bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bortezomib Sensitizes Non-Hodgkin’s Lymphoma Cells to Apoptosis Induced by Antibodies to TRAIL Receptors R1 and R2.
Authors: Smith Mitchell Reed , Jin Fang , Joshi Indira 
Published: April 2020

Abstract
TRAIL-R1 and -R2 signaling induces apoptosis via a pathway that activates caspase 8. The proteosome inhibitor bortezomib may act via several pathways. Agonistic antibodies to TRAIL-R1 and -R2 and bortezomib are in clinical trials in solid tumors and hematologic malignancies. To develop rational combinations for future clinical studies, we investigated the actions of these agents on non-Hodgkin s lymphoma (NHL) cell lines. The t(14;18)+, EBV- NHL cell lines DoHH2 and WSU-FSCCL were treated with agonistic monoclonal antibodies to TRAIL-R1 (HGS-ETR1) and -R2 (HGS-ETR2) (Human Genome Sciences, Rockville, MD) and/or bortezomib. While HGS-ETR 1 and HGS-ETR 2 are effective inducers of apoptosis in FSCCL, DoHH2, which expresses dim TRAIL-R1 (DR4, HGS-ETR1 target) and TRAIL-R2 (DR5, HGS-ETR2 target), shows minimal growth inhibition or apoptosis induction by HGS-ETR1 or HGS-ETR2. Bortezomib has modest effects on DoHH2 cells in growth inhibition and apoptosis assays. HGS-ETR1 and HGS-ETR2 induction of apoptosis in WSU-FSCCL is efficiently blocked by the caspase inhibitor ZVAD. In contrast, bortezomib effects are not blocked by ZVAD, indicating an independent mechanism of action. To determine if these separate pathways would provide enhanced combination activity, DoHH2 cells were pre-treated with bortezomib for 30 min, followed by incubation with HGS-ETR1 or HGS-ETR2. This led to supra-additive induction of apoptosis (annexin V staining). We conclude that bortezomib sensitizes DoHH2 cells to the action of HGS-ETR1 and HGS-ETR2. Further, bortezomib induces apoptosis in DoHH2 cells by an independent mechanism, and the combination of TRAIL-receptor signaling and bortezomib may be a useful combination to explore.
Rituximab Plus CHOP Followed by Maintenance Rituximab as Initial Therapy for Aggressive Non-Hodgkin’s Lymphoma (NHL); Initial Results of Induction Therapy, Including Rituximab Pharmacokinetics, in a Phase II Study.
Authors: Huang Jane E. , Saleh Alfred , Lee J. Thomas , Langmuir Virginia , Zhang Fan , Hainsworth John 
Published: April 2020

Abstract
Background: This study was designed to investigate the activity, safety, and pharmacokinetics of rituximab (Rituxan®, R) plus CHOP induction therapy followed by maintenance R in previously untreated patients with aggressive NHL. The initial results of R-CHOP induction therapy are reported here.
Methods: 105 patients with aggressive NHL (diffuse large B-cell or follicle center/follicular grade III by REAL; Type D, F, G or H by IWF) were enrolled into this open-label, multi-center, community based, single-arm, Phase II trial. Patients received 6 or 8 cycles (per standard practice at each site) of R-CHOP induction therapy (cyclophosphamide 750 mg/m2, vincristine 1.4 mg/m2, doxorubicin 50 mg/m2 IV on Day 1, prednisone 100 mg/day Days 1–5). R 375 mg/m2 was given on Day 1 of each cycle, except for cycle 1, when it was given 2–3 days before CHOP administration. Subjects with documented responses (CR/CRu or PR) to induction receive maintenance R (4 weekly infusions) beginning 28 days after the completion of induction and repeated every 6 months for 2 years. The primary endpoints were CR/CRu after the completion of induction and the incidence of R infusion-related toxicity in induction and maintenance. Overall response rate (ORR), infusion times, serious adverse events (SAE), and the partial rituximab pharmacokinetic profile were also measured.
Results: Baseline characteristics of patients enrolled were: median age 59 y (49.5% ≥60 y), IPI ≥3 in 31.4 % patients, Ann Arbor Stage II,III, IV in 21.9%, 39.0%, and 39.0% of patients, respectively. CR/CRu at the end of induction in 105 patients was 51.4% (80.0% ORR). 1.9% of patients had progressive disease (PD) during induction. SAE occurred in 33% of subjects during induction with the most common event being febrile neutropenia (14.3%). 5 subjects died during induction (pulmonary embolus, ruptured abdominal aortic aneurysm, pneumonia x2, unknown cause). Grade 3–4 rituximab infusion-related toxicity occurred in 3.9% of subjects during Cycle 1 which decreased to 0% by Cycle 5. 64.3% of patients received their R infusion within 3 hours on Cycle 2; this increased to 74.7% patients at cycle 6. The partial pharmacokinetic profile (peak and trough concentration) of R was measured in 10 patients and will be presented at the meeting.
Conclusion: Rituximab + CHOP chemotherapy is well tolerated and has an excellent response rate when given in the community setting. The outcomes of maintenance therapy in this study await further follow-up.
Brachytherapy Combined with CpG ODN Enhances Development of a Tumor Antigen-Specific CD8 Response.
Authors: Rich Nathan T. , Dahle Chris E. , Modrick Joseph M. , Buatti John , Weiner George J. 
Published: April 2020

Abstract
Background: CpG Oligodeoxynucleotides (CpG ODN) are TLR9 agonists that have potent immunostimulatory effects and function well as immune adjuvants. Preliminary data suggests that combining CpG ODN with apoptosis-inducing agents can enhance the development of a tumor specific immune response. We hypothesize that administration, in a temporally and spatially coordinated fashion, of a therapy that induces apoptosis of lymphoma cells with an immunostimulatory agent such as CpG ODN will enhance the development of an anti-lymphoma T-cell response.
Methods: C57Bl/6 mice were inoculated subcutaneously with 2x10^6 EG7 lymphoma cells (EL4 murine T cell lymphoma line with an Ova transgene). On day 11 mice were treated with brachytherapy (radiation therapy administered by temporary placement of an 125-I pellet within the tumor), intra-tumor CpG-ODN or both CpG ODN and brachytherapy. A standard radiation dose equivalent to exposure to a 5 mCi pellet for 10 minutes was used as brachytherapy for each mouse. Sham radiation (placement of a non-radioactive seed in the tumor) and control (non-CpG) ODN were used as controls. Seven days after treatment, spleens were harvested and stained with CD8a-FITC and Ova-tetramer-PE to identify Ova-specific CD8 cells. Non-specific tetramer binding was detected using LCMV-tetramer-PE as a control.
Results: The combination of brachytherapy and CpG ODN led to the development of an enhanced Ova-specific CD8 response as measured by the percent of CD8(+) cells that were positive for Ova-tetramer minus the percent that were positive for the control tetramer.
Percent of CD8 Cells that Stain with Ova Tetramer
No CpG ODN CpG ODN No Radiation 0.6 4.1 Radiation 0.7 10.0
Similar results were found in repeated experiments where brachytherapy and CpG ODN were administered daily times three.
Conclusions: Brachytherapy administered via temporary placement of a radioactive seed in a lymphoma, followed immediately by injection of immunostimulatory CpG ODN into the same tumor bed, results in enhanced development of a tumor antigen specific T-cell response. Ongoing studies are exploring the anti-tumor activity of this response, how it compares to the combination of external beam radiation and CpG ODN, whether such responses can be induced against native antigens, and how CpG ODN compare to other immunostimulatory agents when used in this capacity.
Anti-CD45 Mediated Cytolysis of Human T-Cell Lymphoma Cells.
Authors: Wulf Gerald G. , Boehnke Anita , Glass Bertram , Truemper Lorenz 
Published: April 2020

Abstract
Anti-CD45 mediated cytoreduction is an effective means for T-cell depletion in rodents and humans. In man, the CD45-specific rat monoclonal antibodies YTH24 and YTH54 are IgG2b subclass, exert a predominantly complement-dependent cytolytic activity against normal T-lymphocytes, and have been safely given to patients as part of conditioning therapies for allogeneic stem cell transplantation. The efficacy of such antibodies against human lymphoma is unknown. Therefore, we evaluated the cytolytic activity of YTH24 and YTH54 by complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), as well as by direct apoptotic and antiproliferative effects, against a panel of Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL) cell lines, and against primary specimens. Significant CDC activity (&gt;50% cytolysis) of the antibodies YTH54 and YTH24 was observed against three of five T-cell lymphoma lines, but against only one of nine B-cell lymphoma lines and none of four HD cell lines. The combination of YTH54 and YTH24 induced ADCC in all T-cell lymphoma cell lines and three primary leukemic T-cell lymphoma specimens, but were ineffective in B-cell lymphoma and HD cell lines.There were only minor effects of either antibody or the combination on lymphoma cell apoptosis or cell cycle arrest. In summary, anti-CD45 mediated CDC and ADCC via the antibodies YTH24 and YTH54 are primarily effective against lymphoma cells with T-cell phenotype, and may be an immunotherapeutic tool for the treatment of human T-cell lymphoma.
A Phase II Study of Xcellerated T Cells™ in Patients with Relapsed or Refractory Indolent Non-Hodgkin’s Lymphoma (NHL).
Authors: Bartlett Nancy L. , Gribben John G. , Boccia Ralph V. , Milder Michael S. , Aboulafia David M. , Castro Januario , Flinn Ian , Hayes-Lattin Brandon , Kaplan Lawrence , Lin Thomas , Lucas Jennifer B. , Maloney David G. , McLaughlin Peter , McSweeney Peter A. , Mohrbacher Ann , Redfern Charles , Steis Ronald , Stephenson Joe J. , Strair Roger , Berenson Ronald J. , Frohlich Mark W. 
Published: April 2020

Abstract
Background: T cells can be activated and expanded ex vivo using the Xcellerate™ Process, in which peripheral blood mononuclear cells (PBMC) are incubated with anti-CD3 and anti-CD28 antibody-coated magnetic beads (Xcyte™-Dynabeads®). In an ongoing trial of Xcellerated T Cells in subjects with chronic lymphocytic leukemia, marked and sustained reductions in lymphadenopathy and splenomegaly were observed (Wierda et al., ASCO 2004). Increases in neutrophil, platelet and NK cell counts were also documented. This study is designed to determine if similar effects can be observed in subjects with indolent non-Hodgkin’s lymphoma (NHL).
Methods: Subjects must have indolent NHL (follicular, small lymphocytic, marginal zone, or mantle cell lymphoma), have relapsed or refractory disease, and have received at least 1 but not more than 4 prior treatment regimens. PBMC are collected by leukapheresis for the Xcellerate Process, and subjects subsequently receive two infusions of 20–60 x 109 Xcellerated T Cells separated by 6–8 weeks. Approximately 40 subjects will be treated.
Results: Seven subjects have been enrolled and Xcellerated T Cells have been manufactured in 5 subjects to date. T cells expanded 181.8 ± 88.5 fold and the final product was &gt;99.0 ± 0.0% T cells (mean + SD). One subject with small lymphocytic lymphoma has been treated with two infusions of 38.6 x 109 Xcellerated T Cells. There have been no serious adverse events to date. Following the first treatment, the lymphocyte count increased from 1.8 x 109/L to 2.9 x 109/L on Day 28. The neutrophil count also increased from 2.9 x 109/L to 5.5 x 109/L six weeks following infusion. The subject had a significant reduction in cervical lymphadenopathy and a slight decrease in bulky mesenteric lymphadenopathy six weeks following the first infusion.
Conclusions: Xcellerated T Cells can be manufactured in subjects with indolent NHL. Treatment leads to significant increases in T cell and neutrophil counts. Preliminary data suggest a reduction in peripheral lymphadenopathy. Data on additional subjects will be presented.
Naïve T Cell Level and TCR Vβ Repertoire Usage in Patients with Chronic Myelogenous Leukemia.
Authors: Li Yangqiu , Geng Suxia , Yang Lijian , Chen Shaohua , Yin Qingsong 
Published: April 2020

Abstract
During early T lymphopoiesis, rearrangement of the V, D and J segments of the TCR genes result in deletion of the intervening chromosomal DNA and formation of circular excision circles, the so-called signal joint T-cell receptor rearrangement excision circles (sjTRECs, TRECs). TRECs are assumed to have a high stability, and can not multiply and consequently are diluted during T cell proliferation. It has been used to evaluate thymic function in T-cell immune reconstruction after treatment in HTLV-I-infected or stem cell transplantation. Defects of cellular immunity, however, may also play a role in hematologic malignancies. On the other hand, examination of T cell receptor (TCR) gene repertoire is important to analysis the immune status of the patients with malignant neoplasms, because clonal expansion of T cells permit the identification of specific antigen response of T cells. Little is known about the feature of T-cell immune state in CML. In order to evaluate the thymic recent output function and the expansion feature of TCR V beta subfamily T cells in patients with chronic myelogenous leukemia (CML in chronic phase), TRECs level and TCR V beta repertoire usage and clonality were analyzed. Quantitative detection of TRECs in DNA of peripheral blood mononuclear cells from 20 cases with CML, purified CD4+ or CD8+ cells from 3 cases with CML were preformed by real-time PCR (TaqMan) analysis. And the TRECs-number was related to the number of T-cells by determination of the number of CD3-positive cells. The expression and cloanlity analysis of TCR V beta repertoire were detected by RT-PCR and genescan technique in PBMC from the 14 out of 20 patients. 9 normal individuals served as controls. A dramatic reduction of TRECs values in patients with CML was showed. The mean value of TRECs was 0.06±0.16 copies /1000 T cells in CML patients and 6.84±4.71 copies /1000 T cells in normal individuals, respectively (p&lt;0.01). In 16 out of 20 CML cases no TRECs copies could be detected in peripheral blood, and lower value of TRECs could be identified in sorted CD4+ or CD8+ cells. The expression of 1–12 V beta subfamilies was found in samples from 14 patients. Clonal expanded T cells from 13 cases could be identified in some V beta subfamilies, which were preferentially used in V beta 3, V beta 10, V beta 19, V beta 21 and V beta 22 subfamilies. In conclusion, this is, to our knowledge, the first description of TRECs level in CML patients. These results showed a prominent reduction of TREC levels in CML. The predominant usage and clonal expansion of TCR Vβ subfamily T cells could be identified in CML patients, indicating the host could have the ability for specific immune response to leukemia associated antigen, in despite of T cell immunodeficiency was showed in patients.
Successful Peripheral Blood Stem Cell (PBSC) Mobilisation with G-CSF in Patients with Chronic Myeloid Leukaemia Achieving Complete Cytogenetic Remission with Imatinib.
Authors: Carella A.M. , Corsetti Maria T. , Bodenizza Carlo , Iuliano Francesco , Pucci Giulia , Jacopino Pasquale , Martino Bruno , Brugiatelli Maura , Ferrara Felicetto 
Published: April 2020

Abstract
The clinical studies have demonstrated the efficacy of Imatinib in the induction of hematological remission, cytogenetic remission (CCR) and molecular reduction of the bcl-abl transcript as shown by RT-qPCR. Unfortunately, the optimal long-term management of patients who achieve CCR after Imatinib is unknown. It is unclear that Imatinib alone will prove to be curative and initial responders may eventually lose Imatinib responsiveness. Therefore it may be prudent to collect autologous PBSC in CCR patients treated with Imatinib with low levels of detectable leukemia analyzed by molecular tests. We evaluated G-CSF mobilisation of PBSC in 18 patients who have achieved CCR with Imatinib. Our data demonstrated that the target CD34+ cell yields of ≥ 2.0x106/kg was attained with G-CSF at the dose of 10 mg/kg/day in 4/8 (50%) patients during uninterrupted Imatinib therapy and in 8/10 (80%) when Imatinib was temporarily interrupted. Three patients (37%) in the first group and 7 patients (70%) in the second group achieved &gt;1x106/kg CD34+ cell yield per apheresis. Twelve patients were evaluated on PBSC for bcr-abl by RT-qPCR. Three patients were negative and in the other 9 patients, a median of 0.20 (range, 0.02–8.6) remained detectable. These data compared favourably with a median of 0.04 (range, 0.02 – 0.86) of all measurements taken before mobilisation. There was no impact of G-CSF mobilisation on the CML as measured by cytogenetic and serial blood bcr-abl levels. In conclusion, PBSC mobilisation with Imatinib and G-CSF in CCR patients is feasible, CD34+ cell yield is significantly better with temporary withheld of Imatinib, G-CSF did not preferentially mobilize leukemic progenitors and leukemic burden did not show significant change in the months following G-CSF mobilisation.
Imatinib Therapy for Chronic Myeloid Leukemia Patients Who Relapse after Allogeneic Stem Cell Transplantation: A Molecular Analysis.
Authors: Palandri Francesca , Martinelli Giovanni , Amabile Marilina , Bonifazi Francesca , Bandini Giuseppe , Benedetti Fabio , Usala Emilio , Angelucci Emanuele , Tiribelli Mario , Fanin Renato , Sorio Marco , Arpinati Mario , Testoni Nicoletta , Falcioni Sadia , Giannini Maria Benedetta , Poerio Angela , Soverini Simona , Pane Fabrizio , Rosti Gianantonio , Tura Sante , Baccarani Michele 
Published: April 2020

Abstract
We analyzed clinical and molecular follow-up of 16 patients with chronic myeloid leukemia (CML) relapsing after allogeneic stem cell transplantation (SCT).
The median interval between allogeneic SCT and relapse was 26 months (7–162). Two patients had failed treatment with donor lymphocyte infusions prior to Imatinib; four patients had received therapy with IFN alpha. All patients were treated with Imatinib (400 or 600 mg/daily). One patient had received Imatinib before allogeneic SCT. The overall complete hematological (CHR) and cytogenetic responses (CCyR) were 100% for all patients either relapsed in CP or AP. All patients achieved complete molecular response (CMR), intended as 3 logs reduction of BCR-ABL/B2M within 18 months; 8/16 patients obtained a CMR within three months, independently of the phase of the disease at of relapse. Median follow-up after start of Imatinib therapy was 24 months (range 6–36). Chimerism status evaluated in 9 patients showed conversion to full donor chimerism after therapy in all but one of them. Imatinib has significant activity against CML in relapse after allogeneic bone marrow transplantation with durable cytogenetic and molecular remissions obtainable in all patients.
Imatinib Achieves High Rates of Complete Citogenetic Remission (CCR) in CML Patients Relapsed after Autografting anf IFN-α Therapy.
Authors: Corsetti Maria T. , Beltrami Germana , Carella A.M. 
Published: April 2020

Abstract
Background: Imatinib, a selective inhibitor of the bcr-abl tyrosine kinase, induces CCR in the majority of patients with CML in first chronic phase (CP). In the present study we addressed the question if such achievement of CCR can occur also in patients relapsed after autografting and IFN-α therapy.
Methods: from 1991 to 2001, 50 patients with early chronic phase were treated with hydroxyurea; subsequently, when WBC count was less than 10x109/L, the patients were treated with idarubicin containing regimen (ICE/mini-ICE protocols), mobilization of diploid or prevalently diploid peripheral blood stem cells (PBSC) with G-CSF during the early phase of recovery after chemotherapy and high-dose therapy followed by autologous diploid PBSC previously collected and cryopreserved. After engraftment, the patients received maintenance therapy with IFN-α (3MU/three times weekly). From september 2000, Imatinib became available for CML patients relapsed after IFN-α treatment. From that time all patients who relapsed after autografting and IFN-α received rescue therapy with Imatinib at 400 mg/daily for CP (Novartis protocol CSTI-106) and 600 mg/daily for accelerated phase (AP) (Novartis protocol-Italian Cooperative Study Group CSTI-003). Imatinib was given to 22 patients cytogenetically relapsed in CP and to 1 patient evoluted in AP.
Results: At the time of analysis (July 31, 2004), the median treatment duration with Imatinib was 32 months (range, 1 to 47). Four patients stopped Imatinib between 9 and 12 months for no response/progression. The patient in AP died of heart failure one month after starting Imatinib; since this patient have had previous history of cardiac failure, it is not clear if this event should be correlated with Imatinib therapy; two other patients died for progression. Imatinib induced major cytogenetic responses in 16/23 patients (70%) of whom 14/23 achieving CCR (61%). At a median follow up of 36 months the PFS and OS were 78% and 87%, respectively. Grade ≥III hematological toxicity occurred in 5 patients; this toxicity resolved with temporary discontinuation of the treatment.
Conclusion: Imatinib is an effective therapy for CP-CML patients who relapsed after autografting and IFN-α. The high rate of sustained haematological and cytogenetic responses achieved with Imatinib were associated to a favourable and manageable toxicity profile.
The NK and NKT Cell Compartment Is Suppressed in CML Patients before and after Imatinib Treatment.
Authors: Chen Christiane I.-U. , Maecker Holden , Lee Peter P. 
Published: April 2020

Abstract
In CML patients, lymphocyte subsets have been shown to be disturbed. NK cells as well as CD8+ T cells have been shown to be significantly lower in patients with relapse after BMT than without relapse (Jiang et al., 1996). After successful treatment (IFN- α and BMT/SCT), MHC-restricted CD8+ T cells as well as MHC-unrestricted cytotoxic NK and lymphokine activated killer (LAK) cells play an important role in controlling the disease (Meseri et al., 1993, de Castro et al., 2003, Molldrem et al., 2000), which can lead not only to hematological, but also cytogenetic responses. The development of imatinib mesylate, a selective inhibitor of the bcr/abl tyrosine kinase, as a first-line therapy enormously enhanced treatment options for CML patients, and has led to hematologic, and occasionally cytogenetic, responses at various stages of disease. To explore, if CML patients, who develop clinical responses with imatinib mesylate treatment, have normalization of their lymphocyte subsets with restoration of CD8+ and NK cells, we studied peripheral blood T cell, B cell, and NK cell subpopulations in patients in chronic or accelerated phase before and after treatment with imatinib mesylate. In 5 CML patients, 8-color flow cytometry was applied to investigate the lymphocyte subsets using anti-CD3, anti-CD4, anti-CD8, anti-CD19, anti-CD56, anti-CD25, anti-CD27, and anti-CD45RA antibodies. 5 healthy donors served as controls. There was no significant difference in CD19+ B cells or CD3+ T cells as well as its CD4+ and CD8+ subsets between CML patients and healthy controls. T regulatory cells (CD4+CD25+) were also similar in patients in comparison to the healthy controls (0.6% – 3% vs 2.3%). In contrast, CD3–CD56+ NK cells (4% vs 14%, p&lt;0.05) as well as NK T cells (CD3+CD56+ 1% vs 14%, p&lt;0.02; CD8+CD56+ 2% vs 17%, p&lt;0.03) were profoundly decreased in CML patients compared to the healthy controls prior to treatment with imatinib mesylate. Importantly, these abnormalities persisted even during treatment and following hematological responses (range 10 months – 35 months) (CD3-CD56+ 4–8%, CD3+CD56+ 0.5–5.5%, CD8+CD56+ 2.7–7%). On further analysis, these NK and NKT cells were mostly effector (CD45RA+CD27−, 50–80%) or memory (CD45RA-CD27+, 10–30%) cells. These results suggest, that CML not only disturbs the myeloid and the lymphoid compartment before treatment, but persistently impairs the MHC-unrestricted cytotoxic NK cells and NKT cells after treatment with imatinib mesylate, even in patients in hematological (and cytogenetic) remission with normal white cell counts (2.0 – 8.0/nl). Further investigations are required to better understand the mechanism of the prolonged and specific NK and NKT cell suppression in imatinib mesylate treated patients, and its impact on the course of the disease.