scholarly journals Nematode Asparaginyl-tRNA Synthetase Resolves Intestinal Inflammation in Mice with T-Cell Transfer Colitis

2012 ◽  
Vol 20 (2) ◽  
pp. 276-281 ◽  
Author(s):  
Michael A. Kron ◽  
Ahmed Metwali ◽  
Sanja Vodanovic-Jankovic ◽  
David Elliott
Keyword(s):  
T Cell ◽  
Cellular Response ◽  
Intestinal Inflammation ◽  
Trna Synthetase ◽  
Therapeutic Effects ◽  
Cell Transfer ◽  
Content Type ◽  
Anti Inflammatory ◽  
T Cell Transfer

ABSTRACTThe therapeutic effects of a controlled parasitic nematode infection on the course of inflammatory bowel disease (IBD) have been demonstrated in both animal and human models. However, the inability of individual well-characterized nematode proteins to recreate these beneficial effects has limited the application of component immunotherapy to human disease. The nematodes that cause chronic human lymphatic filariasis,Brugia malayiandWuchereria bancrofti, are among the parasites that induce immune suppression. Filarial lymphatic pathology has been shown to involve NF-κB pathway-dependent production of vascular endothelial growth factor (VEGF), and stimulation of VEGF expression has also been reported by interleukin 8 (IL-8) via NF-κB pathways. Previously, we have shown that the filarial asparaginyl-tRNA synthetase (rBmAsnRS) interacts with IL-8 receptors using a combination of extracellular loops that differ from those bound by IL-8. To test the hypothesis that rBmAsnRS might induce an anti-inflammatory effectin vivo, we studied the effects of rBmAsnRS in an established murine colitis model using T-cell transfer mice. T-cell transfer colitis mice treated intraperitoneally with 100 μg of rBmAsnRS four times over 2 weeks showed resolution of cellular infiltration in the colonic mucosa, along with induction of a CD8+cellular response. In addition, rBmAsnRS induced a rise in IL-10 production from CD3+and lipopolysaccharide (LPS)- and cytosine phosphate guanosine (CPG)-stimulated splenic cells. In summary, this work demonstrates a novel anti-inflammatory nematode protein, supports the hygiene hypothesis, and supports continued refinement of alternative immunotherapies for treatment of IBD.

scholarly journals Ameliorating effect of anti-Fas ligand MAb on wasting disease in murine model of chronic colitis

2003 ◽  
Vol 285 (4) ◽  
pp. G754-G760 ◽  
Author(s):  
N. Dan ◽  
T. Kanai ◽  
T. Totsuka ◽  
R. Iiyama ◽  
M. Yamazaki ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Lamina Propria ◽  
Fas Ligand ◽  
Intestinal Inflammation ◽  
Therapeutic Effects ◽  
Cell Transfer ◽  
Chronic Colitis ◽  
Wasting Disease ◽  
T Cell Transfer

Fas/Fas ligand (FasL) interaction has been implicated in the pathogenesis of various diseases. To clarify the involvement of Fas/FasL in the pathogenesis of intestinal inflammation, we investigated the preventive and therapeutic effects of neutralizing anti-FasL monoclonal antibody (MAb) on the development of chronic colitis induced by adaptive transfer of CD4+CD45RBhigh T cells to SCID mice. Administration of anti-FasL MAb from 1 day after T cell transfer (prevention study) resulted in a significant improvement of clinical manifestations such as wasting and diarrhea. However, histological examination showed that mucosal inflammation in the colon, such as infiltration of T cells and macrophages, was not improved by the anti-FasL MAb treatment. In vitro studies showed that anti-FasL MAb did not inhibit IFN-γ production by anti-CD3/CD28-stimulated lamina propria CD4+ T cells but suppressed TNF-α and IL-1β production by lamina propria mononuclear cells. Therapeutic administration of anti-FasL MAb from 3 wk after T cell transfer also improved ongoing wasting disease but not intestinal inflammation. These results suggest that the Fas/FasL interaction plays a critical role in regulating systemic wasting disease but not local intestinal inflammation.

scholarly journals Aronia Berry Supplementation Mitigates Inflammation in T Cell Transfer-Induced Colitis by Decreasing Oxidative Stress

Nutrients ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 1316 ◽  
Author(s):  
Ruisong Pei ◽  
Jiyuan Liu ◽  
Derek A. Martin ◽  
Jonathan C. Valdez ◽  
Justin Jeffety ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Antioxidant Enzymes ◽  
T Cell ◽  
Intestinal Inflammation ◽  
H2o2 Production ◽  
Cell Transfer ◽  
Fdg Uptake ◽  
Antioxidant Function ◽  
T Cell Transfer ◽  
Gpx Activity

Oxidative stress is involved in the pathogenesis and progression of inflammatory bowel disease. Consumption of aronia berry inhibits T cell transfer colitis, but the antioxidant mechanisms pertinent to immune function are unclear. We hypothesized that aronia berry consumption could inhibit inflammation by modulating the antioxidant function of immunocytes and gastrointestinal tissues. Colitis was induced in recombinase activating gene-1 deficient (Rag1-/-) mice injected with syngeneic CD4+CD62L+ naïve T cells. Concurrent with transfer, mice consumed either 4.5% w/w aronia berry-supplemented or a control diet for five weeks. Aronia berry inhibited intestinal inflammation evidenced by lower colon weight/length ratios, 2-deoxy-2-[18F]fluoro-d-glucose (FDG) uptake, mRNA expressions of tumor necrosis factor alpha (TNF-α), and interferon gamma (IFN-γ) in the colon. Aronia berry also suppressed systemic inflammation evidenced by lower FDG uptake in the spleen, liver, and lung. Colitis induced increased colon malondialdehyde (MDA), decreased colon glutathione peroxidase (GPx) activity, reduced glutathione (rGSH) level, and suppressed expression of antioxidant enzymes in the colon and mesenteric lymph node (MLN). Aronia berry upregulated expression of antioxidant enzymes, prevented colitis-associated depletion of rGSH, and maintained GPx activity. Moreover, aronia berry modulated mitochondria-specific antioxidant activity and decreased splenic mitochondrial H2O2 production in colitic mice. Thus, aronia berry consumption inhibits oxidative stress in the colon during T cell transfer colitis because of its multifaceted antioxidant function in both the cytosol and mitochondria of immunocytes.

Adoptive Transfer of Adenovirus Specific T-Cells in Children with Systemic Adenovirus Infection after Allogeneic Stem Cell Transplantation.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 80-80
Author(s):  
Tobias F. Feuchtinger ◽  
Susanne Matthes-Martin ◽  
Celine Richard ◽  
Thomas Lion ◽  
Klaus Hamprecht ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Adoptive Transfer ◽  
Cell Transfer ◽  
New Treatment ◽  
T Cell Transfer

Abstract Allogeneic stem cell transplantation (SCT) has become an increasing treatment option for a variety of malignant and non-malignant disease. During immune reconstitution the host is at significant risk for viral infections. Human adenovirus (HAdV) infection is especially in children an important and serious complication. Virus-specific T-cells are essential for the clearance of HAdV, since antiviral chemotherapy has been insufficient to date. We present a new treatment option using virus-specific donor T-cells for adoptive transfer of immunity to patients with systemic HAdV-infection. We isolated in 6 patients with systemic HAdV-infection after SCT virus-specific T-cells of the donor, according to INF-γ secretion after short in vitro stimulation with viral antigen, resulting in a combination of CD4+ and CD8+ T-cells. Between 5-50x103/kg T-cells were infused for adoptive transfer. For follow-up, the infection and the in-vivo expansion of infused T-cells were evaluated. Isolated cells showed high specificity and markedly reduced but residual alloreactivity in-vitro. In three of four evaluable patients the infused T-cells underwent an in-vivo expansion and in these three patients the viral load decreased in peripheral blood after adoptive T-cell transfer. In-vivo expansion of specific T-cells was dose-independent. T-cell infusion was well tolerated. One patient experienced GvHD°II of the skin after T-cell transfer. In conclusion specific T-cell immunotherapy as a new treatment approach for children was performed in 6 cases of systemic HAdV-infection after allogeneic SCT. Induction of a specific T-cell response through adoptive transfer has been shown feasible and effective to protect from HAdV-related complications.

scholarly journals Hyperoside Suppresses Renal Inflammation by Regulating Macrophage Polarization in Mice With Type 2 Diabetes Mellitus

2021 ◽  
Vol 12 ◽  
Author(s):  
Jialing Liu ◽  
Yanmei Zhang ◽  
Hongqin Sheng ◽  
Chunling Liang ◽  
Huazhen Liu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Macrophage Polarization ◽  
Fasting Blood Glucose ◽  
Therapeutic Effects ◽  
Protective Effects ◽  
Monocyte Chemoattractant Protein 1 ◽  
Anti Inflammatory

Accumulating evidence reveals that both inflammation and lymphocyte dysfunction play a vital role in the development of diabetic nephropathy (DN). Hyperoside (HPS) or quercetin-3-O-galactoside is an active flavonoid glycoside mainly found in the Chinese herbal medicine Tu-Si-Zi. Although HPS has a variety of pharmacological effects, including anti-oxidative and anti-apoptotic activities as well as podocyte-protective effects, its underlying anti-inflammatory mechanisms remain unclear. Herein, we investigated the therapeutic effects of HPS on murine DN and the potential mechanisms responsible for its efficacy. We used C57BLKS/6J Lepdb/db mice and a high glucose (HG)-induced bone marrow-derived macrophage (BMDM) polarization system to investigate the potentially protective effects of HPS on DN. Our results showed that HPS markedly reduced diabetes-induced albuminuria and glomerular mesangial matrix expansion, accompanied with a significant improvement of fasting blood glucose level, hyperlipidaemia and body weight. Mechanistically, pretreatment with HPS effectively regulated macrophage polarization by shifting proinflammatory M1 macrophages (F4/80+CD11b+CD86+) to anti-inflammatory M2 ones (F4/80+CD11b+CD206+) in vivo and in bone marrow-derived macrophages (BMDMs) in vitro, resulting in the inhibition of renal proinflammatory macrophage infiltration and the reduction in expression of monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor (TNF-α) and inducible nitric oxide synthase (iNOS) while increasing expression of anti-inflammatory cytokine Arg-1 and CD163/CD206 surface molecules. Unexpectedly, pretreatment with HPS suppressed CD4+ T cell proliferation in a coculture model of IL-4-induced M2 macrophages and splenic CD4+ T cells while promoting their differentiation into CD4+IL-4+ Th2 and CD4+Foxp3+ Treg cells. Taken together, we demonstrate that HPS ameliorates murine DN via promoting macrophage polarization from an M1 to M2 phenotype and CD4+ T cell differentiation into Th2 and Treg populations. Our findings may be implicated for the treatment of DN in clinic.

scholarly journals P032 MiR-511 deficiency aggravates T cell transfer colitis in mice

2021 ◽  
Vol 15 (Supplement_1) ◽  
pp. S147-S147
Author(s):  
S Rahman ◽  
A Elfiky ◽  
P H P van Hamersveld ◽  
C Verseijden ◽  
O Welting ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intestinal Inflammation ◽  
Activity Index ◽  
Disease Activity Index ◽  
Cell Populations ◽  
Spleen Weight ◽  
Cell Transfer ◽  
Rag 1 ◽  
T Cell Transfer

Abstract Background MiR-511 is embedded in intron region 5 of the CD206/MRC1 gene, expressed by macrophage and dendritic cell populations. In this study, we aimed to investigate the effect of MiR-511 deficiency on intestinal inflammation in a murine T cell transfer colitis model. Methods A double MiR-511- and Rag-1 (knockout) KO mouse was generated and a T cell transfer colitis was induced by intraperitoneal injection of naïve T cells from donor WT mice. Since these mice lack mature T and B cells, first signs of inflammation appeared at week 3 after T cell injection. An endoscopy score was obtained to determine inflammation at week 3 and 5, respectively. The experiment was terminated at week 5 and severity of inflammation was assessed on the basis of weight loss, colon weight/length ratio, histology score, spleen weight and disease activity index. In addition, flow cytometry was performed for analysing immune cell populations (monocyte, macrophages, dendritic cells, neutrophils) in the colons of both control and colitis groups and T cells in the spleens of colitis group, respectively. Results Following the induction of T cell transfer colitis, colon weight/length ratio, spleen weight and endoscopic score were significantly increased in the double KO mice compared to Rag-1 KO control mice. A higher histology score and disease activity index in the double KO with no change in weight loss compared to Rag-1 KO control mice was observed. A significant increase in monocyte population in the colons of double KO was seen and increased numbers of monocytes was also observed in the double KO control group with no inflammation. Also, a higher influx of T cells in the double KO mice with a significant increase in Foxp3 and IL4 population was observed in the group with colitis. Conclusion MiR-511 deficiency aggravates intestinal inflammation compared to Rag-1 KO control mice. Also, a higher presence of monocyte as well as T cell populations were observed in these mice. Together these data show that MiR-511 is involved in the regulation of intestinal health. Future research will focus on underlying mechanisms.

scholarly journals Activation of PPARγ and δ by dietary punicic acid ameliorates intestinal inflammation in mice

2011 ◽  
Vol 106 (6) ◽  
pp. 878-886 ◽  
Author(s):  
Josep Bassaganya-Riera ◽  
Margaret DiGuardo ◽  
Montse Climent ◽  
Cristina Vives ◽  
Adria Carbo ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Intestinal Inflammation ◽  
Foxp3 Expression ◽  
Sodium Sulphate ◽  
Molecular Evidence ◽  
Punicic Acid ◽  
Anti Inflammatory

The goal of the present study was to elucidate the mechanisms of immunoregulation by which dietary punicic acid (PUA) prevents or ameliorates experimental inflammatory bowel disease (IBD). The expression of PPARγ and δ, their responsive genes and pro-inflammatory cytokines was assayed in the colonic mucosa. Immune cell-specific PPARγ null, PPARδ knockout and wild-type mice were treated with PUA and challenged with 2·5 % dextran sodium sulphate (DSS). The prophylactic efficacy of PUA was examined in an IL-10− / −  model of IBD. The effect of PUA on the regulatory T-cell (Treg) compartment was also examined in mice with experimental IBD. PUA ameliorated spontaneous pan-enteritis in IL-10− / −  mice and DSS colitis, up-regulated Foxp3 expression in Treg and suppressed TNF-α, but the loss of functional PPARγ or δ impaired these anti-inflammatory effects. At the cellular level, the macrophage-specific deletion of PPARγ caused a complete abrogation of the protective effect of PUA, whereas the deletion of PPARδ or intestinal epithelial cell-specific PPARγ decreased its anti-inflammatory efficacy. We provide in vivo molecular evidence demonstrating that PUA ameliorates experimental IBD by regulating macrophage and T-cell function through PPARγ- and δ-dependent mechanisms.

Adoptive Transfer of Hexon-Specific T-Cells as a Treatment of Adenovirus Reactivation Following Allogeneic Stem Cell Transplantation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 796-796
Author(s):  
Kathrin Opherk ◽  
Friedhelm R Schuster ◽  
Wolfgang Andreas Bethge ◽  
Peter Bader ◽  
Johann Greil ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adoptive Immunotherapy ◽  
Therapeutic Option ◽  
T Cell Responses ◽  
Cell Transfer ◽  
Adoptive T Cell Transfer ◽  
Cell Responses ◽  
T Cell Transfer

Abstract Abstract 796 In pediatric patients human adenovirus (HAdV) was identified as a common viral pathogen responsible for significant morbidity and mortality post allo SCT. Antiviral chemotherapy is often insufficient. Given that T-cell immunity is crucial for protection against adenoviral infection/reactivation, cellular immunotherapy is a promising therapeutic option. The capsid protein Hexon has been shown to contain immunodominant T-cell epitopes, with T-cell responses in the majority of the healthy population. Therefore a prospective phase I/II clinical study was performed analysing safety and feasibility of adoptive Hexon-specific T-cell transfer in patients after allogeneic SCT and HAdV infection refractory to Cidofovir treatment. Hexon-specific T-cells were isolated from the SCT-donor by using the IFNγ secretion system and small T-cell populations were immediately infused, without in vitro expansion steps. Fourty pediatric and adult patients with a mean age of 15 years were treated according to the study protocol after haploidentical, matched unrelated and matched sibling donor SCT between day 11 and 327 post SCT. The T-cell dose varied from 300-25000 T-cells/kg. No acute toxicitiy was observed. In two patients GvHD °I-°II of the skin occured within two weeks after administration of specific T-cells, one patient also developed GvHD of the gut. In vivo T-cell responses were absent in all patients before adoptive T-cell transfer and detectable in 70% of evaluable patients within the first weeks after adoptive transfer, associated with a clinical and/or virological response to the adoptive T-cell transfer. However, in patients with adenoviral disease response rate was lower and 6 of 14 evaluable patients succumbed with the infection within few days, in spite of adoptive immunotherapy. This lead to the assumption, that adoptive treatment in patients with severe infection related morbidity was to late during the course of infection. In conclusion we could show that adoptive immunotherapy is safe, feasible and a promising therapeutic option in patients with HAdV infection. Infusion of small IFNγ producing Hexon-specific T-cells populations resulted in an in vivo expansion of specific T-cells in the majority of cases. Emergence of in vivo T-cell responses was closely associated with a clearance or reduction of the viral load. Disclosures: No relevant conflicts of interest to declare.

Tumor responses and early onset cytokine release syndrome in synovial sarcoma patients treated with a novel affinity-enhanced NY-ESO-1-targeting TCR-redirected T cell transfer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2530-2530 ◽  
Author(s):  
Mikiya Ishihara ◽  
Shigehisa Kitano ◽  
Hiroyoshi Hattori ◽  
Yoshihiro Miyahara ◽  
Hidefumi Kato ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Synovial Sarcoma ◽  
Early Onset ◽  
Cell Kinetics ◽  
Cell Transfer ◽  
Cytokine Release ◽  
Clinical Responses ◽  
T Cell Transfer

2530 Background: Adoptive transfer of TCR-redirected T cells has been reported to exhibit efficacy in some of melanoma and sarcoma patients. However, there have not been well known about cytokine release syndrome (CRS) or its relations to tumor responses. This study evaluates clinical responses in association with the cell kinetics and CRSs after transfer of high-affinity NY-ESO-1 TCR-gene transduced T cells in NY-ESO-1-expressiong cancer patients (NCT02366546). Methods: We developed a novel-type affinity-enhanced NY-ESO-1-specific TCR and an originally-developed retrovirus vector that encodes siRNA to silence endogenous TCR creation. The NY-ESO-1/TCR sequence is mutated for high affinity with replacements of G50A and A51E in CDR2 region. This is a first-in-man clinical trial of the novel NY-ESO-1-specfic TCR-T cell transfer to evaluate the safety, in vivo cell kinetics and clinical responses. It was designed as a cell-dose escalation from 5 x108 to 5 x109 cells. NY-ESO-1-expressing refractory cancer patients were enrolled, with 3+3 cohort design. Cyclophosphamide (1,500mg/m2) were administered prior to the TCR-T cell transfer as pre-conditioning. Results: 9 patients were treated with the NY-ESO-1/TCR-T cell transfer. The TCR-T cells expanded in peripheral blood with a dose-dependent manner, associated with rapid proliferation within 5 days after the cell transfer. 3 patients receiving 5x109 cells developed early-onset CRSs, with elevations of serum IL-6, IFN-γ. The CRSs developed on day1 or 2 after the cell transfer. They were well managed with tocilizumab treatment. 3 synovial sarcoma patients exhibited tumor shrinkages of partial responses, and they all had high-expression of NY-ESO-1 in the tumor samples, namely, 75% or more. Exploratory analysis revealed that multiple chemotactic cytokines including CCL2 and CCL7, and IL-3 increased in the serum from the patients with CRS. The proportions of effector-memory phenotype T cells in the infused cell-product were significantly associated with CRS development. Conclusions: The affinity-enhanced NY-ESO-1/TCR-T cell transfer exhibited early-onset CRS in association with in vivo cell proliferation and sequential tumor responses in the patients with high-NY-ESO-1-expressing synovial sarcoma. Clinical trial information: NCT02366546.

scholarly journals Therapeutic Immunity by Adoptive Tumor-primed CD4+ T-cell Transfer in Combination With In Vivo GITR Ligation

2009 ◽  
Vol 17 (7) ◽  
pp. 1274-1281 ◽  
Author(s):  
Zuqiang Liu ◽  
Shenghe Tian ◽  
Louis D Falo ◽  
Shimon Sakaguchi ◽  
Zhaoyang You
Keyword(s):  
T Cell ◽  
Cd4 T Cell ◽  
Cell Transfer ◽  
T Cell Transfer

scholarly journals Cytokine Release Syndrome and Tumor Responses in a First-in-Man Trial of a Novel Affinity-Enhanced TCR-Gene Transduced T Cell Transfer Targeting NY-ESO-1 Antigen

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 841-841
Author(s):  
Shinichi Kageyama ◽  
Mikiya Ishihara ◽  
Shigehisa Kitano ◽  
Yoshihiro Miyahara ◽  
Hidefumi Kato ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Therapy ◽  
Cell Kinetics ◽  
Cell Transfer ◽  
T Cell Therapy ◽  
Car T Cell ◽  
Car T ◽  
T Cell Transfer

Abstract Adoptive cell transfers of receptor gene-engineered T cells include chimeric antigen receptor-gene transduced T (CAR-T) cell therapy and TCR-gene transduced T (TCR-T) cell therapy. In CD19-CAR-T cell therapy, high incidence of cytokine release syndrome (CRS) is associated with in vivo CAR-T cell proliferation and its clinical efficacy. In human TCR-T cell therapies, there have not been well known about CRS and its association with in vivo T cell kinetics or tumor responses. We have been developing a novel-type affinity-enhanced NY-ESO-1-specific TCR, and an original retrovirus vector that encodes siRNA to silence endogenous TCR creation. The NY-ESO-1 TCR is mutated for high affinity with replacements of G50A and A51E in CDR2 region, which is restricted with HLA-A*02:01 and A*02:06. We extensively examined potential cross-reactivities to different antigen-peptides in preclinical studies, and the high-affinity NY-ESO-1 TCR did not recognize analogous peptides. The new generation retroviral TCR-vector provides enhanced expression of transduced tumor-specific TCRs and an inhibition effect of formations of self-reactive TCRs. This is a first-in-man clinical trial of the novel NY-ESO-1-specfic TCR-T cell transfer to evaluate the safety, in vivo cell kinetics and clinical responses. It is designed as a cell-dose escalation from 5 x108 to 5 x109 cells. NY-ESO-1-expressing refractory cancer patients were enrolled, with 3+3 cohort design. Cyclophosphamide with/without fludarabine were administered prior to the TCR-T cell transfer as pre-conditioning. Six patients were treated with the NY-ESO-1 TCR-T cell transfer, and evaluated for the safety and in vivo cell kinetics. The TCR-T cells appeared in peripheral blood with a dose-dependent manner, associated with in vivo proliferation in an early phase. In three patients given 5x108 cells, no toxicities were seen. Two patients receiving 5x109 cells developed early-phase CRS (G2), with elevations of serum IL-6 and IFN-gamma. They were managed the treatment of anti-IL-6 receptor monoclonal antibody, tocilizumab. In a patient who developed CRS, an event of lung injury (G3) occurred, which was associated with marked infiltration of the NY-ESO-1 TCR-T cells. It was successfully treated with steroid. Two synovial sarcoma patients exhibited tumor responses of PRs. In one patient, progression-free survival lasted more than 8 months. In summary, the affinity-enhanced NY-ESO-1 TCR-T cell transfer exhibited CRSs in association with in vivo cell proliferation and sequential tumor responses. Disclosures No relevant conflicts of interest to declare.

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