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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 3  |  Page : 797-802

Combination of thermal ablation and activated functional killer cells immunotherapy for cancer: A retrospective study


1 Department of Minimally Invasive Tumor Therapies Center, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences; Graduate School of Perking Union Medical College, China Academy of Medical Sciences, Beijing, China
2 Department of Minimally Invasive Tumor Therapies Center, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China
3 Biotherapy Center, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, China

Date of Submission06-Jan-2021
Date of Acceptance29-Mar-2021
Date of Web Publication9-Jul-2021

Correspondence Address:
Xiaoguang Li
1, Dahua Street, Dongcheng District, Beijing, China. 9, Dongdan Street, Dongcheng District, Beijing
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_26_21

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 > Abstract 


Purpose: The purpose was to evaluate the effect of thermal ablation combined with activated functional killer (AFK) cells immunotherapy for patients with malignant tumors.
Materials and Methods: A cohort of 10 patients with malignancies received thermal ablation combined with AFK cells immunotherapy. Progression-free survival (PFS), overall survival, laboratory test, and postoperative complications were assessed.
Results: The success rate of the combination therapy was 100% and no severe complications occurred. Five patients maintained in PFS (50%) during the follow-up. The median PFS was 11 months (range 3.5–16.75 months). The hemoglobin (P = 0.023), hematocrit (P = 0.034), and lymphocyte ratio (P = 0.023); neutrophil-to-lymphocyte ratio (P = 0.038), neutrophil ratio (P = 0.016), albumin (P = 0.006), and alkaline phosphatase (P = 0.029); CA-125 (P = 0.033); and D-dimer (P = 0.011) changed significant after ablation. Whereas the white blood cell count (P = 0.003), neutrophil count (P = 0.024), lymphocyte count (P =0.003), monocyte ratio (P = 0.008), and eosinophil ratio (P = 0.005) changed significantly after combination therapy. The lymphocytes (P = 0.001) in the surviving patients increased more significantly after treatment. After the combination therapy, the percentage of CD3 + cells (P = 0.016) and CD3+ CD8+ cells (P = 0.002) increased, while CD3-CD16+ CD56+ (P = 0.002) and CD4+/CD8+ (P = 0.016) decreased.
Conclusion: Combination of thermal ablation and AFK cells immunotherapy is a safe and effective method for patients with malignancy. And adoptive immunotherapy with AFK cells may be helpful to prevent recurrence after thermal ablation in patients with advanced cancer.

Keywords: Adoptive immunotherapy, malignant tumors, microwave ablation, radiofrequency ablation


How to cite this article:
Li Y, Li Y, Bie Z, Li B, Ma J, Li X. Combination of thermal ablation and activated functional killer cells immunotherapy for cancer: A retrospective study. J Can Res Ther 2021;17:797-802

How to cite this URL:
Li Y, Li Y, Bie Z, Li B, Ma J, Li X. Combination of thermal ablation and activated functional killer cells immunotherapy for cancer: A retrospective study. J Can Res Ther [serial online] 2021 [cited 2021 Jul 29];17:797-802. Available from: https://www.cancerjournal.net/text.asp?2021/17/3/797/321026




 > Introduction Top


Malignant tumors have become a greater cause of death in the world.[1],[2] Although many new treatments have been invented and many combination therapies have been used,[3] cancer often recurs after treatment.[4] Thermal ablation techniques, including radiofrequency ablation (RFA), microwave ablation (MWA), percutaneous laser ablation, etc., are minimally invasive and widely used for local treatment of solid tumors.[5] In the early stage, it can cure the cancer as surgery in some cases,[6] while in the advanced stage, it can reduce the tumor load and ameliorate clinical symptoms. Autologous activated functional killer (AFK) cell, also known as RetroNectin-activated killer cell, is one of the adoptive immunotherapies.[7] Adoptive immunotherapy is considered to help to reduce the recurrence and metastasis rate of malignant tumors.[8] In this study, we retrospectively analyzed the efficacy, safety, and laboratory examination and imaging data of thermal ablation combined with AFK in the treatment of metastases or multiple tumors.


 > Materials and Methods Top


Ethical approval

This study was approved by the ethics committee of our hospital and carried out following the Helsinki Declaration.

Patients

Inclusion criteria

Recurrent tumors (pathological diagnosis); age≥18 years old; Eastern Cooperative Oncology Group (ECOG) score≤2; normal heart, kidneyand liver function. Patients who have received local treatment previously can participate in this study, but local treatment must be stopped at least 3 months before enrolment.

Exclusion criteria

Extensive metastasis of multiple organs, and the expected survival time < 3 months; any severe and/or uncontrolled disease; severe organ dysfunction; severe infections; allogeneic organ transplantation; pregnancy or lactation.

Data collection

We collected baseline data of all patients from medical records, including demographic characteristics, past medical history, clinical features, tumor characteristics (lesion size, histopathology, staging), thermal ablation (treatment methods, power, duration), laboratory examination indexes (blood routine indicators, liver and renal function indexes, coagulation function indexes, tumor markers, etc.), imaging data (enhanced computed tomography, magnetic resonance imaging, bone scintigraphy, etc.), and previous treatments (surgery, chemotherapy, radiotherapy, targeted therapy, minimally invasive treatment, etc.).

Study design

Each patient had accepted one thermal ablation and more than two times of AFK cell therapy in sequence. The AFK cell therapy was administrated once a month without interruption. The follow-up period for the patients was not <12 months from the date of thermal ablation.

Radiofrequency ablation

Patients who received RFA used the Olympus Celon POWER system (Olympus Corporation, Tokyo, Japan) with the CelonProSurge applicator. The procedure was performed under the guidance of CT. The main steps were as follows. First, the patient was positioned according to the location of the lesion and planned approach. Second, CT images were obtained by scanning with a 5 mm slice thickness. Marked the applicator entry point on the body surface, disinfected local skin, and covered with a sterile towel, then patients received analgesia (10 mg morphine subcutaneous injection), sedation (25 mg promethazine hydrochloride intramuscular injection), and local anesthesia (1% lidocaine 6–10 ml). The number of applicators, approach of applicators placement, radiofrequency power, and length of time were determined according to the size and number of tumors. The applicator was inserted into the center of the lesion along the designed path. Then, another CT was performed to confirm that the functional part was accurately placed in the target lesion and the estimated ablation area could cover the lesion. If necessary, the direction and depth of the applicators could be adjusted to different parts of the tumor to obtain complete ablation. The goal of ablation was to fully cover all therapeutic targets in one treatment, and the ablation range was 5–10 mm beyond the edge of the tumor. After ablation, CT was performed to estimate the ablation area and detect possible complications. Vital signs and potential complications were monitored in the ward for 48 h, including pain at the treatment site, intrahepatic hemorrhage and subcapsular hematoma, liver abscess, and damage to adjacent organs (such as colon perforation, etc.).

Microwave ablation

The instrument used for MWA was made by Nanjing Weijing Medical Equipment Co. Ltd. (Jiangsu, China); the main steps are the same as RFA and 2.5 mm reconstruction for CT images if necessary. According to the treatment site, the possible complications would be detected by CT after treatment. The complications of abdominal ablation were the same as RFA, and the complications of pulmonary ablation included pain, hemoptysis, shortness of breath, and chest tightness. Patients also needed to be monitoring in the ward for 48 h.

Preparation of activated functional killer cells

Fifty milliliters of heparinized peripheral blood was obtained through the antecubital vein from each patient. The initial blood samples were collected before the administration of thermal ablation, and the subsequent blood samples were collected before the AFK cells infusion. Peripheral blood mononuclear cells were isolated from peripheral blood with Ficoll-Hypaque by density centrifugation. And then cultured in a T75 culture bottle (Corning, Corning, USA) which was precoated with OKT3 and CH-296 (TaKaRa Bio, Shiga, Japan), and containing 70 mL GT-T551-H3 (TaKaRa Bio) culture medium with 1% inactivated autologous plasma and 500 U/ml interleukin (IL)-2. After incubated in a 37°C 5% CO2 incubator for 5 days, the cell suspension was transferred to a CultiLifeEva bag (TaKaRa Bio) containing 300 ml of the above-mentioned culture medium continued culturing for 10 days, shaking the bag every 2 days, and adding 1–2 volume of culture medium according to the cell states.

Before infusion, 0.4% Trypan blue (Solarbio, Beijing, China) was used to evaluate the activity of the final cell suspension by dye exclusion test. The possible contamination of bacteria, fungi, mycoplasma, and endotoxin was assessed 2 times during the procedure and 1 time before infusion.

Immunophenotype assay of activated functional killer cells

The immunophenotype of AFK cells was analyzed before infusion. The phenotypes of CD3+, CD3+CD4+, CD3+CD8+, CD3-CD16+CD56+, CD3+CD16+CD56+, and CD4+CD25+ were detected by flow cytometry. The following antibodies were purchased from BD Biosciences (Franklin Lakes, NJ, USA): CD3-APC, CD4-PerCP, CD8-FITC, CD25-PE, CD16-FITC, and CD56-PerCP.

Activated functional killer cells infusion

The production of AFK cells in each culture was not <1010, then divided into 3 times, and infused for 3 consecutive days.

Safety evaluation

Acute and long-term AEs and serious AEs (SAEs) were recorded during the follow-up period, according to the Common Terminology Criteria for Adverse Events version 5.0 of the National Cancer Institute.

Follow-up

The follow-up was calculated from the date of thermal ablation therapy and through outpatient clinic or telephone. The end date of follow-up was March 31, 2020. The changes in blood routine, liver and renal function, tumor markers, coagulation function, and the percentage of peripheral blood lymphocyte subsets were monitored. CT or MR was performed every 3 months to observe the recurrence of the tumor. The progression-free survival (PFS) and overall survival (OS) were recorded from the beginning of thermal ablation therapy until the disease progressed for the first time or died of any cause. The death was confirmed through the registration at the civil affairs department of China.

Statistical analysis

The data are expressed as mean ± standard deviation, median (25th–75th quartile), or number (percentage). For all variables, the Shapiro–Wilk test is used for normal distribution. For descriptive analyses, Pearson Chi-square, Wilcoxon rank-sum tests, McNemar's tests, and paired sample t-tests were used between-group comparisons. PFS and OS were estimated by Kaplan–Meier survival analysis. P < 0.05 was considered significant. Statistical analyses were performed with SPSS version 23.0 (SPSS, Chicago, IL, USA).


 > Results Top


This study included 10 patients who were treated in our department from December 2016 to March 2019, with five women and five men (median age 57.6 years, range 36–82 years). All patients had confirmed malignancy, 4 nonsmall cell lung cancers (NSCLC), 1 colon cancer with colorectal liver metastases, 1 cardial cancer, 1 hepatocellular carcinoma (HCC), 1 esophageal cancer, 1 cholangiocarcinoma, and 1 pancreatic cancer. Except for one patient at the early stage of NSCLC, who had the NSCLC family history and frequently appeared new lesion, all the other patients were at the advanced stage of cancer.

Before this combination treatment, 3 patients underwent radical resection, 1 patient at the early stage received 1-time MWA, and the rest of the patients lost the opportunity of operation because of their condition. All patients relapsed/progressed after previous combined therapy. According to the site of ablation, RFA or MWA was chosen. Pulmonary ablation and most other sites were treated with MWA, and liver thermal ablation was treated with RFA. One patient only completed 2-times AFK transfusion because of illness deterioration, and 4 patients continued AFK therapy during the follow-up.

During at least 12-month follow-up, 3 patients continued to deteriorate and eventually died; 2 patients were found to progress during subsequent reexamination and switched to other treatments; the remaining 5 patients maintained the original treatment after this combination therapy or added AFK cells therapy [the PFS and OS were shown in [Figure 1]]. The median PFS was 11 months (range 3.5–16.75 months). The details of the patient characteristics are shown in [Table 1].
Figure 1: The progression-free survival (a) and overall survival (b) of combination therapy patients in the follow-up period

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Table 1: Patients characteristics

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There are no serious treatment-related adverse events observed in all patients during the follow-up. Only one patient (10.0%) had a pneumothorax and one patient (10.0%) had an infection of the lung by Aspergillus. The pneumothorax was transient and well-controlled by chest tube drainage. The Aspergillus infection was cured with oral antifungal drugs for 1 month. No related complications were found in the rest of the patients.

Imaging evaluation after thermal ablation

The purpose of thermal ablation therapy was to completely ablate the tumor with obvious normal tissue at the edge and no collateral damage. Imaging examination after thermal ablation is very important for evaluating the success of treatment, detecting tumor residue or recurrence, and diagnosing new lesions. In this study, CT scan showed no enhance in the focus indicated complete ablation after thermal ablation, and all tumors were ablated completely.

The assessment of activated functional killer cells

The quantity of AFK cells infused into each patient was (0.834–2.203) ×1010, with an average of 1.381 × 1010.

The quality of AFK cells was evaluated by the activity by the dye exclusion test and the possible contamination of bacteria, fungi, mycoplasma, and endotoxin. The cell viability of AFK cells was more than 90%, and no pollution was found.

Lymphocyte subsets were determined before AFK cells administration. The percentages of CD3+, CD3+CD4+, CD3+CD8+, CD3+CD16+CD56+, CD3-CD16+CD56+, and CD4+CD25+ were respectively 94.65% ± 4.46%, 11.04% ± 3.50%, 83.81% ± 1.56%, 1.00% ± 1.02%, 2.22% ± 3.52% and 17.59% ± 7.72%, respectively [Figure 2].
Figure 2: The lymphocyte subsets before activated functional killer cells administration

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Analysis of the laboratory examination changes

We compared the changes of laboratory examination of patients before and after thermal ablation and found statistical differences in several blood routine indexes: Hemoglobin (P = 0.023), hematocrit (P = 0.034), and lymphocyte ratio (P = 0.023) decreased; neutrophil-to-lymphocyte ratio (NLR; P = 0.038), neutrophil ratio (P = 0.016) increased compared with those before ablation. There was no significant statistical difference in other blood routine indexes. In the biochemical examination, there was a significant statistical difference in the decrease of albumin (P = 0.006) and alkaline phosphatase (P = 0.029) after thermal ablation, but there was no significant difference in other biochemical indicators. CA-125 (P = 0.033) increased after thermal ablation shown significant statistical difference, other tumor markers were lower than before with no significant statistical difference. Compared with preoperative C-reactive protein (CRP) increased, but no significant statistical difference was found. D-dimer (P = 0.011) increased after therapy shown a significant statistical difference, but there was no significant statistical difference in the change of blood coagulation indexes.

We compared the changes of laboratory examination of patients before and after combined treatment. In blood routine test, white blood cell (P = 0.003), neutrophil (P = 0.024), lymphocyte (P = 0.003) increased, monocyte ratio (P = 0.008), eosinophil ratio (P = 0.005) decreased compared with those before treatment shown significant statistical difference, while there was no significant statistical difference in the changes of other blood routine indicators. There was no significant statistical difference in the changes of biochemical routine, tumor markers, blood coagulation, and other laboratory examination.

We also compared the changes in laboratory tests between the surviving patients and the dead patients before and after combination treatment, respectively. The number of lymphocytes (P = 0.001) in the blood routine of the surviving patients increased significantly after treatment, but there was no statistical difference in the increase of lymphocytes in dead patients. There was no significant statistical difference in the other laboratory index changes.

Evaluation of the immunophenotype of peripheral blood lymphocytes subsets

As shown in [Figure 3], the percentage of CD3+, CD3+ CD8+ and CD3+ CD16+ CD56+ cells increased after combination treatment, while CD3+CD4+, CD3-CD16+ CD56+ and CD4+/CD8+ decreased. After combined treatment, the percentage of CD3 + cells increased from 61.18 ± 4.85 to 71.78 ± 8.73 (P = 0.016), and the percentage of CD3+ CD8+ cells increased from 25.42 ± 9.87 to 50.12 ± 9.61 (P = 0.002). CD3-CD16+CD56+ decreased from 20.31 ± 7.21 to 10.10 ± 10.51 (P = 0.002). CD4+/CD8+ decreased from 1.45 ± 0.98 to 0.54 ± 0.34 (P = 0.016). There was no significant difference in the changes of other lymphocyte subsets.
Figure 3: The immunophenotype of peripheral blood lymphocytes subsets before and after combination therapy (*P < 0.05; ***P < 0.001)

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 > Discussion Top


Thermal ablation therapy is more and more widely used in the local treatment of tumors, especially in patients who cannot undergo or refuse surgery. The local treatment causes tumor coagulative necrosis through thermal effect and reduces the tumor load.[9] At the same time, released neoplastic antigens can change the tumor microenvironment and immune status of the body, then stimulate the body to produce an antitumor immune response.[10] This kind of response is weak[11],[12] and cannot control the progression of the tumor sufficiently, so there are many patients still progressed and worsened. And our study shows that adding related systematic treatment, such as adoptive cellular immunotherapy (ACI), will be very valuable. Some studies show that thermal therapy amplifies effects by immunotherapy.[13],[14] It also provides the basis for the development of adjuvant immunotherapy in patients with thermal ablation.

Autologous ACI is a method that infusion autologous active cells to bring more antitumor effector cells to hypoimmunity patients, which can eliminate tumors or control recurrence by relying on autologous immune cells.[15] In a meta-analysis in 2017,[16] ACI significantly improved OS and PFS in NSCLC compared with the control treatment group. A study has confirmed that cytokine-induced killer cell immunotherapy is helpful to clear the minimal residual lesions in HCC patients after TACE and RFA treatment and prevent tumor recurrence.[17] Therefore, ACI is a beneficial method after minimally invasive therapy.

In this study, we retrospectively analyzed the data of cancer patients who received combination therapy in our hospital since 2016. There were no obvious serious complications during the therapy period, which proved the safety of the combination of the above two treatments. Among the subjects, 3 patients had extensive metastasis before, while the combination therapy was administrated at the final stage of the disease. During the follow-up, their condition continued to deteriorate and eventually died. Two patients progressed from disease, and the rest were stable. We compared the changes of laboratory examination between the surviving patients and the demised ones before and after combined treatment, finding the lymphocytes in the blood routine of the surviving patients increased significantly after treatment, but there was no statistical difference in the increase of lymphocytes in the dead patients after treatment. There was no significant statistical difference in the other indicators' changes. All the above shown the outcome of combination therapy on end-stage patients is also very poor, so the timing of combination therapy is very important and should be carried out as early as possible.

For ablation therapy, we chose different ablation methods according to the different sites of the lesions, lung and abdominal lesions chose MWA for the faster ablation speed, and hepatic lesion ablation chose RFA due to the milder mode. At present, studies have confirmed that incomplete ablation can accelerate tumor progress,[18],[19] while complete ablation does not have this reaction. Therefore, we adjusted the ablation duration and power according to the lesion, and the postoperative CT images also showed that the lesion achieved complete ablation, besides, reduced the tumor load of the body. Furthermore, we analyzed the changes in patients' laboratory examinations before and after ablation. Red blood cell, hematocrit, and hemoglobin decreased indicate the potential blood loss after ablation. Alanine aminotransferase and aspartate aminotransferase increased while albumin and alkaline phosphatase decreased after ablation, which revealed the live injury of ablation treatment.[20] The neutrophils ratio, NLR, CA-125, CRP, and D-dimer increased significantly after thermal ablation, which shown the inflammatory response of the body. Therefore, thermal ablation has a significant effect on the body condition of patients, which may not be beneficial.

The output of AFK cells was 0.834–2.203 × 1010, most of the cells were CD3+ T cells, and CD3+CD8+ (Tc) cells were obvious. We analyzed the changes in laboratory examination of patients before and after combined treatment and found that due to AFK cell infusion, the proportion of leukocytes, neutrophils, and lymphocytes increased, while the percentage of monocytes and eosinophils decreased. There was no significant difference in the changes of other blood indexes, suggesting that thermal ablation combined with adoptive immunotherapy of AFK cells was safe in the treatment of advanced tumors. After combined treatment, the levels of CD3+ and CD3+ CD8+ cells in peripheral blood were significantly increased, indicating the enhancement of the antitumor effect. Besides, we found that CD3-CD16+ CD56+ (NK) cells decreased after treatment. Some studies have illuminated the mechanism of hyperthermia enhancing NK cell-mediated tumor killing.[21] We speculated that the CD3-CD16+ CD56+ cells in the AFK cells add the activated original NK cells in the peripheral blood performed the tumor-killing function together just after infusion, so the NK cells in the peripheral blood decreased.


 > Conclusion Top


Based on the results, we concluded that the combination of thermal ablation and AFK cells immunotherapy is safe and effective for patients with malignancy. In addition, the adoptive immunotherapy with AFK cells may be helpful to prevent tumor recurrence after thermal ablation in selected patients.

Limitation

In this preliminary retrospective study, we verified the safety and some efficacy of the combination therapy. But as the small sample size, and the mixed type of cancers, the result was in low statistical power, the real efficacy of thermal ablation combined with AFK cell therapy will be verified in our randomized controlled trial experiments. How the combination therapy works together in the body is also not clear, and we are now doing further research on the mechanism of combination therapy.

Acknowledgment

This study was supported by the Graduate Innovation Fund of Peking Union Medical College (No. 2019-1002-88). The authors thank Mrs. Xiaodong Xu for her guidance of flow analysis.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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