male patient with inoperable stage IIIb cholangiocarcinoma, characterized by high levels of the sodium-dependent vitamin C transporter-2 (SVCT2) in immune cells. Despite an initial lack of tumor reduction following chemotherapy, the patient showed a significant decrease in tumor markers and stabilization of the tumor after undergoing radiation and proton therapy. Subsequently, CIK cell therapy, combined with high-dose vitamin C, was administered 52 times over 6 years. The patient’s tumor size reduced, and no cancer activity was detected for 7 years and 10 months post-diagnosis, indicating a successful long-term outcome without recurrence. This study suggests that CIK cell therapy, particularly in patients with elevated SVCT2 levels, may offer a promising adjuvant treatment for cholangiocarcinoma and potentially other cancers. Further research is needed to validate SVCT2 as a biomarker for the effectiveness of CIK cell therapy.
INTRODUCTION
Despite a relatively low incidence rate of 7.8 per 100,000, intrahepatic bile duct cancer has a 5-year survival rate of only 15.9%, reflecting a poor prognosis in Korea [1]. The main treatment for cholangiocarcinoma is surgery, but in cases where surgery is not possible, only chemotherapy and radiation therapy can be used. Unfortunately, given the limited efficacy of chemotherapy in cholangiocarcinoma, alternative therapeutic strategies are required, with cytokine-induced killer (CIK) cell therapy emerging as a potential approach to augment immune-mediated tumor control [2]. This treatment involves culturing immune cells for 2 weeks before re-administering them to the patient. However, there is no data indicating which patients would benefit most from this therapy. For immune cell therapy to be effective, vitamin C must enter the immune cells in large quantities [3]. For vitamin C to enter the immune cells, the level of sodium-dependent vitamin C transporter-2 (SVCT2), a vitamin C transporter, must be high in these cells [4]. This study reports a case of CIK cell treatment following radiotherapy in a patient with biliary tract cancer with high SVCT2 levels in immune cells, along with a literature review. Written informed consent was obtained from the patient for this publication.
CASE REPORT
The patient, a 49-year-old man with no prior history of surgery or underlying medical conditions, presented to the hospital in October 2016 with upper abdominal pain. Initial imaging and evaluation confirmed a diagnosis of stage IIIb cholangiocarcinoma involving the portal vein. Percutaneous transhepatic biliary drainage was performed, and biopsy confirmed the diagnosis. Computed tomography (CT) and magnetic resonance imaging revealed a 3.5 cm tumor within the portal vein (Fig. 1).
Abdominal computed tomography (CT) scan and magnetic resonance imaging. (A) CT findings at the time of diagnosis in 2016. (B) Magnetic resonance, abdomen revealed a type IV Klatskin tumor at the hepatic hilum, with invasion of the left portal vein and both hepatic arteries.
From November 21, 2016, to March 3, 2017, the patient underwent five cycles of chemotherapy, comprising 1,900 mg of gemcitabine and 50 mg of cisplatin per cycle. Following treatment, the carbohydrate antigen 19-9 (CA19-9) level decreased from 160 U/mL pre-chemotherapy to 55 U/mL after the fifth cycle, although the tumor size on CT imaging remained unchanged. The patient opted to discontinue chemotherapy and proceeded with radiation and proton therapy from March 23 to April 17, 2017. Treatment included 36 Gy of intensity-modulated radiation therapy delivered in 12 sessions to address hepatic vascular invasion and 25 Gy of proton beam therapy delivered in five sessions targeting the primary bile duct site. Posttreatment evaluation revealed no change in tumor size but a further reduction in CA19-9 levels to 32 U/mL (Table 1).
The results of tumor marker test
From May 2018 to July 2024, the patient received a total of 52 sessions of CIK cell therapy alongside weekly intravenous administration of 70 g of vitamin C. Testing of the SVCT2 in immune cells (natural killer [NK] cells, T cells, dendritic cells) revealed elevated levels of 6.85 ng/mL. Imaging in 2023, including positron emission tomography-CT and abdominal CT, demonstrated a reduction in tumor size to 2.5 cm with no evidence of metabolic activity, suggesting an inactive tumor state (Fig. 2). Surgical options, including left hepatic lobectomy and pylorus-preserving pancreaticoduodenectomy, were considered but deferred due to high intraoperative bleeding risk and the patient’s preference against surgery. The patient remains under surveillance, with surgery to be reconsidered only if stent occlusion occurs and the patient consents. The patient’s cancer has remained stable and without recurrence for 7 years and 10 months since diagnosis. These findings suggest that the combined administration of CIK cell therapy and high-dose intravenous vitamin C, following radiation and proton therapy, may have contributed to long-term suppression and eradication of the patient’s cancer.
Abdominal CT scan and PET-CT whole body scan. (A, B) Current CT findings in 2023, showing tumor regression posttreatment. (C, D) Follow-up PET-CT confirmed a diagnosis of inactive cancer. PET-CT, positron emission tomography-computed tomography.
DISCUSSION
Since cholangiocarcinoma is often found in an advanced stage at the time of diagnosis, surgery is often not possible, so the prognosis is very poor [5]. Recently, an immunotherapy drug called Imfinzi has been developed, which has improved treatment results compared to existing treatments. According to data published by Oh et al. [6], the 2-year survival rate increased in the group treated with durvalumab in combination with existing chemotherapy drugs (24.9% vs. 10.4%, P<0.001) and the objective response rate also improved (26.7% vs. 18.7%) compared to the group treated with only existing chemotherapy drugs. Although treatment results have improved with the use of durvalumab compared to previous therapies, they are not yet fully satisfactory. Cholangiocarcinoma is an immunogenic tumor. Compared to other solid tumors, it is characterized by a small number of tumor parenchymal cells and a large number of tumor stromal cells [7]. The tumor microenvironment in cholangiocarcinoma is predominantly regulated by inflammatory processes and a high presence of immune cells, including T and B lymphocytes, macrophages, neutrophils, and NK cells. These immune cells play a critical role in recognizing subtle differences between tumor and normal cells. Through this detection, they signal T-lymphocytes, which are key components of the immune system, to initiate and regulate the adaptive immune response, thereby contributing to immune surveillance and potential tumor control [8]. On the other hand, tumor-infiltrating lymphocytes in the adaptive immune response of cholangiocarcinoma are a very heterogeneous population, including CD8+ T cells, CD4+ T cells, B cells, and Tregs [9]. They play an important role in cholangiocarcinoma immune surveillance and tumor cell removal. These results suggest that CIK cell therapy has shown potential as a cancer treatment over the years.
Numerous studies have demonstrated the efficacy of CIK cell therapy across various cancers, including lung, kidney, breast, pancreatic, and liver cancers [10–13]. In liver cancer, CIK cell therapy has been shown to reduce recurrence rates and improve survival, particularly with 16 administrations following hepatectomy [2]. A phase 3 randomized controlled trial further reported that CIK cells enhance immune function in patients with hepatocellular carcinoma, reducing recurrence rates. Notably, in patients receiving curative treatment for hepatocellular carcinoma, adjuvant CIK cell immunotherapy led to significant improvements in recurrence-free survival and overall survival that were sustained for over 5 years, even without additional immunotherapy [14]. In gastric cancer, the combination of CIK cell therapy with chemotherapy significantly prolonged survival and reduced mortality risk, with greater therapeutic benefits observed with increased treatment frequency [15].
Furthermore, high-dose intravenous vitamin C has been found to selectively generate hydrogen peroxide, inducing oxidative stress that damages cancer cells while sparing normal tissues. This mechanism depletes nicotinamide adenine dinucleotide (NAD+) and adenosine triphosphate, disrupting cancer cell metabolism and inducing cell death. Vitamin C also inhibits epithelial-mesenchymal transition, alters microtubule dynamics by increasing α-tubulin acetylation, and promotes collagen synthesis in the tumor stroma, collectively suppressing tumor growth and metastasis. These multi-targeted actions, combined with its low toxicity, underscore its potential as a complementary therapy in cancer treatment.
However, there are currently limited studies identifying which patients would benefit most from CIK cell therapy, and no established biomarkers. This paper is the first to identify SVCT2, a vitamin C transporter in NK and T cells, as a potential biomarker. SVCT2 facilitates vitamin C uptake into immune cells, enhancing their activity. Culturing highly active immune cells may lead to more effective cancer eradication. While further research is needed, SVCT2 holds promise as a predictive marker for immunotherapy, offering a targeted approach to improving treatment outcomes.
Notes
No potential conflict of interest relevant to this article was reported.
FUNDING
None.