Publications by authors named "Ga-Young Song"

17 Publications

  • Page 1 of 1

Expansion of cytotoxic natural killer cells in multiple myeloma patients using K562 cells expressing OX40 ligand and membrane-bound IL-18 and IL-21.

Cancer Immunol Immunother 2021 Jul 20. Epub 2021 Jul 20.

Research Center for Cancer Immunotherapy, Gwangju, South Korea.

Background: Natural killer (NK) cell-based immunotherapy is a promising treatment approach for multiple myeloma (MM), but obtaining a sufficient number of activated NK cells remains challenging. Here, we report an improved method to generate ex vivo expanded NK (eNK) cells from MM patients based on genetic engineering of K562 cells to express OX40 ligand and membrane-bound (mb) IL-18 and IL-21.

Methods: K562-OX40L-mbIL-18/-21 cells were generated by transducing K562-OX40L cells with a lentiviral vector encoding mbIL-18 and mbIL-21, and these were used as feeder cells to expand NK cells from peripheral blood mononuclear cells of healthy donors (HDs) and MM patients in the presence of IL-2/IL-15. Purity, expansion rate, receptor expression, and functions of eNK cells were determined over four weeks of culture.

Results: NK cell expansion was enhanced by short exposure of soluble IL-18 and IL-21 with K562-OX40L cells. Co-culture of NK cells with K562-OX40L-mbIL-18/-21 cells resulted in remarkable expansion of NK cells from HDs (9,860-fold) and MM patients (4,929-fold) over the 28-day culture period. Moreover, eNK cells showed increased expression of major activation markers and enhanced cytotoxicity towards target K562, U266, and RPMI8226 cells.

Conclusions: Our data suggest that genetically engineered K562 cells expressing OX40L, mbIL-18, and mbIL-21 improve the expansion of NK cells, increase activation signals, and enhance their cytolytic activity towards MM cells.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00262-021-02982-9DOI Listing
July 2021

Expanded natural killer cells augment the antimyeloma effect of daratumumab, bortezomib, and dexamethasone in a mouse model.

Cell Mol Immunol 2021 Jul 12;18(7):1652-1661. Epub 2021 May 12.

Research Center for Cancer Immunotherapy, Chonnam National University Hwasun Hospital and Chonnam National University Medical School, Gwangju, Korea.

The use of natural killer (NK) cells is a promising and safe immunotherapeutic approach in the field of cancer immunotherapy. However, combination treatments are required to enhance the effector functions and therapeutic efficacy of NK cells. In this study, we investigated the potential of daratumumab (Dara), bortezomib, and dexamethasone (Dvd) to augment the antitumor effects of NK cells in a multiple myeloma (MM) xenograft mouse model. NK cells were expanded and activated using the K562-OX40 ligand and membrane-bound IL-18 and IL-21 in the presence of IL-2 and IL-15 from peripheral blood mononuclear cells from MM patients. A human MM xenograft model was established using human RPMI8226-RFP-FLuc cells in NOD/SCID IL-2Rγ (NSG) mice. Tumor-bearing mice were divided into six treatment groups: no treatment, expanded NK cells (eNKs), Dara, Dara + eNKs, Dvd, and Dvd + eNKs. Dvd treatment strongly enhanced the cytotoxicity of eNKs by upregulating expression of NK cell activation ligands, downregulating expression of NK cell inhibitory ligands, and promoting antibody-dependent cellular cytotoxicity. The combination of eNKs with Dvd significantly prolonged mouse survival and reduced the tumor burden and serum M-protein level. Furthermore, Dvd pretreatment significantly increased eNK persistence and homing to MM sites. Our findings suggest that Dvd treatment potentiates the antimyeloma effects of NK cells expanded and activated ex vivo by modulating immune responses in MM-bearing mice.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41423-021-00686-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8245645PMC
July 2021

Prognostic impact of F-FDG PET/CT in patients with multiple myeloma presenting with renal impairment.

Int J Hematol 2021 May 21;113(5):668-674. Epub 2021 Jan 21.

Departments of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo, 519-763, Republic of Korea.

Renal insufficiency (RI) is a frequent manifestation of multiple myeloma (MM) at time of diagnosis but there is no reliable prognostic factor for patients with MM presenting with RI. This study investigated the prognostic impact of F-fluorodeoxyglucose (F-FDG) positron emission tomography/computed tomography (PET/CT) in patients with MM with RI at diagnosis. The records of 209 patients with MM between June 2011 and November 2018 were retrospectively analyzed. PET/CT positivity was defined as the presence of more than three focal lesions or the presence of extramedullary disease. Of 209 patients, 90 (43.1%) had RI and showed similar survival outcomes to patients who had normal renal function. In total, 113 patients (54.0%) were PET/CT-positive, and 46.6% of patients with RI were PET/CT-positive at baseline. In patients with RI, those who were PET/CT-positive showed significantly inferior survival outcomes to those who were PET/CT-negative [progression-free survival (PFS), 12.7 vs. 34.0 months, P < 0.001; overall survival (OS), 42.2 months vs. not reached, P = 0.001]. On multivariate analysis, PET/CT positivity was significantly associated with PFS and OS in patients with RI. In conclusion, PET/CT is a reliable imaging technique for predicting survival outcomes in patients with MM with RI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12185-021-03079-wDOI Listing
May 2021

Allogeneic transplant can abrogate the risk of relapse in the patients of first remission acute myeloid leukemia with detectable measurable residual disease by next-generation sequencing.

Bone Marrow Transplant 2021 05 5;56(5):1159-1170. Epub 2020 Dec 5.

Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada.

In patients with acute myeloid leukemia (AML) consolidation treatment options are between allogeneic hematopoietic stem cell transplantation (HCT) and chemotherapy, based on disease risk at the time of initial presentation and age. Measurable residual disease (MRD) following induction chemotherapy could be incorporated as a useful parameter for treatment decisions. The present study evaluated treatment outcomes according to the next-generation sequencing (NGS)-based MRD status and the type of consolidation therapy in patients with normal karyotype (NK)-AML. By sequencing 278 paired samples collected at diagnosis and first remission (CR1), we identified 361 mutations in 124 patients at diagnosis and tracked these at CR1. After excluding mutations associated with age-related clonal hematopoiesis, 82 mutations in 50 of the 124 patients (40.3%) were detected at CR1. Survival benefit was observed in favor of allogeneic HCT over chemotherapy consolidation in the MRD subgroup with respect to overall survival (HR 0.294, p = 0.003), relapse-free survival (HR 0.376, p = 0.015) and cumulative incidence of relapse (HR 0.279, p = 0.004) in multivariate analysis, but not in the MRD subgroup. In summary, these data support allogeneic HCT in NK-AML patients with detectable MRD by NGS in CR1. Randomized clinical trials will be required to confirm this observation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-01165-xDOI Listing
May 2021

Open-label, single arm, multicenter phase II study of VIDL induction chemotherapy followed by upfront autologous stem cell transplantation in patients with advanced stage extranodal NK/T-cell lymphoma.

Bone Marrow Transplant 2021 05 4;56(5):1205-1208. Epub 2020 Dec 4.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

The clinical outcome of advanced-stage Extranodal NK/T cell lymphoma (ENKTL) patients using conventional chemotherapy is extremely poor. The aim of this study was to investigate the outcomes of advanced-stage ENKTL patients treated with non-anthracycline-based chemotherapy followed by upfront autologous stem cell transplant (ASCT). From 8 institutions, 27 patients were recruited from February 2016 to May 2019. Patients were treated with 4 cycles of VIDL induction chemotherapy. Patients who achieved complete response (CR) or partial response (PR) underwent upfront ASCT. This study is registered with clinicaltrial.gov, # NCT02544425. Twenty patients (74.1%) completed 4 cycles of VIDL induction. The overall response rate of VIDL was 74.1%, including 17 (63.0%) with CR and 3 (11.1%) with PR. Primary toxicity of the induction regimen was grade 3 or 4 neutropenia, and no treatment-related mortality was reported. Seventeen patients proceeded with upfront ASCT, and 9 patients relapsed after ASCT, among whom, 4 was central nervous system (CNS) relapse. The median duration of response was 15.2 months (95% CI, 6.3-24.1 months). This study suggested that VIDL induction chemotherapy followed by upfront ASCT is feasible and effective for the treatment of advanced-stage ENKTL. However, CNS relapse prevention is needed in the treatment of advanced-stage ENKTL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41409-020-01160-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113056PMC
May 2021

Adrenal insufficiency in hospitalized patients with multiple myeloma.

Leuk Lymphoma 2021 02 2;62(2):501-503. Epub 2020 Nov 2.

Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Republic of Korea.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1834095DOI Listing
February 2021

Endothelial activation and stress index (EASIX) is a reliable predictor for overall survival in patients with multiple myeloma.

BMC Cancer 2020 Aug 24;20(1):803. Epub 2020 Aug 24.

Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo, 519-763, Republic of Korea.

Background: Recently, the endothelial Activation and Stress Index (EASIX) score has been reported to predict overall survival (OS) after allogeneic stem cell transplantation. This study evaluated the prognostic role of EASIX score in patients with newly diagnosed multiple myeloma (MM).

Methods: This retrospective study analyzed the records of 1177 patients with newly diagnosed MM between February 2003 and December 2017 from three institutions in the Republic of Korea. Serum lactate dehydrogenase (LDH), creatinine, and platelet count at diagnosis were measured in all included patients. EASIX scores were calculated using the formula-LDH (U/L) × Creatinine (mg/dL) / platelet count (10/L) and were evaluated based on log2 transformed values.

Results: The median age of patients was 63 years (range, 22-92), and 495 patients (42.1%) underwent autologous stem cell transplantation (ASCT). The median log2 EASIX score at diagnosis was 1.1 (IQR 0.3-2.3). Using maximally selected log-rank statistics, the optimal EASIX cutoff value for OS was 1.87 on the log2 scale (95% CI 0.562-0.619, p < 0.001). After median follow-up for 50.0 months (range, 0.3-184.1), the median OS was 58.2 months (95% CI 53.644-62.674). Overall, 372 patients (31.6%) showed high EASIX scores at diagnosis, and had significantly inferior OS compared to those with low EASIX (log2 EASIX ≤1.87) (39.1 months vs. 67.2 months, p < 0.001). In multivariate Cox analysis, high EASIX was significantly associated with poor OS (HR 1.444, 95% CI 1.170-1.780, p = 0.001). In the subgroup analysis of patients who underwent ASCT, patients with high EASIX showed significantly inferior OS compared to those with low EASIX (52.8 months vs. 87.0 months, p < 0.001). In addition, in each group of ISS I, II, and III, high EASIX was associated with significantly inferior OS (ISS 1, 45.2 months vs. 76.0 months, p = 0.001; ISS 2, 42.3 months vs. 66.5 months, p = 0.002; ISS 3, 36.8 months vs. 55.1 months, p = 0.001).

Conclusion: EASIX score at diagnosis is a simple and strong predictor for OS in patients with newly diagnosed MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-020-07317-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446202PMC
August 2020

Frontline therapy for newly diagnosed patients with multiple myeloma.

Blood Res 2020 Jul;55(S1):S37-S42

Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, Hwasun, Korea.

Since the introduction of an alkylator to the treatment of multiple myeloma (MM), new effective agents have been developed, such as immunomodulatory drugs including thalidomide, lenalidomide, and pomalidomide; proteasome inhibitors including bortezomib, carfilzomib, and ixazomib; monoclonal antibodies including daratumumab and elotuzumab; and deacetylase inhibitors including panobinostat. Numerous regimens with these new agents have been developed and they have contributed in improving survival outcomes in MM patients. In addition, the recommended therapies for newly diagnosed MM change every year based on the results of clinical trials. This review will discusses the appropriate induction therapies based on recent clinical trials for patients with newly diagnosed MM.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.5045/br.2020.S007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386893PMC
July 2020

Prognostic significance of interim PET/CT response for the treatment of advanced-stage marginal zone lymphoma in the post-rituximab era.

Sci Rep 2020 07 15;10(1):11649. Epub 2020 Jul 15.

Chonnam National University Hwasun Hospital, Hwasun, Jeollanam-do, Republic of Korea.

There are still controversies about the use of interim positron emission tomography/computed tomography (PET/CT) in indolent non-Hodgkin lymphoma due to the variable fluorodeoxyglucose (FDG) avidity. Therefore, this study aimed to evaluate the roles of interim PET/CT in marginal zone lymphoma (MZL), a representative indolent lymphoma. We analyzed the data of 146 MZL patients. All were treated with rituximab-containing immunochemotherapy. Interim PET/CT scan was performed after 2-3 cycles of therapy, and the response was assessed using the Deauville 5-point scales (5-PS) and a semi-quantitative assessment using the SUVmax reduction rate (ΔSUVmax). Progression-free survival (PFS) was well stratified according to a visual assessment of interim PET/CT using 5-PS (p < 0.001). Particularly, there was a significant difference in PFS between patients with interim score 1-2 and those with score 3. However, ΔSUVmax did not predict the survival outcome using 59.8% of the optimal cutoff value. In the multivariate analysis, failure to achievement of grade 1-2 in interim PET/CT was significantly associated with inferior PFS (HR, 2.154; 95% CI 1.071-4.332; p = 0.031). The interim PET/CT response based on the 5-PS is useful for predicting PFS of patients with MZL in the post-rituximab era.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-020-68310-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7363857PMC
July 2020

Quantitative Assessment of Interim PET/CT Could Have More Prognostic Relevance than Visual Assessment for Predicting Clinical Outcome of Extranodal Diffuse Large B Cell Lymphoma.

In Vivo 2020 Jul-Aug;34(4):2127-2134

Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, School of Medicine, Chonnam National University, Hwasun, Republic of Korea

Background/aim: The present study retrospectively investigated the predictive accuracy of interim positron emission tomography/computed tomography (iPET/CT) based on the Deauville 5-point scale (5-PS) and a quantitative SUV-based assessment in patients with extranodal (EN) diffuse large B cell lymphoma (DLBCL).

Patients And Methods: The Deauville 5-PS and the SUVmax reduction (ΔSUVmax) assessment for interpreting the response to iPET/CT were used.

Results: A total of 163 patients were enrolled in this study. With a median follow-up of 52.5 months, ΔSUVmax successfully predicted the survival outcomes of patients with one extranodal (EN) involvement in terms of overall survival (OS) (p=0.012) and progression-free survival (PFS) (p<0.001). Visual assessment using the Deauville 5-PS did not predict survival outcomes in patients with one or more EN involvements in terms of OS and PFS.

Conclusion: The quantitative SUV-based assessment with iPET/CT was a significant prognosticator for long-term survival outcomes, especially in patients with one EN involvement.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.21873/invivo.12018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7439899PMC
June 2021

Intravenous busulfan and melphalan versus high-dose melphalan as a conditioning regimen for early autologous stem cell transplantation in patients with multiple myeloma: a propensity score-matched analysis.

Leuk Lymphoma 2020 11 25;61(11):2714-2721. Epub 2020 Jun 25.

Seoul National University Hospital, Seoul, Republic of Korea.

We compared the efficacy and toxicity of busulfan and melphalan (BUMEL) and those of high-dose melphalan (HDMEL) as conditioning regimens for autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM) through a propensity score-matched analysis. No significant difference in the complete response and overall response rate after ASCT was observed between BUMEL and HDMEL. After a median follow-up of 37.3 months in the BUMEL group and 50.8 months in the HDMEL group, the median progression-free survival was calculated to be 32.9 months and 25.2 months ( = 0.995). With respect to non-hematologic toxicities, infections were more frequently reported in the BUMEL group ( < 0.001). Three patients who received BUMEL developed veno-occlusive disease (VOD), and all of them recovered without administration of defibrotide. In conclusion, BUMEL is an effective alternative conditioning regimen in terms of efficacy, but attention should be paid to toxicities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/10428194.2020.1783448DOI Listing
November 2020

Optimal chemo-mobilization for the collection of peripheral blood stem cells in patients with multiple myeloma.

BMC Cancer 2019 Jan 14;19(1):59. Epub 2019 Jan 14.

Department of Hematology-Oncology, Chonnam National University Hwasun Hospital, 322 Seoyangro, Hwasun, Jeollanamdo, 519-763, Republic of Korea.

Background: For successful autologous stem cell transplantation, the collection of a sufficient number of hematopoietic stem cells after induction therapy is essential for transplant candidates with multiple myeloma (MM).

Methods: In this study, we compared the efficacy and safety of stem cell mobilization using cyclophosphamide (CY; 3.0 g/m on day 1) or etoposide (VP-16; 375 mg/m on days 1 and 2) in patients with MM. Granulocyte-colony stimulating factor (G-CSF, 10 μg/kg/day, subcutaneously) was administered from the onset of neutropenia to the final day of collection.

Results: Sixty-five patients were mobilized with a combination of CY and G-CSF, and 63 were mobilized with a combination of VP-16 and G-CSF. All patients were mobilized within 7 months of beginning frontline treatment. The median number of CD34 cells collected was significantly higher in the VP-16 mobilization group than in the CY mobilization group (27.6 ×  10 CD34/kg vs. 9.6 × 10 CD34/kg, P <  0.001). The rate of mobilization failure, defined as < 2.0 × 10 CD34/kg collected in three apheresis procedures, was lower in the VP-16 group than in the CY group (1.6% vs. 10.8%, P = 0.062). Severe infections during the mobilization period were more frequent in the CY group than in the VP-16 group (18.5% vs. 7.9%, P = 0.117).

Conclusion: In conclusion, an intermediate dose of VP-16 with G-CSF appears to be an effective and tolerable chemo-mobilization method compared to CY and G-CSF, particularly in cases where use plerixafor in MM is difficult.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12885-019-5285-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332580PMC
January 2019

Non-covalently functionalized carbon nanostructures for synthesizing carbon-based hybrid nanomaterials.

J Nanosci Nanotechnol 2014 Feb;14(2):1425-40

Carbon nanostructures (CNSs) such as carbon nanotubes, graphene sheets, and nanodiamonds provide an important type of substrate for constructing a variety of hybrid nanomaterials. However, their intrinsic chemistry-inert surfaces make it indispensable to pre-functionalize them prior to immobilizing additional components onto their surfaces. Currently developed strategies for functionalizing CNSs include covalent and non-covalent approaches. Conventional covalent treatments often damage the structure integrity of carbon surfaces and adversely affect their physical properties. In contrast, the non-covalent approach offers a non-destructive way to modify CNSs with desired functional surfaces, while reserving their intrinsic properties. Thus far, a number of surface modifiers including aromatic compounds, small-molecular surfactants, amphiphilic polymers, and biomacromolecules have been developed to non-covalently functionalize CNS surfaces. Mediated by these surface modifiers, various functional components such as organic species and inorganic nanoparticles were further decorated onto their surfaces, resulting in versatile carbon-based hybrid nanomaterials with broad applications in chemical engineering and biomedical areas. In this review, the recent advances in the generation of such hybrid nanostructures based on non-covalently functionalized CNSs will be reviewed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1166/jnn.2014.9048DOI Listing
February 2014

Fabrication of monometallic nanoparticles using alkyl-terminated hyperbranched polyglycidols as a stabilizer and reducer.

J Nanosci Nanotechnol 2013 Sep;13(9):5997-6004

The WCU Center for Synthetic Polymer Bioconjugate Hybrid Materials, Department of Polymer Science and Engineering, Pusan National University, Busan 609-735, Korea.

A series of alkyl-terminated hyperbranched polyglycidols (HBPs) have been synthesized via an anionicring-opening multi-branching polymerization of glycidolusing trifunctional 1,1,1-tris(hydroxymethyl)propane as an initiator, followed by the ring-opening polymerization of 1,2-epoxyhexane, 1,2-epoxydodecaneand 1,2-epoxytetradecane. The resulting polymers possess polydispersities below 1.5 and the degree of polymerization could be controlled by the ratio of glycidol monomer to the initiator. Depending on ratio of glycidol to alkyl oxide, polarity and solubility could also be tuned. The HBPs have been demonstrated to be an effective reducer and stabilizer for the synthesis of highly water-soluble monometallic (Au, Ag, Pd and Pt) nanoparticles in the absence of any additional reducers and surfactants. The size of nanoparticles could be tuned by changing the concentration of the metal ion precursors. The optical properties of the as-prepared metal nanoparticles are investigated by UV-vis spectroscopy and their structural characteristics were defined by electron microscope image.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1166/jnn.2013.7645DOI Listing
September 2013

Hyperbranched polyglycerol hydrogels prepared through biomimetic mineralization.

Colloids Surf B Biointerfaces 2013 Mar 23;103:31-7. Epub 2012 Oct 23.

Chemical Department, Far-East Federal University, Vladivostok 690950, Russia.

Hyperbranched polyglycerols find increasing usage in biomedicine owing to their excellent biocompatibility like polysaccharides. To prepare hydrogels, they are cross-linked mainly by treating with toxic epoxy reagents. Here we suggest a one-stage nontoxic procedure for the jellification of aqueous solutions that was previously developed for nongelable polysaccharides. It was carried out via the biomimicking mineralization. As the silica precursor, tetrakis(2-hydroxyethyl)orthosilicate containing ethylene glycol residues was employed. It could mineralize directly hydroxyl-containing macromolecules passing a stage of the sol formation. Jellification was performed in one stage in the neutral pH region at the ambient conditions. An organic solvent was not needed because of high hydrophilicity of both the precursor and polyglycerols. An as-prepared hydrogel is ready for applications because of the absence of toxic products. Its structure and mechanical properties were characterized by scanning and transmission electron microscopy as well as dynamic rheology. It was demonstrated that hyperbranched polyglycerols were encased into silica matrix that formed three-dimensional mesoporous network. A study of initial solutions of hyperbranched polyglycerols by the dynamic light scattering revealed their aggregation. This important result was confirmed by direct observations of aggregated macromolecules with high resolution scanning electron microscopy. Entrapped aggregates were also found in the silica matrix.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.colsurfb.2012.10.026DOI Listing
March 2013