Publications by authors named "Evren Alici"

57 Publications

Short-term IL-15 priming leaves a long-lasting signalling imprint in mouse NK cells independently of a metabolic switch.

Life Sci Alliance 2021 04 16;4(4). Epub 2021 Feb 16.

Department of Medicine Huddinge, Centre for Haematology and Regenerative Medicine (HERM), Karolinska Institutet, Huddinge, Sweden

IL-15 priming of NK cells is a broadly accepted concept, but the dynamics and underlying molecular mechanisms remain poorly understood. We show that as little as 5 min of IL-15 treatment in vitro, followed by removal of excess cytokines, results in a long-lasting, but reversible, augmentation of NK cell responsiveness upon activating receptor cross-linking. In contrast to long-term stimulation, improved NK cell function after short-term IL-15 priming was not associated with enhanced metabolism but was based on the increased steady-state phosphorylation level of signalling molecules downstream of activating receptors. Inhibition of JAK3 eliminated this priming effect, suggesting a cross talk between the IL-15 receptor and ITAM-dependent activating receptors. Increased signalling molecule phosphorylation levels, calcium flux, and IFN-γ secretion lasted for up to 3 h after IL-15 stimulation before returning to baseline. We conclude that IL-15 rapidly and reversibly primes NK cell function by modulating activating receptor signalling. Our findings suggest a mechanism by which NK cell reactivity can potentially be maintained in vivo based on only brief encounters with IL-15 trans-presenting cells.
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http://dx.doi.org/10.26508/lsa.202000723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7918643PMC
April 2021

Phosphodiesterase 4A confers resistance to PGE2-mediated suppression in CD25 /CD54 NK cells.

EMBO Rep 2021 Mar 22;22(3):e51329. Epub 2021 Jan 22.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Inadequate persistence of tumor-infiltrating natural killer (NK) cells is associated with poor prognosis in cancer patients. The solid tumor microenvironment is characterized by the presence of immunosuppressive factors, including prostaglandin E2 (PGE2), that limit NK cell persistence. Here, we investigate if the modulation of the cytokine environment in lung cancer with IL-2 or IL-15 renders NK cells resistant to suppression by PGE2. Analyzing Cancer Genome Atlas (TCGA) data, we found that high NK cell gene signatures correlate with significantly improved overall survival in patients with high levels of the prostaglandin E synthase (PTGES). In vitro, IL-15, in contrast to IL-2, enriches for CD25 /CD54 NK cells with superior mTOR activity and increased expression of the cAMP hydrolyzing enzyme phosphodiesterase 4A (PDE4A). Consequently, this distinct population of NK cells maintains their function in the presence of PGE2 and shows an increased ability to infiltrate lung adenocarcinoma tumors in vitro and in vivo. Thus, strategies to enrich CD25 /CD54 NK cells for adoptive cell therapy should be considered.
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http://dx.doi.org/10.15252/embr.202051329DOI Listing
March 2021

Improved survival in multiple Myeloma patients undergoing autologous stem cell transplantation is entirely in the standard cytogenetic risk groups.

Eur J Haematol 2021 Jan 20. Epub 2021 Jan 20.

Department of Medicine, Center for Hematology and Regenerative Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden.

Introduction: Novel drugs and drug combinations have improved outcomes for multiple myeloma patients. However, subgroups of patients still have a poor progression-free survival (PFS) and overall survival (OS). In an attempt to identify how the novel drugs affect the outcome in standard-risk and high-risk patients, respectively, we have investigated 715 multiple myeloma (MM) patients who have undergone high dose treatment followed by autologous stem cell transplantation at our center during 1995 - 2020. Outcomes during three time periods, 1995-1999 (period I), 2000-2009 (period II), and 2010-2020 (period III), were compared separately for standard-risk and high-risk patients. Risk stratification was based on chromosome analysis for periods II and III.

Results: The whole cohort of patients showed significantly improved OS with time during the three periods being at a median of 5.8, 7.0, and 10.0 years, respectively. There is also a weak tendency for improved PFS, that is, a median of 2.4, 2.6, and 2.9 years, respectively, during the same periods. However, the separate analysis of standard-risk and high-risk patients showed that the overall improvement with time was due to improved standard-risk patients (median OS 8.4 years for the period I and not reached for period II and III). In contrast, no significant improvement was seen in high-risk patients. For patients with del17p, PFS was even worse during period III as compared to period II (median 1.6 vs 3.2 years respectively).

Conclusion: Our results show that the dramatic improvement in outcome for MM patients during the last 20 years only applies for standard-risk patients, while high-risk MM patients still are doing poorly, indicating that the novel drugs developed during this time are preferentially effective in standard-risk patients. New treatment modalities like CAR-T cells, CAR-NK cells, and/or bispecific antibodies should be tried in clinical studies early in the course of the disease, especially in patients with high-risk cytogenetics.
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http://dx.doi.org/10.1111/ejh.13585DOI Listing
January 2021

Dynamic follow-up of smoldering multiple myeloma identifies a subset of patients at high risk of progression.

Am J Hematol 2021 03 19;96(3):E63-E65. Epub 2020 Dec 19.

Center for Hematology and Regenerative Medicine (HERM), Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

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http://dx.doi.org/10.1002/ajh.26062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7898535PMC
March 2021

Comparative evaluation of involved free light chain and monoclonal spike as markers for progression from monoclonal gammopathy of undetermined significance to multiple myeloma.

Am J Hematol 2021 01 29;96(1):23-30. Epub 2020 Sep 29.

Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell disorder, with a 1% yearly risk of progression to multiple myeloma (MM). Evolution of M-spike and serum free light chain (sFLC) during follow-up could identify patients at high risk of progression. In this region-wide study, including 4756 individuals, 987 patients with MGUS were identified, and baseline factors as well as evolving involved FLC (iFLC) were evaluated as potential markers for risk of progression from MGUS to MM. Furthermore, evolving iFLC and M-spike were assessed quarterly for a median of 5 years. At baseline, patients that progressed had significantly higher iFLC compared to non-progressors. The risk factors of M-spike >1.5 g/dL, age >65 years and iFLC >100 mg/L were all independently associated with increased risk of MGUS to MM progression. For patients that had any two or three risk factors, the 5-year cumulative probability of progression was significantly higher (31%) compared to no risk factors (2%). Evolving iFLC >100 mg/L during follow-up was consistently associated with increased risk of progression. Based on our observations, we propose to include iFLC as a monitoring tool for all MGUS patients. Furthermore, we recommend a quarterly monitoring in all high-risk patients. Finally, we suggest that the risk of MGUS progression should be stratified with age, M-spike, and iFLC at baseline.
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http://dx.doi.org/10.1002/ajh.25999DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7756706PMC
January 2021

Outcome of COVID-19 in multiple myeloma patients in relation to treatment.

Eur J Haematol 2020 Dec 18;105(6):751-754. Epub 2020 Aug 18.

Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm, Sweden.

COVID-19 has emerged as a global pandemic. Cancer patients have been reported to be at higher risk for adverse outcome of COVID-19. Studies are ongoing to decipher the risk factors and risk groups among cancer patients as well as strategies to refine treatment approaches. Here, we report eight patients with multiple myeloma that underwent immunomodulatory therapies with daratumumab or lenalidomide-based combination treatments and one patient with smoldering multiple myeloma, all of which presented with symptomatic COVID-19. We report that patients that succumbed to COVID-19 presented with either progressive tumor disease under daratumumab treatment or were in remission under lenalidomide-dexamethasone treatment.
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http://dx.doi.org/10.1111/ejh.13502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436812PMC
December 2020

Thioredoxin activity confers resistance against oxidative stress in tumor-infiltrating NK cells.

J Clin Invest 2020 10;130(10):5508-5522

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

To improve the clinical outcome of adoptive NK cell therapy in patients with solid tumors, NK cells need to persist within the tumor microenvironment (TME) in which the abundance of ROS could dampen antitumor immune responses. In the present study, we demonstrated that IL-15-primed NK cells acquired resistance against oxidative stress through the thioredoxin system activated by mTOR. Mechanistically, the activation of thioredoxin showed dependence on localization of thioredoxin-interacting protein. We show that NK cells residing in the tumor core expressed higher thiol densities that could aid in protecting other lymphocytes against ROS within the TME. Furthermore, the prognostic value of IL15 and the NK cell gene signature in tumors may be influenced by tobacco smoking history in patients with non-small-cell lung cancer (NSCLC). Collectively, the levels of reducing antioxidants in NK cells may not only predict better tumor penetrance but potentially even the immune therapy response.
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http://dx.doi.org/10.1172/JCI137585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7524507PMC
October 2020

Impact of performance status on overall survival in patients with relapsed and/or refractory multiple myeloma: Real-life outcomes of daratumumab treatment.

Eur J Haematol 2020 Aug 29;105(2):196-202. Epub 2020 May 29.

Karolinska Institutet Department of Medicine Huddinge, Stockholm, Sweden.

Background: Little is reported on the real-life impact of daratumumab in relapsed and/or refractory multiple myeloma patients (RRMM). We analyzed a cohort of 156 patients who received daratumumab as a single agent concerning ECOG status, eGFR, cytogenetics, lines of prior treatment, and their impact on survival.

Results: Eighty-two (53%) patients were triple refractory, 54 (35%) patients were single or double refractory, and 20 (12%) patients were non-refractory. Following daratumumab treatment, the progression-free survival (PFS) in these groups was 7.2%, 11.4%, and 53% (P < .001), and overall survival (OS) was 34%, 73%, and 58% (P < .001) at 36 months, respectively. Poor ECOG, three lines of prior treatment, and triple refractoriness were all associated with inferior PFS and OS in a multivariate analysis including ECOG, high-risk chromosomal aberrations, refractoriness, number of treatment lines, and eGFR.

Conclusion: Daratumumab remains an attractive treatment option, especially in patients with poor performance and increased frailty. Furthermore, our observations suggest that patients with ECOG 2 and 3 status require additional supportive and/or palliative therapies to compensate for a potentially effective but encompassing late-line therapy. In conclusion, further prospective studies are needed to elucidate the impact of ECOG 2 and 3 status in patients with RRMM.
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http://dx.doi.org/10.1111/ejh.13426DOI Listing
August 2020

Generation of Retinal Pigment Epithelial Cells Derived from Human Embryonic Stem Cells Lacking Human Leukocyte Antigen Class I and II.

Stem Cell Reports 2020 04 19;14(4):648-662. Epub 2020 Mar 19.

Department of Clinical Sciences, Intervention and Technology, Karolinska Insitutet, 17177 Stockholm, Sweden; Gynecology and Reproductive Medicine, Karolinska Universitetssjukhuset, 14186 Stockholm, Sweden; Ming Wai Lau Center for Reparative Medicine, Stockholm Node, Karolinska Institutet, 17177 Stockholm, Sweden. Electronic address:

Human embryonic stem cell-derived retinal pigment epithelial (hESC-RPE) cells could serve as a replacement therapy in advanced stages of age-related macular degeneration. However, allogenic hESC-RPE transplants trigger immune rejection, supporting a strategy to evade their immune recognition. We established single-knockout beta-2 microglobulin (SKO-B2M), class II major histocompatibility complex transactivator (SKO-CIITA) and double-knockout (DKO) hESC lines that were further differentiated into corresponding hESC-RPE lines lacking either surface human leukocyte antigen class I (HLA-I) or HLA-II, or both. Activation of CD4+ and CD8+ T-cells was markedly lower by hESC-RPE DKO cells, while natural killer cell cytotoxic response was not increased. After transplantation of SKO-B2M, SKO-CIITA, or DKO hESC-RPEs in a preclinical rabbit model, donor cell rejection was reduced and delayed. In conclusion, we have developed cell lines that lack both HLA-I and -II antigens, which evoke reduced T-cell responses in vitro together with reduced rejection in a large-eyed animal model.
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http://dx.doi.org/10.1016/j.stemcr.2020.02.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160308PMC
April 2020

Boosting Natural Killer Cell-Mediated Targeting of Sarcoma Through DNAM-1 and NKG2D.

Front Immunol 2020 28;11:40. Epub 2020 Jan 28.

Dr. Kiran C. Patel College of Allopathic Medicine, Nova Southeastern University, Fort Lauderdale, FL, United States.

Sarcomas are malignancies of mesenchymal origin that occur in bone and soft tissues. Many are chemo- and radiotherapy resistant, thus conventional treatments fail to increase overall survival. Natural Killer (NK) cells exert anti-tumor activity upon detection of a complex array of tumor ligands, but this has not been thoroughly explored in the context of sarcoma immunotherapy. In this study, we investigated the NK cell receptor/ligand immune profile of primary human sarcoma explants. Analysis of tumors from 32 sarcoma patients identified the proliferative marker PCNA and DNAM-1 ligands CD112 and/or CD155 as commonly expressed antigens that could be efficiently targeted by genetically modified (GM) NK cells. Despite the strong expression of CD112 and CD155 on sarcoma cells, characterization of freshly dissociated sarcomas revealed a general decrease in tumor-infiltrating NK cells compared to the periphery, suggesting a defect in the endogenous NK cell response. We also applied a functional screening approach to identify relevant NK cell receptor/ligand interactions that induce efficient anti-tumor responses using a panel NK-92 cell lines GM to over-express 12 different activating receptors. Using GM NK-92 cells against primary sarcoma explants ( = 12) revealed that DNAM-1 over-expression on NK-92 cells led to efficient degranulation against all tested explants ( = 12). Additionally, NKG2D over-expression showed enhanced responses against 10 out of 12 explants. These results show that DNAM-1 or NKG2D GM NK-92 cells may be an efficient approach in targeting sarcomas. The degranulation capacity of GM NK-92 cell lines was also tested against various established tumor cell lines, including neuroblastoma, Schwannoma, melanoma, myeloma, leukemia, prostate, pancreatic, colon, and lung cancer. Enhanced degranulation of DNAM-1 or NKG2D GM NK-92 cells was observed against the majority of tumor cell lines tested. In conclusion, DNAM-1 or NKG2D over-expression elicited a dynamic increase in NK cell degranulation against all sarcoma explants and cancer cell lines tested, including those that failed to induce a notable response in WT NK-92 cells. These results support the broad therapeutic potential of DNAM-1 or NKG2D GM NK-92 cells and GM human NK cells for the treatment of sarcomas and other malignancies.
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http://dx.doi.org/10.3389/fimmu.2020.00040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001093PMC
February 2021

CD73 immune checkpoint defines regulatory NK cells within the tumor microenvironment.

J Clin Invest 2020 03;130(3):1185-1198

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

High levels of ecto-5'-nucleotidase (CD73) have been implicated in immune suppression and tumor progression, and have also been observed in cancer patients who progress on anti-PD-1 immunotherapy. Although regulatory T cells can express CD73 and inhibit T cell responses via the production of adenosine, less is known about CD73 expression in other immune cell populations. We found that tumor-infiltrating NK cells upregulate CD73 expression and the frequency of these CD73-positive NK cells correlated with larger tumor size in breast cancer patients. In addition, the expression of multiple alternative immune checkpoint receptors including LAG-3, VISTA, PD-1, and PD-L1 was significantly higher in CD73-positive NK cells than in CD73-negative NK cells. Mechanistically, NK cells transport CD73 in intracellular vesicles to the cell surface and the extracellular space via actin polymerization-dependent exocytosis upon engagement of 4-1BBL on tumor cells. These CD73-positive NK cells undergo transcriptional reprogramming and upregulate IL-10 production via STAT3 transcriptional activity, suppressing CD4-positive T cell proliferation and IFN-γ production. Taken together, our results support the notion that tumors can hijack NK cells as a means to escape immunity and that CD73 expression defines an inducible population of NK cells with immunoregulatory properties within the tumor microenvironment.
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http://dx.doi.org/10.1172/JCI128895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269592PMC
March 2020

Translocation (11;14) in newly diagnosed multiple myeloma, time to reclassify this standard risk chromosomal aberration?

Eur J Haematol 2019 Dec 6;103(6):588-596. Epub 2019 Oct 6.

Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

Objectives: The most common translocation in multiple myeloma (MM) is t(11;14)(q13;q32), and its importance as prognostic factor has been controversial. The aim was to analyze its prognostic value.

Method: In this retrospective study of 469 newly diagnosed myeloma patients, outcomes in patients with (11;14) and standard risk (t(11;14)SR) or high risk (t(11;14)HR) cytogenetics were compared to outcomes of patients without t(11;14) and SR (non-t(11;14)SR) or HR (non-t(11;14)HR), respectively.

Results: Overall progression-free survival (PFS) was shorter in t(11;14)SR than non-t(11;14)SR (median 28.9 vs 35.3 months); however, the difference was not significant (P = .2). Overall survival (OS) did not differ significantly between the groups. In the subgroup of patients that did not receive high-dose treatment, PFS was shorter for t(11;14)SR compared to non-t(11;14)SR, 10.6 vs 24.6 months (P = .01). Although OS were shorter for t(11,14)SR compared to non-t(11;14)SR (5-year OS 41.7% vs 63.8%), the difference was not significant (P = .1). In HDT patients, no significant difference was observed for OS or PFS between those with or without t(11;14).

Conclusion: This study shows that t(11;14) is associated with poorer outcome in MM, particularly in non-high-dose-treated SR patients. It should be considered an intermediate or high-risk marker in these patients.
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http://dx.doi.org/10.1111/ejh.13325DOI Listing
December 2019

Upfront bortezomib, lenalidomide, and dexamethasone compared to bortezomib, cyclophosphamide, and dexamethasone in multiple myeloma.

Eur J Haematol 2019 Sep 7;103(3):247-254. Epub 2019 Jul 7.

Department of Medicine, Karolinska Institutet, Stockholm, Sweden.

Objectives: At our center, patients with multiple myeloma (MM) were treated upfront with bortezomib, cyclophosphamide, and dexamethasone (VCD) until cyclophosphamide was replaced with lenalidomide in the combination (VRD). These treatments have never been compared head-to-head in large real-life patient material.

Method: A retrospective analysis of patients treated with VRD and VCD in the first line, both with and without subsequent high-dose treatment (HDT) and autologous stem cell transplantation. A total of 681 patients were included, 117 receiving VRD (71 with, 46 without HDT) and 564 receiving VCD (351 with, 213 without HDT).

Results: Overall response rate (≥partial response) was higher with VRD compared to VCD in the entire VRD group (98% vs 88%, P < 0.001) and in the non-HDT group (98% vs 79%, P < 0.001). Progression-free survival (PFS) at 18 months was longer with VRD compared to VCD in the entire VRD group, the non-HDT group and the HDT group (88% vs 63%, 82% vs 32% and 91% vs 73%, respectively). Overall survival at 18 months was better for VRD-treated patients in the entire VRD group (95% vs 89%, P = 0.048).

Conclusion: Upfront VRD gives better responses and longer PFS compared to VCD in MM patients with or without subsequent HDT.
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http://dx.doi.org/10.1111/ejh.13280DOI Listing
September 2019

Engineering antigen-specific NK cell lines against the melanoma-associated antigen tyrosinase via TCR gene transfer.

Eur J Immunol 2019 08 17;49(8):1278-1290. Epub 2019 May 17.

Nanotechnology Research and Application Center, Sabanci University, Istanbul, Turkey.

Introduction of Chimeric Antigen Receptors to NK cells has so far been the main practical method for targeting NK cells to specific surface antigens. In contrast, T cell receptor (TCR) gene delivery can supply large populations of cytotoxic T-lymphocytes (CTL) targeted against intracellular antigens. However, a major barrier in the development of safe CTL-TCR therapies exists, wherein the mispairing of endogenous and genetically transferred TCR subunits leads to formation of TCRs with off-target specificity. To overcome this and enable specific intracellular antigen targeting, we have tested the use of NK cells for TCR gene transfer to human cells. Our results show that ectopic expression of TCR α/β chains, along with CD3 subunits, enables the functional expression of an antigen-specific TCR complex on NK cell lines NK-92 and YTS, demonstrated by using a TCR against the HLA-A2-restricted tyrosinase-derived melanoma epitope, Tyr . Most importantly, the introduction of a TCR complex to NK cell lines enables MHC-restricted, antigen-specific killing of tumor cells both in vitro and in vivo. Targeting of NK cells via TCR gene delivery stands out as a novel tool in the field of adoptive immunotherapy which can also overcome the major hurdle of "mispairing" in TCR gene therapy.
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http://dx.doi.org/10.1002/eji.201948140DOI Listing
August 2019

Characterization of human natural killer cells for therapeutic use.

Cytotherapy 2019 03 23;21(3):315-326. Epub 2019 Mar 23.

Department of Haematology, Cancer Institute, University College London, London, UK. Electronic address:

As a part of the innate immune system, natural killer (NK) cells are cytotoxic lymphocytes that can exert cytotoxic activity against infected or transformed cells. Furthermore, due to their expression of a functional Fc receptor, they have also been eluded as a major effector fraction in antibody-dependent cellular cytotoxicity. These characteristics have led to multiple efforts to use them for adoptive immunotherapy against various malignancies.  There are now at least 70 clinical trials testing the safety and efficacy of NK cell products around the world in early-phase clinical trials. NK cells are also being tested in the context of tumor retargeting via chimeric antigen receptors, other genetic modification strategies, as well as tumor-specific activation strategies such as bispecific engagers with or without cytokine stimulations. One advantage of the use of NK cells for adoptive immunotherapy is their potential to overcome HLA barriers. This has led to a plethora of sources, such as cord blood hematopoietic stem cells and induced pluripotent stem cells, which can generate comparatively high cytotoxic NK cells to peripheral blood counterparts. However, the variety of the sources has led to a heterogeneity in the characterization of the final infusion product. Therefore, in this review, we will discuss a comparative assessment strategy, from characterization of NK cells at collection to final product release by various phenotypic and functional assays, in an effort to predict potency of the cellular product.
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http://dx.doi.org/10.1016/j.jcyt.2018.11.001DOI Listing
March 2019

Infectious complications and NK cell depletion following daratumumab treatment of Multiple Myeloma.

PLoS One 2019 13;14(2):e0211927. Epub 2019 Feb 13.

Division of Hematology, Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.

Treatment with Daratumumab (Dara), a monoclonal anti-CD38 antibody of IgG1 subtype, is effective in patients with multiple myeloma (MM). However, Dara also impairs the cellular immunity, which in turn may lead to higher susceptibility to infections. The exact link between immune impairment and infectious complications is unclear. In this study, we report that nine out of 23 patients (39%) with progressive MM had infectious complications after Dara treatment. Five of these patients had viral infections, two developed with bacterial infections and two with both bacterial and viral infections. Two of the viral infections were exogenous, i.e. acute respiratory syncytial virus (RSV) and human metapneumovirus (hMPV), while five consisted of reactivations, i.e. one herpes simplex (HSV), 1 varicella-zoster (VZV) and three cytomegalovirus (CMV). Infections were solely seen in patients with partial response or worse. Assessment of circulating lymphocytes indicated a selective depletion of NK cells and viral reactivation after Dara treatment, however this finding does not exclude the multiple components of viral immune-surveillance that may get disabled during this monoclonal treatment in this patient cohort. These results suggest that the use of antiviral and antibacterial prophylaxis and screening of the patients should be considered.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211927PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374018PMC
November 2019

Functional Assessment for Clinical Use of Serum-Free Adapted NK-92 Cells.

Cancers (Basel) 2019 Jan 10;11(1). Epub 2019 Jan 10.

Center for Hematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, 141 83 Stockholm, Sweden.

Natural killer (NK) cells stand out as promising candidates for cellular immunotherapy due to their capacity to kill malignant cells. However, the therapeutic use of NK cells is often dependent on cell expansion and activation with considerable amounts of serum and exogenous cytokines. We aimed to develop an expansion protocol for NK-92 cells in an effort to generate a cost-efficient, xeno-free, clinical grade manufactured master cell line for therapeutic applications. By making functional assays with NK-92 cells cultured under serum-free conditions (NK-92) and comparing to serum-supplemented NK-92 cells (NK-92) we did not observe significant alterations in the viability, proliferation, receptor expression levels, or in perforin and granzyme levels. Interestingly, even though NK-92 cells displayed decreased degranulation and cytotoxicity against tumor cells in vitro, the degranulation capacity was recovered after overnight incubation with 20% serum in the medium. Moreover, lentiviral vector-based genetic modification efficiency of NK-92 cells was comparable with NK-92 cells. The application of similar strategies can be useful in reducing the costs of manufacturing cells for clinical use and can help us understand and implement strategies towards chemically defined expansion and genetic modification protocols.
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http://dx.doi.org/10.3390/cancers11010069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356567PMC
January 2019

The Role of CXC Chemokine Receptors 1-4 on Immune Cells in the Tumor Microenvironment.

Front Immunol 2018 25;9:2159. Epub 2018 Sep 25.

Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL, United States.

Chemokines govern leukocyte migration by attracting cells that express their cognate ligands. Many cancer types show altered chemokine secretion profiles, favoring the recruitment of pro-tumorigenic immune cells and preventing the accumulation of anti-tumorigenic effector cells. This can ultimately result in cancer immune evasion. The manipulation of chemokine and chemokine-receptor signaling can reshape the immunological phenotypes within the tumor microenvironment in order to increase the therapeutic efficacy of cancer immunotherapy. Here we discuss the three chemokine-chemokine receptor axes, CXCR1/2-CXCL1-3/5-8, CXCR3-CXCL9/10/11, and CXCR4-CXCL12 and their role on pro-tumorigenic immune cells and anti-tumorigenic effector cells in solid tumors. In particular, we summarize current strategies to target these axes and discuss their potential use in treatment approaches.
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http://dx.doi.org/10.3389/fimmu.2018.02159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6167945PMC
October 2019

Lenalidomide versus lenalidomide + dexamethasone prolonged treatment after second-line lenalidomide + dexamethasone induction in multiple myeloma.

Cancer Med 2018 06 19;7(6):2256-2268. Epub 2018 Apr 19.

Department of Hematology, Karolinska University Hospital, Stockholm, Sweden.

Lenalidomide (Len) plus dexamethasone (Dex) is approved for the treatment of relapsed or refractory multiple myeloma (RRMM). It is possible that single-agent Len may be effective as prolonged treatment regimen in RRMM once patients demonstrate an initial response to Len+Dex induction. Patients with RRMM who responded to first-line Len+Dex in an observational study (NCT01430546) received up to 24 cycles of either Len (25 mg/day) or Len+Dex (25 mg/day and 40 mg/week) as prolonged treatment in a subsequent phase 2 clinical trial (NCT01450215). In the observational study (N = 133), median time to response was 1.7 (range 0.6-9.6) months. A complete response to all treatments received in both studies was observed in 11% of patients; very good partial response and partial response rates were 31% and 38%, respectively. Corresponding response rates in the subgroup of patients who did not enter the phase 2 trial (n = 71) were 3%, 18%, and 39%, respectively. Rates of disease progression at 2 years in the phase 2 trial were 47% versus 31% for Len versus Len+Dex (P = 0.14). After 36 months median follow-up in surviving patients, median time to progression was not reached with Len+Dex and was 24.9 months (95% confidence interval 12.5-not calculable, P < 0.001) with Len. Three-year OS among the total observational study population was 61% (95% CI, 52-69%). The corresponding rate among patients who entered the phase 2 clinical trial was 73% (95% CI, 60-83%) and was significantly lower among those patients who achieved ≥PR but did not proceed into the phase 2 trial (55%; P = 0.01). In the phase 2 trial, OS was 73% in both treatment arms (P = 0.70). Neutropenia and thrombocytopenia were more common with prolonged (phase 2 trial) versus short-term (observational study) Len administration but remained manageable. Prolonged treatment with Len with or without Dex provides sustained, clinically relevant responses and demonstrates an acceptable safety profile.
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http://dx.doi.org/10.1002/cam4.1422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010717PMC
June 2018

Direct evidence for a polygenic etiology in familial multiple myeloma.

Blood Adv 2017 Apr 7;1(10):619-623. Epub 2017 Apr 7.

Hematology and Transfusion Medicine, Department of Laboratory Medicine, Lund University, Lund, Sweden.

Although common risk alleles for multiple myeloma (MM) were recently identified, their contribution to familial MM is unknown. Analyzing 38 familial cases identified primarily by linking Swedish nationwide registries, we demonstrate an enrichment of common MM risk alleles in familial compared with 1530 sporadic cases ( = 4.8 × 10 and 6.0 × 10, respectively, for 2 different polygenic risk scores) and 10 171 population-based controls ( = 1.5 × 10 and 1.3 × 10, respectively). Using mixture modeling, we estimate that about one-third of familial cases result from such enrichments. Our results provide the first direct evidence for a polygenic etiology in a familial hematologic malignancy.
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http://dx.doi.org/10.1182/bloodadvances.2016003111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728350PMC
April 2017

Case Report: Treatment of light-chain amyloidosis with daratumumab monotherapy in two patients.

Eur J Haematol 2018 Apr 1;100(4):386-388. Epub 2018 Jan 1.

Department of Medicine, Karolinska Institutet Department of Medicine Huddinge, Huddinge, Sweden.

Immunoglobulin light-chain amyloidosis (AL) affects multiple organs, most prominently the kidney and the heart. Renal and cardiac impairment are both associated with poor prognosis and most patients die as a consequence of renal or cardiac failure. Monoclonal antibodies such as daratumumab (human IgG1 anti-CD38) and elotuzumab (anti-SLAMF7) have shown promising efficacy for the treatment of relapsed and refractory multiple myeloma. In this case report we show 2 patients with severe AL, one with severe heart failure and one with heart and renal failure, undergoing treatment with daratumumab. Both patients showed a rapid decrease in FLC in response to daratumumab infusions, with few associated adverse events. Using therapeutic CD38 antibodies as a front-line treatment for AL could induce rapid responses while maintaining a tolerable safety profile in these ultra-fragile patients.
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http://dx.doi.org/10.1111/ejh.13008DOI Listing
April 2018

Pharmacogenetic study of the impact of ABCB1 single-nucleotide polymorphisms on lenalidomide treatment outcomes in patients with multiple myeloma: results from a phase IV observational study and subsequent phase II clinical trial.

Cancer Chemother Pharmacol 2018 01 25;81(1):183-193. Epub 2017 Nov 25.

Unit for Hematology, Department of Medicine, Karolinska Institute, Huddinge, Sweden.

Purpose: Despite therapeutic advances, patients with multiple myeloma (MM) continue to experience disease relapse and treatment resistance. The gene ABCB1 encodes the drug transporter P-glycoprotein, which confers resistance through drug extrusion across the cell membrane. Lenalidomide (Len) is excreted mainly via the kidneys, and, given the expression of P-gp in the renal tubuli, single-nucleotide polymorphisms (SNPs) in the ABCB1 gene may influence Len plasma concentrations and, subsequently, the outcome of treatment. We, therefore, investigated the influence of ABCB1 genetic variants on Len treatment outcomes and adverse events (AEs).

Methods: Ninety patients with relapsed or refractory MM, who received the second-line Len plus dexamethasone in the Rev II trial, were genotyped for the ABCB1 SNPs 1199G>A (Ser400Asn, rs2229109), 1236C>T (silent, rs1128503), 2677G>T/A (Ala893Ser, rs2032582), and 3435C>T (silent, rs1045642) using pyrosequencing, and correlations to response parameters, outcomes, and AEs were investigated.

Results: No significant associations were found between genotype and either best response rates or hematological AEs, and 1236C>T, 2677G>T or 3435C>T genotypes had no impact on survival. There was a trend towards increased time to progression (TTP) in patients carrying the 1199A variant, and a significant difference in TTP between genotypes in patients with standard-risk cytogenetics.

Conclusions: Our findings show a limited influence of ABCB1 genotype on lenalidomide treatment efficacy and safety. The results suggest that 1199G>A may be a marker of TTP following Len treatment in standard-risk patients; however, larger studies are needed to validate and clarify the relationship.
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http://dx.doi.org/10.1007/s00280-017-3481-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5754426PMC
January 2018

Disclosing the Parameters Leading to High Productivity of Retroviral Producer Cells Lines: Evaluating Random Versus Targeted Integration.

Hum Gene Ther Methods 2017 04;28(2):78-90

1 Instituto de Biologia Experimental e Tecnológica , Oeiras, Portugal .

Gammaretrovirus and lentivirus are the preferred viral vectors to genetically modify T and natural killer cells to be used in immune cell therapies. The transduction efficiency of hematopoietic and T cells is more efficient using gibbon ape leukemia virus (GaLV) pseudotyping. In this context gammaretroviral vector producer cells offer competitive higher titers than transient lentiviral vectors productions. The main aim of this work was to identify the key parameters governing GaLV-pseudotyped gammaretroviral vector productivity in stable producer cells, using a retroviral vector expression cassette enabling positive (facilitating cell enrichment) and negative cell selection (allowing cell elimination). The retroviral vector contains a thymidine kinase suicide gene fused with a ouabain-resistant Na,K-ATPase gene, a potential safer and faster marker. The establishment of retroviral vector producer cells is traditionally performed by randomly integrating the retroviral vector expression cassette codifying the transgene. More recently, recombinase-mediated cassette exchange methodologies have been introduced to achieve targeted integration. Herein we compared random and targeted integration of the retroviral vector transgene construct. Two retroviral producer cell lines, 293 OuaS and 293 FlexOuaS, were generated by random and targeted integration, respectively, producing high titers (on the order of 10 infectious particles·ml). Results showed that the retroviral vector transgene cassette is the key retroviral vector component determining the viral titers notwithstanding, single-copy integration is sufficient to provide high titers. The expression levels of the three retroviral constructs (gag-pol, GaLV env, and retroviral vector transgene) were analyzed. Although gag-pol and GaLV env gene expression levels should surpass a minimal threshold, we found that relatively modest expression levels of these two expression cassettes are required. Their levels of expression should not be maximized. We concluded, to establish a high producer retroviral vector cell line only the expression level of the genomic retroviral RNA, that is, the retroviral vector transgene cassette, should be maximized, both through (1) the optimization of its design (i.e., genetic elements composition) and (2) the selection of high expressing chromosomal locus for its integration. The use of methodologies identifying and promoting integration into high-expression loci, as targeted integration or high-throughput screening are in this perspective highly valuable.
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http://dx.doi.org/10.1089/hgtb.2016.149DOI Listing
April 2017

Independent control of natural killer cell responsiveness and homeostasis at steady-state by CD11c+ dendritic cells.

Sci Rep 2016 12 1;6:37996. Epub 2016 Dec 1.

Center for Hematology and Regenerative Medicine (HERM), Department of Medicine Huddinge, Karolinska Institutet, Stockholm, Sweden.

During infection and inflammation, dendritic cells (DC) provide priming signals for natural killer (NK) cells via mechanisms distinct from their antigen processing and presentation functions. The influence of DC on resting NK cells, i.e. at steady-state, is less well studied. We here demonstrate that as early as 1 day after DC depletion, NK cells in naïve mice downregulated the NKG2D receptor and showed decreased constitutive phosphorylation of AKT and mTOR. Subsequently, apoptotic NK cells appeared in the spleen concomitant with reduced NK cell numbers. At 4 days after the onset of DC depletion, increased NK cell proliferation was seen in the spleen resulting in an accumulation of Ly49 receptor-negative NK cells. In parallel, NK cell responsiveness to ITAM-mediated triggering and cytokine stimulation dropped across maturation stages, suggestive of a functional deficiency independent from the homeostatic effect. A role for IL-15 in maintaining NK cell function was supported by a gene signature analysis of NK cell from DC-depleted mice as well as by in vivo DC transfer experiments. We propose that DC, by means of IL-15 transpresentation, are required to maintain not only homeostasis, but also function, at steady-state. These processes appear to be regulated independently from each other.
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http://dx.doi.org/10.1038/srep37996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5131354PMC
December 2016

Wnt/β-Catenin Stimulation and Laminins Support Cardiovascular Cell Progenitor Expansion from Human Fetal Cardiac Mesenchymal Stromal Cells.

Stem Cell Reports 2016 Apr 24;6(4):607-617. Epub 2016 Mar 24.

Division of Cardiothoracic Surgery and Anesthesiology, Department of Molecular Medicine and Surgery, Karolinska Institutet, 17177 Stockholm, Sweden; Cell Therapy Institute, Nova Southeastern University, Fort Lauderdale, FL 33314, USA. Electronic address:

The intrinsic regenerative capacity of human fetal cardiac mesenchymal stromal cells (MSCs) has not been fully characterized. Here we demonstrate that we can expand cells with characteristics of cardiovascular progenitor cells from the MSC population of human fetal hearts. Cells cultured on cardiac muscle laminin (LN)-based substrata in combination with stimulation of the canonical Wnt/β-catenin pathway showed increased gene expression of ISL1, OCT4, KDR, and NKX2.5. The majority of cells stained positive for PDGFR-α, ISL1, and NKX2.5, and subpopulations also expressed the progenitor markers TBX18, KDR, c-KIT, and SSEA-1. Upon culture of the cardiac MSCs in differentiation media and on relevant LNs, portions of the cells differentiated into spontaneously beating cardiomyocytes, and endothelial and smooth muscle-like cells. Our protocol for large-scale culture of human fetal cardiac MSCs enables future exploration of the regenerative functions of these cells in the context of myocardial injury in vitro and in vivo.
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http://dx.doi.org/10.1016/j.stemcr.2016.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4834052PMC
April 2016

Perforin Promotes Amyloid Beta Internalisation in Neurons.

Mol Neurobiol 2017 03 16;54(2):874-887. Epub 2016 Jan 16.

Division for Neurogeriatrics, Department of Neurobiology, Care Sciences and Society (NVS), Center for Alzheimer Research, Karolinska Institutet, Novum 5th floor, Huddinge, 141 57, Sweden.

Studies on the mechanisms of neuronal amyloid-β (Aβ) internalisation are crucial for understanding the neuropathological progression of Alzheimer's disease (AD). We here investigated how extracellular Aβ peptides are internalised and focused on three different pathways: (i) via endocytic mechanisms, (ii) via the receptor for advanced glycation end products (RAGE) and (iii) via the pore-forming protein perforin. Both Aβ and Aβ were internalised in retinoic acid differentiated neuroblastoma (RA-SH-SY5Y) cells. A higher concentration was required for Aβ (250 nM) compared with Aβ (100 nM). The internalised Aβ showed a dot-like pattern of distribution whereas Aβ accumulated in larger and distinct formations. By confocal microscopy, we showed that Aβ and Aβ co-localised with mitochondria, endoplasmic reticulum (ER) and lysosomes. Aβ treatment of human primary cortical neurons (hPCN) confirmed our findings in RA-SH-SY5Y cells, but hPCN were less sensitive to Aβ; therefore, a 20 (Aβ) and 50 (Aβ) times higher concentration was needed for inducing uptake. The blocking of endocytosis completely inhibited the internalisation of Aβ peptides in RA-SH-SY5Y cells and hPCN, indicating that this is a major pathway by which Aβ enters the cells. In addition, the internalisation of Aβ, but not Aβ, was reduced by 55 % by blocking RAGE. Finally, for the first time we showed that pore formation in cell membranes by perforin led to Aβ internalisation in hPCN. Understanding how Aβ is internalised sheds light on the pathological role of Aβ and provides further ideas of inhibitory strategies for preventing Aβ internalisation and the spreading of neurodegeneration in AD.
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http://dx.doi.org/10.1007/s12035-016-9685-9DOI Listing
March 2017

Natural Killer Cell-Based Therapies Targeting Cancer: Possible Strategies to Gain and Sustain Anti-Tumor Activity.

Front Immunol 2015 30;6:605. Epub 2015 Nov 30.

Cell Therapies Institute, Nova Southeastern University , Fort Lauderdale, FL , USA ; Cell and Gene Therapy Group, Center for Hematology and Regenerative Medicine (HERM), Karolinska University Hospital Huddinge, NOVUM , Stockholm , Sweden ; Hematology Center, Karolinska University Hospital Huddinge , Stockholm , Sweden.

Natural killer (NK) cells were discovered 40 years ago, by their ability to recognize and kill tumor cells without the requirement of prior antigen exposure. Since then, NK cells have been seen as promising agents for cell-based cancer therapies. However, NK cells represent only a minor fraction of the human lymphocyte population. Their skewed phenotype and impaired functionality during cancer progression necessitates the development of clinical protocols to activate and expand to high numbers ex vivo to be able to infuse sufficient numbers of functional NK cells to the cancer patients. Initial NK cell-based clinical trials suggested that NK cell-infusion is safe and feasible with almost no NK cell-related toxicity, including graft-versus-host disease. Complete remission and increased disease-free survival is shown in a small number of patients with hematological malignances. Furthermore, successful adoptive NK cell-based therapies from haploidentical donors have been demonstrated. Disappointingly, only limited anti-tumor effects have been demonstrated following NK cell infusion in patients with solid tumors. While NK cells have great potential in targeting tumor cells, the efficiency of NK cell functions in the tumor microenvironment is yet unclear. The failure of immune surveillance may in part be due to sustained immunological pressure on tumor cells resulting in the development of tumor escape variants that are invisible to the immune system. Alternatively, this could be due to the complex network of immune-suppressive compartments in the tumor microenvironment, including myeloid-derived suppressor cells, tumor-associated macrophages, and regulatory T cells. Although the negative effect of the tumor microenvironment on NK cells can be transiently reverted by ex vivo expansion and long-term activation, the aforementioned NK cell/tumor microenvironment interactions upon reinfusion are not fully elucidated. Within this context, genetic modification of NK cells may provide new possibilities for developing effective cancer immunotherapies by improving NK cell responses and making them less susceptible to the tumor microenvironment. Within this review, we will discuss clinical trials using NK cells with a specific reflection on novel potential strategies, such as genetic modification of NK cells and complementary therapies aimed at improving the clinical outcome of NK cell-based immune therapies.
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http://dx.doi.org/10.3389/fimmu.2015.00605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4663254PMC
December 2015

Autologous Peripheral Blood Mononuclear Cells as Treatment in Refractory Acute Respiratory Distress Syndrome.

Respiration 2015 28;90(6):481-92. Epub 2015 Nov 28.

Division of Ear, Nose and Throat, Advanced Center for Translational Regenerative Medicine, Department for Clinical Science, Intervention and Technology, Karolinska Institutet, Huddinge, Stockholm, Sweden.

Background: Acute respiratory distress syndrome (ARDS) is a devastating disorder. Despite enormous efforts in clinical research, effective treatment options are lacking, and mortality rates remain unacceptably high.

Objectives: A male patient with severe ARDS showed no clinical improvement with conventional therapies. Hence, an emergent experimental intervention was performed.

Methods: We performed intratracheal administration of autologous peripheral blood-derived mononuclear cells (PBMCs) and erythropoietin (EPO).

Results: We found that after 2 days of initial PBMC/EPO application, lung function improved and extracorporeal membrane oxygenation (ECMO) support was reduced. Bronchoscopy and serum inflammatory markers revealed reduced inflammation. Additionally, serum concentration of miR-449a, b, c and miR-34a, a transient upregulation of E-cadherin and associated chromatin marks in PBMCs indicated airway epithelial differentiation. Extracellular vesicles from PBMCs demonstrated anti-inflammatory capacity in a TNF-α-mediated nuclear factor-x03BA;B in vitro assay. Despite improving respiratory function, the patient died of multisystem organ failure on day 38 of ECMO treatment.

Conclusions: This case report provides initial encouraging evidence to use locally instilled PBMC/EPO for treatment of severe refractory ARDS. The observed clinical improvement may partially be due to the anti-inflammatory effects of PBMC/EPO to promote tissue regeneration. Further studies are needed for more in-depth understanding of the underlying mechanisms of in vivo regeneration.
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http://dx.doi.org/10.1159/000441799DOI Listing
September 2016

Re-challenging with anti-CD38 monotherapy in triple-refractory multiple myeloma patients is a feasible and safe approach.

Br J Haematol 2016 08 12;174(3):473-7. Epub 2015 Oct 12.

Centre for Haematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden.

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http://dx.doi.org/10.1111/bjh.13776DOI Listing
August 2016

Deletion of Chromosomal Region 8p21 Confers Resistance to Bortezomib and Is Associated with Upregulated Decoy TRAIL Receptor Expression in Patients with Multiple Myeloma.

PLoS One 2015 17;10(9):e0138248. Epub 2015 Sep 17.

Center for Hematology and Regenerative Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden; Center for Diseases of Aging, Vaccine and Gene Therapy Institute of Florida, Port St. Lucie, Florida, United States of America; Haematology Centre, Karolinska University Hospital, Huddinge, Stockholm, Sweden.

Loss of the chromosomal region 8p21 negatively effects survival in patients with multiple myeloma (MM) that undergo autologous stem cell transplantation (ASCT). In this study, we aimed to identify the immunological and molecular consequences of del(8)(p21) with regards to treatment response and bortezomib resistance. In patients receiving bortezomib as a single first line agent without any high-dose therapy, we have observed that patients with del(8)(p21) responded poorly to bortezomib with 50% showing no response while patients without the deletion had a response rate of 90%. In vitro analysis revealed a higher resistance to bortezomib possibly due to an altered gene expression profile caused by del(8)(p21) including genes such as TRAIL-R4, CCDC25, RHOBTB2, PTK2B, SCARA3, MYC, BCL2 and TP53. Furthermore, while bortezomib sensitized MM cells without del(8)(p21) to TRAIL/APO2L mediated apoptosis, in cells with del(8)(p21) bortezomib failed to upregulate the pro-apoptotic death receptors TRAIL-R1 and TRAIL-R2 which are located on the 8p21 region. Also expressing higher levels of the decoy death receptor TRAIL-R4, these cells were largely resistant to TRAIL/APO2L mediated apoptosis. Corroborating the clinical outcome of the patients, our data provides a potential explanation regarding the poor response of MM patients with del(8)(p21) to bortezomib treatment. Furthermore, our clinical analysis suggests that including immunomodulatory agents such as Lenalidomide in the treatment regimen may help to overcome this negative effect, providing an alternative consideration in treatment planning of MM patients with del(8)(p21).
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0138248PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4574561PMC
June 2016