MAGE3 and Survivin activated dendritic cell immunotherapy for the treatment of non-small cell lung cancer

  • Authors:
    • Dong Li
    • Song He
  • View Affiliations

  • Published online on: March 28, 2018     https://doi.org/10.3892/ol.2018.8362
  • Pages: 8777-8783
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Abstract

Dendritic cell (DC) immunotherapy is an optimal cancer treatment, resulting in its emergence as a therapeutic choice; however, there are limited studies investigating dual antigen‑pulsed DC immunotherapy in non‑small cell lung cancer (NSCLC). In order to determine the effect of a recombinant melanoma‑associated antigen (rMAGE‑3) and recombinant Survivin (rSurvivin) peptide‑pulsed DC immunotherapy in patients with NSCLC, the present clinical study was performed. DC immunotherapy was generated from the monocytes of patients with NSCLC and primed with rMAGE‑3 and rSurvivin peptides. The present open‑label, non‑randomised study enrolled 16 patients with histologically confirmed stage I‑IIIB NSCLC between December 2013 and October 2014. A prime immunotherapy (9.1x107 cells/dose) and a single boost (8.2x107 cells/dose) were administered 1 month apart intradermally and the patients were evaluated for immunological and clinical response. DC immunotherapy was well tolerated, with no serious adverse events. There was a single incidence of grade 1 fever, chills and fatigue. Out of the 16 patients enrolled, 11 patients showed stable disease and 5 showed disease progression. There was a significant increase in IFN‑γ expression on day 60 vs. day 0 (P=0.048). An increasing trend in the mean cluster of differentiation (CD)4:CD8 values of day 30 and day 90 was observed, but this was not significant. The present study established that DCs primed with rMAGE‑3 and rSurvivin may be used in NSCLC treatment. However, a larger study is required to address prominent issues, including secretion of immunosuppressive cytokines and mechanisms of tumour escape from immune surveillance. Several factors associated with the manufacturing and quality of immunotherapy also require standardisation.

Introduction

In total, 80–85% of all patients with lung cancer are diagnosed with non-small cell lung cancer (NSCLC), resulting in NSCLC being the most common type of lung cancer (1). In addition, NSCLC has remained a crucial cause of mortality in patients with carcinoma, despite notable advances in early diagnosis and treatment modalities. In the light of the discovery of dendritic cells and current approaches in two major areas, tumour-associated antigens (TAAs) and adoptive cellular targeting, immunotherapy has resulted in an improved prognosis for the treatment of patients with NSCLC at an advanced stage of disease (2). Among the numerous immunotherapies, dendritic cell (DC)-based adoptive immunotherapy has emerged as the most viable option for such patients. DCs are professional antigen-presenting cells that efficiently activate T lymphocytes by presenting the antigens to immature cluster of differentiation (CD)4+ cells via major histocompatibility complex (MHC) class II and CD8+ cells through MHC class I (3,4). Studies have reported that DCs may be generated from autologous monocytes (CD14+ cells condensed by apheresis) by making use of a culture medium that is complimented with interleukin (IL) 4, granulocyte-macrophage colony-stimulating factor (GM-CSF) or IL-13 (14) and pulsed ex vivo with TAAs to elicit a potent T cell-mediated immune response and protect against additional tumour challenges (58).

However, collective data on the use of dendritic cell-based immunotherapy for the treatment of NSCLC are limited, and to the best of our knowledge, none of the previously reported clinical trials have exclusively evaluated DC immunotherapies in NSCLC (9,10). Studies have suggested that Survivin and MAGE-3 are overexpressed in NSCLC and may play a vital role in tumourigenesis (11,12). Therefore, the present study was performed to identify the immunological response along with the efficacy and harmlessness of the restorative vaccination using autologous DCs pulsed with recombinant melanoma-associated antigen (rMAGE-3) and recombinant Survivin (rSurvivin) peptide in patients with NSCLC.

Materials and methods

Sample study and design

A total of 16 NSCLC patients were enrolled in the present open-label non-randomised study. All patients had histologically-confirmed diagnoses of stage I–IIIB disease. Patients that had stable disease at the time of screening and had completed definitive therapy (surgical, medical or multimodal) were eligible to participate in the present study. The Ethics Committee of the Central Hospital of Zibo (Zibo, China) approved the study protocol; thus, prior to the start of the current study, written informed consent was collected from all participating patients. The present study followed all the required modifications under the International Conference on Harmonisation and Good Clinical Practice guidelines and was in agreement with the Declaration of Helsinki, 1975. Between December 2013 and October 2014, patients with disease duration of 6 weeks to 3 years (average, 8 months) after definitive therapy were enrolled in the present study. A heterogeneous group of patients was selected with respect to medical history, stage of disease, risk of recurrence and treatment of primary disease. Characteristics of the patients are summarised in Table I.

Table I.

Patient characteristics.

Table I.

Patient characteristics.

Patient codeAge, yearsHistologyTNM stagePrior treatment receivedDuration from last treatment to DC immunotherapy, months
1XU53SquamousIIIAChemotherapy + radiation therapy8
2LI63SquamousIIIAChemotherapy + radiation therapy5
3XB50AdenocarcinomaIIIBNeo/surgery/adjuvant chemotherapy31
4YU65BronchoalveolarIBSurgery6
5NC72AdenocarcinomaIBSurgery8
6QL59AdenocarcinomaIANeo/surgery/adjuvant chemotherapy5
7ZY66AdenocarcinomaIIIASurgery/adjuvant chemotherapy4
8XL57SquamousIIIAChemotherapy + radiation therapy4
9YP52AdenocarcinomaIIBChemotherapy + radiation therapy12
10LO65AdenocarcinomaIBChemotherapy + radiation therapy5
11XE61SquamousIAChemotherapy + radiation therapy7
12NZ58AdenocarcinomaIIIANeo/surgery/adjuvant chemotherapy3
13HE70SquamousIIIASurgery/adjuvant chemotherapy3
14PX56SquamousIIIA Neo/surgery/adjuvant chemotherapy5
15SZ71AdenocarcinomaIIIAChemotherapy + radiation therapy7
16YU62AdenocarcinomaIIB Surgery/chemotherapy11

[i] TNM, tumour-node-metastasis; DC, dendritic cell.

Measurable immunological response to DC immunotherapy was the primary endpoint, and obtaining comparative immunological data from different NSCLC patients that had received a definitive therapy was the secondary endpoint. To evaluate the inhibitory effects of persistent tumour load and to assess the impact of previous radiotherapy and chemotherapy on immunological responses, the patients were primarily stratified according the therapy they had received. Heterogeneity of the patients and small sample size can prevent meaningful evaluation of therapeutic effects. Therefore, it was important to incorporate the immunotherapy into the therapeutic plan of the patient, with little time commitment and risk. Routine safety laboratory measurements were performed to evaluate clinical tolerability, and adverse events were assessed according to the National Cancer Institute Cancer Therapy Evaluation Program and Common Terminology Criteria for Adverse Events (13).

Dosing schedule

The protocol followed, including the dose used and the route and interval of administration, was selected on the basis of the methods used previously (14). The target dose selected was 108 DCs pulsed with rMAGE3 + rSurvivin in a total 3 ml volume, and a prime immunotherapy followed by one boost immunotherapy were intradermally administered in the thigh 1 month apart. Overall, 16 prime and boost injections containing 9.1×107 DCs and 8.2×107 DCs, respectively, were administered. Following immunisation, patients were monitored for 2 h in the outpatient clinic for immediate unexpected adverse events.

Preparation of monocyte-derived DCs (MODCs)

The DC immunotherapies were developed as described by Hirschowitz et al (14). Briefly, each patient was subjected to a 3-h leukapheresis procedure and 1–3×1010 peripheral blood mononuclear cells (PBMCs) were drawn. The cells were then placed in a tissue culture flask at a density of 1×106 cells/cm2 in the presence of 1% human serum albumin (Baxter Healthcare, Deerfield, IL, USA). Subsequent to incubating the cells in 5% CO2 at 37°C for 2 h, the flask was washed with sterile phosphate-buffered saline (PBS) to isolate non-adherent cells. Adherent cells were then resuspended in a clinical grade CellGro DC medium (CellGenix, Breisgau, Germany) containing 1,000 U/ml GM-CSF (CellGenix), 50 ng/ml IL-4 (CellGenix) and were incubated for 5 days in 5% CO2 at 37°C. On the fifth day, DCs were split into 2 aliquots, one for rMAGE3 and the other for rSurvivin. TAA peptides at a concentration of10 µg/ml in 10 ml PBS were individually added to every aliquot and then incubated at 37°C for 2 h. The aliquots were then transferred to a single vial. To induce DC maturation, cytokine cocktail, IL-1β (Peprotech, Rocky Hill, NJ, USA), IL-6 (Peprotech), tumour necrosis factor-α (TNF-α; Peprotech), interferon-γ (IFN-γ; LG Life Sciences, Gurgaon, Haryana, India), prostaglandin E2 (PGE2; Sigma Aldrich; Merck Millipore, Darmstadt, Germany) and poly I:C (Sigma Aldrich; Merck Millipore) were added to the culture between days 5 and 7. DCs were later bathed twice and then resuspended in 1 ml PBS. Identification of the morphology and immunophenotyping for CD14, CD83, CD86, CD1a and human leukocyte antigen-antigen D related (HLA-DR) was performed in MODCs and later detected for its sterility. The final formulation contained rMAGE3-primed and rSurvivin-primed DCs in the ratio of 1:1, and the total cell concentration was 5×106 DCs in each dose. All 5 doses were prepared at a time and were frozen using automated cryopreservation.

Generation of recombinant proteins

Procreation of the cDNAs encoding MAGE-3 or Survivin into the pCTP vector was performed as previously described (15). It was observed that Escherichia coli BL21 (DE3) had both the antigens (MAGE-3 and Survivin) that were in the structure of 6×-His-attached fusion proteins. Nickel-nitrilotriacetic acid column chromatography (Qiagen, Hilden, Germany) was used to purify the antigens. Endotoxin <1.0 EU/µg in limulus amoebocyte lysate test (catalog no. 88282; Thermo Fischer Scientific, Waltham, MA, USA), according to the manufacturer's instructions, and >95% purity in SDS-PAGE analysis were performed for the quality control authentication of all antigens. Working solutions were prepared by dissolving 0.6 mg of each peptide in 30 ml dimethyl sulfoxide (Wak-chemie Medical GmbH, Steinbach, Germany) and 270 ml sterile water, resulting in a final concentration of 2 mg/ml.

In vitro characterisation

Each DC immunotherapy was subjected to sterility testing and characterisation for the expression of CD14, CD86, CD205 and HLA-DR. Mycoplasma contamination was checked with the use of a MycoAlert Mycoplasma Detection kit (Lonza, Auckland, New Zealand). A kinetic chromogenic limulus amoebocyte lysate test (Lonza) was used in order to identify the endotoxin, according to the manufacturer's instructions.

Evaluation of the phenotypes of DCs

The phenotypes of mature DCs, immature DCs and monocytes were determined using one- or two-colour fluorescence analysis. In total, 3×105 cells were resuspended in 50 µl of buffer containing PBS, 2% foetal calf serum (FCS) and 1% sodium azide. The cells were then incubated with 10 µl of appropriate phycoerythrin-labelled monoclonal antibodies (mAbs) at a dilution of 1:100 or fluorescein isothiocyanate (FITC) (HLA-DR: catalog no. 130-098-176; clone, AC122; CD14: catalog no. 130-110-576; clone, REA599; CD86: catalog no. 130-098-182; clone, FM95; CD205: catalog no. 130-104-772; clone, HD30; Miltenyi Biotec, Singapore) at 4°C for 30 min. Subsequent to incubation, the cells were washed twice and resuspended in 500 µl of assay buffer. The fluorescence was analysed by a flow cytometer (FACSCalibur; BD Biosciences, Franklin Lakes, NJ, USA). There was a build up of 15,000 events for every sample, in addition to delineation of the number of positive cells. DCs were characterised using human HLA-DR-, CD14-, CD86- and CD205-specific mAbs (Miltenyi Biotec) and control immunoglobulins G1 and G2a (IgG1 and IgG2a; BD Biosciences).

Intracytoplasmic IFN-γ detection assay

The procedure used was determined by Kern et al (16) for the intracellular staining of IFN-γ released by lymphocytes. Briefly, 5×106 CD14-peripheral mononuclear cells were obtained prior to the first injection (T0) and subsequent to the fourth injection (T4). Co-culturing of the cells was then performed for 18 h with 1×106 mature MODCs pulsed with rMAGE3 + rSurvivin. Protein secretion was blocked during the last 3 h using 10 µmol of monensin (Sigma Aldrich; Merck Millipore). T0 and T4 cells that were not exposed to rMAGE3 + rSurvivin were used as controls. Intermingling of ionomycin (500 ng/ml; Sigma Aldrich; Merck Millipore) and phorbol myristate acetate (PMA; 50 ng/ml; Sigma Aldrich; Merck Millipore) was performed with the cell suspensions in a correspondent experimental lay down. Subsequent to harvesting, washing and permeabilising the cells with a permeabilisation agent (Immunotech Laboratories, Inc.), according to the manufacturer's protocol, the cells were double-stained with IFN-γ-specific or CD69-specific antibody labelled with phycoerythrin (catalog no. 130-098-901; clone, FN50; Miltenyi Biotec) and CD3-specific antibody (catalog no., 130-098-162; clone, BW264/56; dilution, 1:15; Miltenyi Biotec) labelled with FITC. IgG1 antibodies were utilized as isotype controls. The samples were examined using a flow cytometer (FACSCalibur; BD Biosciences).

Ratio of CD4+ and CD8+ cells

The CD4 and CD8 lymphocyte count was analysed in accordance with the technique described by Bapsy et al (17). Briefly, 2–3 ml of peripheral blood was incubated with anti-human CD3-PC5, CD4-FITC, CD8-PE and CD16-FITC mAbs (BD Biosciences). Subsequent to staining the cells, they were fixed with 1% paraformaldehyde and examination was performed using FACSCalibur flow cytometer and CellQuest Pro software (BD Biosciences). Lymphocytes are characterised by their side and forward light scattering properties; therefore, the analysis and acquisition gates were limited to the lymphocyte gate. Cells that expressed CD markers were acquired and analysed in the FL1 or FL2 logarithmic scale by using the set gates.

Delayed-type hypersensitivity test

rMAGE3 + rSurvivin-pulsed DCs and unpulsed DCs were administered intra-dermally into the forearm, at the time of T0 and T4. Erythema >1.5 cm and skin induration 48 h after intradermal injection were considered as positive delayed-type hypersensitivity.

Response evaluation

Patients were followed-up by the primary physicians. The follow-up included physical examination and routine history. Chest X-rays or computed tomography (CT) scans were also obtained for assessment depending on the signs and symptoms of tumour recurrence or at regular intervals. Toxicity was graded according to World Health Organisation criteria.

Statistical evaluation

Paired Student's t-test was used to examine the data. P<0.05 was considered to indicate a statistically significant difference. The correlation between two interval-scaled variables was tested using Pearson's correlation, whereas the correlation between two ordinal-scaled variables was tested using Spearman's rank correlation. Non-parametric Wilcoxon rank sum test was used to compare the immunological outcomes (e.g. ratio of CD4/CD8 count in blood and IFN-γ release from macrophages) between clinical responders (CD4/CD8 >1) and non-responders (IFN-γ >1%). Kaplan-Meier survival analysis was performed using GraphPad Prism software (GraphPad Software, San Diego, CA, USA).

Results

As aforementioned, 16 patients were enrolled in the present study between December 2013 and October 2014. A total of 19 patients were screened, of which 16 patients met the inclusion criteria. Patient characteristics and clinical outcomes are presented in Table II.

Table II.

Treatment characteristics and DC vaccine-associated clinical events.

Table II.

Treatment characteristics and DC vaccine-associated clinical events.

Patient codeRecurrenceTime to recurrence from treatment, monthsTime to recurrence from DC immunotherapy, monthsSurvival from treatment, monthsSurvival from DC immunotherapy, months
1XUNo22NA
2LINo12NA
3XBYes7127
4YUNo17NA
5NCNo25156
6QLNo531612
7ZYYes15312NA
8XLNo20NA
9YPYes14NA
10LONo17NA
11XENo13NA
12NZNo25NA
13HENo16NA
14PXNoNA
15SZYes1116NANA
16YUYes811NA

[i] NA, not applicable; -, not observed; DC, dendritic cell.

Phenotype of DCs

The final immunotherapy products did not express CD14, and the majority of the cells expressed CD86 (90%), CD205 (60–75%) and HLA-DR (55–62%) (Fig. 1). However, with respect to cytokine secretion, antigen-pulsed DC/T cell maturation factor-treated DCs appeared to be more mature compared with naive DCs. Light microscopy of cells cultured for 8 days revealed predominantly mature DCs (Fig. 2).

Delayed-type hypersensitivity test

DCs pulsed with rMAGE3 + rSurvivin were introduced into the forearm intra-dermally to determine DTH reactivity. An induration >1.5 cm in diameter was considered as a non-negative DTH reaction. Subsequent to the first vaccination, every patient showed a truly positive DTH reaction.

In vitro IFN-γ assay

The assay that was elaborated in order to identify the intracellular IFN-γ production in the peripheral T cells was utilized to identify the capability of the DC immunotherapy for the progression of an immune response, specifically against tumour cells. The present study used flow cytometry to assess the production of IFN-γ in CD3+ lymphocytes in patients on days 0 and 60. In CD3+ cells that were generated subsequent to T4 (DC immunotherapy arm) and could not be invigorated with ionomycin or PMA, it was observed that there was a significantly increased level of IFN-γ expression compared with cells obtained on day 0 (P=0.044). IFN-γ expression on day 60 was significantly increased compared with day 0 (P=0.48) (Fig. 2).

CD4:CD8 levels

There was an increasing trend in the mean CD4:CD8 values between day 30 and day 60 (Fig. 3); however, the increase was not statistically significant (P=0.150). In the majority of the patients, the basal values were found to be <2.

Toxicity

In total, 32 DC injections were subcutaneously administered to the thigh. All injections were well tolerated; however, one incident of temporary exanthema was observed in one patient (patient ID, 5NC). It was observed that the exanthema vanished without any supplementary treatment. At the DC injection region, 18.75% (3/16) of patients reported a small itching induration. No patients showed any serious adverse events. Overall, DC immunotherapy was found to be safe and well tolerated and only incidence of grade 1 chills, fever and fatigue was observed.

Response evaluation

At least 12 months of follow up was performed for all patients subsequent to primary immunisation, and the clinical follow-up data are shown in Table II. The disease recurred or progressed in 5 patients, 3 of which succumbed to NSCLC 4–9 months after detection due to disease progression to an advanced stage (stage IV). One NSCLC patient (patient ID, DC10), who had stage I disease and had received radiotherapy and chemotherapy, developed solitary brain metastasis 2 months subsequent to T0. Subsequently, 15 months after local resection of stage IV disease, the patient showed no evidence of NSCLC. One patient with stage IIIB unresectable disease developed local progression 16 months subsequent to T0 and 19 months subsequent to chemoradiation. A sixth patient (patient ID, DC16) with stage IIIA disease that could be resected surgically and had received multimodality therapy developed radiographically persistent nodule 12 months subsequent to T0 and 21 months subsequent to completion of treatment and was currently receiving chemotherapy.

Discussion

The current study has validated the concept of cellular immunotherapy using MODCs as a viable treatment option in treating NSCLC. No patients demonstrated treatment-associated haematological, hepatic, renal or neurological toxicity, or autoimmune disease, indicating that the autologous DC immunotherapy was safe. DCs also met the specifications for quality control described by Sabado et al (18). Aggressive treatment of NSCLC has lead to improved outcomes (19,20), and survival can further be increased by expanding the scope of available therapeutic options for NSCLC (21,22). Immunotherapy specifically targets malignant cells and is an attractive systemic approach. Evidence that autologous tumour immunotherapy expressing GM-CSF (GVAX) elicits a durable clinical response in patients with NSCLC indicates that it is possible to modulate the immune system to benefit NSCLC patients (14). Although it is questionable whether immunotherapy can adequately and consistently treat such considerable diseases, efficient immunotherapy can act as an adjuvant therapy for surgical multimodality or medical therapy that shows definitive clinical responses. The ultimate objective of the present study was to identify the role of immunotherapy as an adjuvant therapy in the treatment of stage I–IIIB NSCLC. Therefore, the main aim of the current study was to identify the immunological response generated by autologous DC immunotherapy in 16 patients with NSCLC. In total, 5 patients experienced disease recurrence or progression, of which 3 patients succumbed to disease progression. In addition, 3 patients experienced therapeutic efficacy. One patient, who had stage IB disease, developed solitary brain metastasis 2 months subsequent to vaccination (DC immunotherapy); however, following surgical resection of stage IV disease, the patient survived for 15 months. Additionally, no disease progression was observed in 2 patients with stage III unresectable disease 23 months and 35 months after chemoradiation, respectively. One patient with bronchoalveolar carcinoma, who had resected stage IIIB disease, also remained tumour-free 19 months subsequent to vaccination and 28 months subsequent to surgical resection.

A positive DTH response against the TAAs used for priming the DC was observed in all patients. Previous studies have not shown a statistically significant increase in the release of IFN-γ (17,18). However, the levels of IFN-γ released by CD3+ cells in the present study support the activation of the immune response by DC immunotherapy. In the present study, MAGE3 and Survivin were used as TAAs for DC immunotherapy and for generating a Th1 immune response; the use of purified and defined MAGE3 and Survivin peptides to prime DCs has already been demonstrated (23,24).

Therapeutic cancer immunotherapies have become a reality (17). Initial failures have increased knowledge of the immune response against tumours and prompted the development of immunotherapies and immunotherapeutic agents that are more potent and considerably less toxic than chemotherapies or targeted therapies (6,10). Trials and approval of the first DC immunotherapy in the US have shown that activating the immune system with a therapeutic cancer immunotherapy can provide clinical benefit to cancer patients for a prolonged period (25). Immunotherapies have been more successful in prostate cancer due to the generally indolent progression of prostate cancer (25). In the present study, only patients with advanced tumour stage were enrolled; however, the optimal setting to apply DC immunotherapy may be minimal residual disease. The foci of on-going and forthcoming studies are various aspects of immunotherapy optimisation, antigen preparation and methods of application (26). The current study showed that DCs can be used in adoptive immunotherapy for the treatment of NSCLC. However, if these promising results can be confirmed in a larger patient population, then DC immunotherapy based on the combination of rMAGE3 and rSurvivin may become a sought after option for treating NSCLC. Several questions associated with the manufacturing and quality of immunotherapy, immune monitoring, patient selection and immunotherapy delivery strategies need to be addressed. Future studies should address prominent issues, including secretion of immunosuppressive cytokines and mechanisms of tumour escape from immune surveillance, through down-regulation of antigen and MHC expression.

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Li D and Li D: MAGE3 and Survivin activated dendritic cell immunotherapy for the treatment of non-small cell lung cancer. Oncol Lett 15: 8777-8783, 2018
APA
Li, D., & Li, D. (2018). MAGE3 and Survivin activated dendritic cell immunotherapy for the treatment of non-small cell lung cancer. Oncology Letters, 15, 8777-8783. https://doi.org/10.3892/ol.2018.8362
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Li, D., He, S."MAGE3 and Survivin activated dendritic cell immunotherapy for the treatment of non-small cell lung cancer". Oncology Letters 15.6 (2018): 8777-8783.
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Li, D., He, S."MAGE3 and Survivin activated dendritic cell immunotherapy for the treatment of non-small cell lung cancer". Oncology Letters 15, no. 6 (2018): 8777-8783. https://doi.org/10.3892/ol.2018.8362