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The pharmacokinetics (PK) of the anti-CD20 monoclonal antibody obinutuzumab was assessed after single intravenous dosing to cynomolgus monkeys. In addition, the pharmacokinetic-pharmacodynamic (PKPD) relationship for B-cell depletion was characterized. The PKPD model was used to estimate the B-cell repopulation during the recovery phase of chronic toxicology studies, thereby supporting the study design, in particular planning the recovery phase duration. Marked immunogenicity against obinutuzumab was observed approximately 10 days after single dose, leading to an up to ∼30-fold increase in obinutuzumab clearance in the affected monkeys. Despite this accelerated clearance, the PK could be characterized, either by disregarding the clearance in noncompartmental PK analysis or by capturing it explicitly as an additional time-dependent clearance process in compartmental modeling. This latter step was crucial to model the PKPD of B-cells as an indirect response to obinutuzumab exposure, showing that-without immune response-the limiting factor is obinutuzumab elimination with concentrations below 0.02 μg/mL required for initiation of B-cell recovery. Overall, the results demonstrate that despite a marked anti-drug antibody response in the nonclinical animal species, the PK and PKPD of obinutuzumab could be characterized successfully by appropriately addressing the immune-modulated clearance pathway in data analysis and modeling.

Proliferative glomerulonephritis with monoclonal immunoglobulin deposits (PGNMID) is a distinct form of glomerulonephritis that often recurs after kidney transplantation causing severe graft injury and often failure.We describe post transplant outcomes and response to therapy in 20 recipients with PGNMID. Evidence of PGNMID recurrence or lack thereof was determined by protocol and clinical biopsies.Histologic recurrence (deposition of monoclonal immunoglobulin) occurred in 18 of 20 recipients (90%), a median of 7 (1 to 65) months post transplant. At diagnosis, recurrence was generally associated with mild or no clinical manifestations and often with mild glomerular morphologic changes by light microcopy. Four of the 18 patients with recurrence did not progress and were not treated. Another 4 patients with recurrences were treated with cyclophosphamide with or without plasmapheresis, and 2 of these grafts were lost from glomerulonephritis. Nine patients with recurrences were treated with anti-CD20 antibodies (rituximab) alone, resulting in improvements in estimated glomerular filtration rate (31.5 ± 16 versus 38.8 ± 13.3 mL/min/1.73 m, P = 0.011) and proteinuria (1280 [117 to 3752] versus 168 [83 to 1613] mg/24 h, P = 0.012) although complete clinical remission was rare. One graft in this later group was lost from recurrence 141 months post transplant. Posttreatment biopsies demonstrated stable or improved glomerular histology in most cases. However, PGNMID did not resolve in any case. Four patients received rituximab 4 months pretransplant to prevent recurrence. However, 3 had mild recurrences.Rituximab treatment of early PGNMID recurrence is effective, resulting in reasonable, long-term graft survival. Whether pretransplant rituximab modifies the course of recurrence requires additional studies.

Technical advances that lead to the era of targeted therapeutics demanded several milestones that were reached in the second half of the previous century. Professor Wacław Szybalski was the first one to perform a stable gene transfer in eukaryotic cells. To do so, he used his own designed system consisting of HPRT-deficient cells and HAT selective medium. Moreover, the first-ever hybridoma cells were also constructed by Wacław Szybalski’s team. These spectacular achievements made him not only a forerunner of gene therapy, but also became a foundation for immunotherapy, as hybridoma and their selection by the HPRT-HAT system turned into a crucial technical step during production of monoclonal antibodies (mAbs). Herein, we present a story of anti-CD20 mAbs, one of the most successful lines of anticancer drugs. When looking back into history, the prototypic mAb rituximab was considered the biggest step forward in the therapy of B-cell malignancies. Nowadays, the second and third generations of anti-CD20 mAbs are approved in clinical use and numerous breakthrough studies on immune effector mechanisms were conducted with the aforementioned immunotherapeutics as a model.

Background: MRG001 is an antibody drug conjugate (ADC), which is composed of a chimeric anti-CD20 monoclonal antibody conjugated via a valine citrulline linker to monomethyl auristatin E (MMAE), an anti-microtubulin agent. In preclinical studies, MRG001 demonstrated significant tumor growth inhibition in rituximab-resistant non-Hodgkin's lymphoma (NHL) models. MRG001 is being evaluated in a first-in-human, open-label, multicenter Phase I study for the safety, tolerability, pharmacokinetics (PK) and preliminary antitumor activity in patients with CD20-positive relapsed or refractory (R/R) B-cell NHL. Methods: MRG001 was evaluated as a monotherapy for the treatment of patients with confirmed CD20-positive R/R B-cell NHL. The study consists of Phase Ia dose escalation and Ib dose expansion. In the Phase Ia dose-escalation study utilizing a "3+3" design, patients with pathologically confirmed R/R NHL received single agent MRG001 intravenously once every 3 weeks (Q3W) for a maximum of 6 treatment cycles. Six dose levels ranging from 0.15 to 2.5 mg/kg were evaluated for safety, PK and preliminary antitumor activity to determine the MTD/RP2D. Results: From June 25, 2019 to May 31, 2021, a total of 21 subjects with DLBCL (n=8), FL (n=12), and MZL (n=1) who met the eligibility criteria had received at least two cycles of MRG001. As of May 31, 2021, 18 subjects were off treatment and 3 subjects were still on treatment. There were 3 subjects enrolled into the 0.15, 0.3 , 0.6, 1.2 and 2.5 mg/kg cohort respectively, and 6 subjects enrolled into the 1.8 mg/kg cohort. Of the 21 subjects enrolled, 12 subjects were male and 9 subjects were female, with age ranging from 27 to 75 years old. Among the 18 subjects who were off treatment, 5 had completed 6 cycles of treatment, and 13 had drug discontinuation (12 due to progression of disease and 1 subject due to withdrawal of the informed consent for personal reasons). Commonly observed drug-related TEAEs were decreased white blood cell/neutrophil/lymphocyte counts, ALT/AST elevation, pyrexia, hypertension, increased LDH, QT prolongation, and thrombocytopenia.TEAEs (29 cases) ≥ Grade 3 were reported in 9 subjects, including 23 drug-related TEAEs in 8 subjects. The most commonly reported Grade 3 or above TRAEs were leukopenia/neutropenia, lymphopenia, hypertension, and ALT elevation. In the 2.5 mg/kg cohort, two subjects experienced drug-related toxicities that met the DLT definition per protocol, including 1 subject with Grade 3 hyperlipidemia and 1 subject with Grade 4 neutropenia that lasted 5 days. There was no death due to AEs. PK samples of total antibody, MRG001 and MMAE were measured at predefined time points and the results showed that the C max and AUC of total antibody, MRG001 and MMAE increased with dose level increase. The T max of MMAE was non-linear to dose level increase, similar trends could be observed in two other parameters including C max and AUC 0-t, which suggested that MMAE was continuously released from MRG001. Among 21 pts who had at least one tumor assessment, 1 CR (5%), 4 PR (19%), 9 SD (43%), and 7 PD (33%). The investigator assessed ORR was 24% and the DCR was 67%. In the starting dose 0.15 mg/kg cohort, one subject with FL acheived PR. Among six subjects (4 with DLBCL and 2 with FL) enrolled in the 1.8 mg/kg cohort, one DLBCL subject achieved CR and another subject with DLBCL achieved PR, ORR was 33.33% (2 out of 6). Three subjects were enrolled in the 2.5 mg/kg cohort, two subjects with FL had PR, both of them had DLT on cycle 1 and had dose reduction to 1.8 mg/kg from cycle 2, ORR was 66.7% (2 out of 3). Conclusion: The dose escalation study of MRG001 has shown manageable safety profiles and encouraging preliminary antitumor activity in patients with NHL. Based on the safety, tolerability, and pharmacokinetic parameters of MRG001, 1.8 mg/kg was determined to be the RP2D and further investigation of MRG001 in patients with NHL is warranted. Disclosures Peng: Lepu Biopharma Co., Ltd.: Current Employment. Sun: Shanghai Miracogen Inc.: Current Employment. Sun: Shanghai Miracogen Inc.: Current Employment. Li: Shanghai Miracogen Inc.: Current Employment.

COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become a global pandemic. Patients with hematological disorders are known to be at high risk of morbidity and mortality from COVID-19, and vaccines against SARS-CoV-2 have been rapidly developed. Although mRNA vaccines against SARS-CoV-2 are reported to be effective, efficacy in patients with hematological malignancies who have received anti-CD20 antibody treatment remains unclear. Here, we prospectively evaluated the efficacy of BNT162b2 mRNA COVID-19 vaccine in patients with B-cell malignancies treated with anti-CD20 antibody. We first evaluated antibody titers in 12 healthy volunteers (median age 75.5 years, range 57-82) and three lymphoma patients undergoing R-CHOP therapy (73, 81, and 81 years old) who had received 2 vaccine doses of BNT162b2 at pre-vaccination, 21 days after the first dose and 14 days after the second dose of vaccination. IgG antibody titers for S1 protein were measured in serum samples by ELISA. In healthy control subjects, titers were clearly increased. In contrast, no patient treated with R-CHOP developed antibodies even after the second vaccination (Figure A). To determine the SARS-CoV-2-specific T-cell reactivity in these three patients, we evaluated interferon (IFN)-γ response to the SARS-CoV-2 spike peptide before and after the second vaccination dose, and detected IFN-γ responses after vaccination in all three patients (Figure B). Next, to investigate the duration of the effect of anti-CD20 antibody on antibody production to BNT162b2, we enrolled 36 patients (median age 74 years, range 50-87) who had received the final dose of anti-CD20 antibody 48-1320 (median 571) days before vaccination. S1 antibody titers were measured 14 days after the second dose of vaccination. Diagnoses included diffuse large B-cell lymphoma (n = 21), follicular lymphoma (n = 9), lymphoplasmacytic lymphoma/Waldenström's macroglobulinemia (n = 3), and mantle cell lymphoma (n = 3). Thirty-four patients had received rituximab-based and 2 had received obinutuzumab-based therapy, with a median of 6 (range 3-20) courses. No patient had received any chemotherapy after the last anti-CD20 antibody dose. No patient vaccinated within close to one year or sooner after the last anti-CD20 antibody administration showed an increase in titers. Furthermore, titers in most patients were lower than in healthy volunteers even among those vaccinated more than three years after the last administration (Figure C). Finally, we investigated surrogate markers of antibody production ability. We found no relationship between the percent of B-cells (CD19-positive cells) and S1 antibody titers (Figure D), whereas all patients (n = 9) with total IgG level below lower normal limit (< 870 mg/dl) had low S1 antibody titers (< 0.16), below the lowest optical density (O.D.) value in healthy donors (Figure E). These findings indicate that the antibody-mediated response to vaccination in patients following treatment with anti-CD20 antibody was considerably impaired for an extended time. Alternative protection strategies for these patients are therefore warranted. Although T-cell responses were detected, we recommend that these patients continue to wear a face mask and wash their hands to prevent COVID-19 even after vaccination. Figure 1 Figure 1. Disclosures Yakushijin: Chugai pharmaceutical Co. Ltd.: Research Funding; Jazz pharmaceuticals: Research Funding; Nippon Shinyaku: Honoraria. Kiyota: Bristol-Myers Squibb: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Astra-Zeneca: Honoraria, Research Funding; Roche Phamaceuticals: Research Funding; Merck Biopharma: Honoraria; Merck Sharp & Dohme: Honoraria; Eisai: Honoraria; Bayer: Honoraria. Matsuoka: Takeda Pharmaceutical Company: Research Funding; Sysmex: Research Funding. Minami: Behring: Research Funding; CSL: Research Funding; Yakult Honsha: Research Funding; Nippon Shinyaku: Research Funding; Astellas Pharma: Research Funding; Asahi-Kasei Pharma: Research Funding; Eli Lilly: Honoraria, Research Funding; Taiho Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Merck Serono: Honoraria, Research Funding; Kyowa-Kirin: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; DaiichiSankyo: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bayer Yakuhin: Honoraria, Research Funding; Nippon Kayaku: Research Funding; Celgene: Honoraria; Ohtsuka Pharmaceutical: Honoraria; Shire Japan: Honoraria; Genomic Health: Honoraria; Abbvie: Honoraria.

Vaccination efforts for COVID-19 are currently underway worldwide. At present, there is insufficient evidence of the vaccine’s efficacy and safety in patients with neurological diseases, such as stroke, dementia and intractable neurological diseases. Despite the fact that many patients with neurological diseases are elderly and often have systemic complications, I believe that neurologists should nonetheless actively recommend vaccination to their patients. However, there are at least three problems that I encounter in my daily clinical practice when I vaccinate patients with neurological diseases. The first problem is that many patients with dementia have no family members or other relatives, and self-determination for vaccination is difficult. The second problem is …

Passenger lymphocyte syndrome (PLS) often occurs after ABO-mismatched solid organ and/or bone marrow transplantation between a donor and recipient. Viable donor B-lymphocytes transferred during organ transplantation produce antibodies against recipient red cell antigens, leading to hemolysis. The incidence of PLS has been reported to be around 9% after renal transplantation. A previous report showed that rituximab (Rit) was useful for treatment of PLS in allogeneic stem cell transplantation, bowel transplant and severe cases of hemolysis. However, the effectiveness of Rit in preventing PLS after renal transplantation has not yet been evaluated. The participants in this study were 85 patients who had undergone ABO-mismatched renal transplantation from January 2005 to April 2013. Rit was administered to these patients before transplantation. None of the patients that received Rit treatment developed PLS. Thus administration of Rit before transplantation effectively controlled the production of antibodies by B-lymphocytes, which probably prevented the development of PLS.

Nearly two decades ago rituximab heralded a new era in management of B cell malignancies significantly increasing response rates and survival. However, despite clear therapeutic advantage, significant numbers of patients become refractory to anti-CD20 mAb therapy, suggesting urgent improvements are required. It is now well recognized that the suppressive tumor microenvironment plays an important role in the outcome of anti-CD20 mAb therapy and that manipulation of this environment may improve the efficacy and produce long-term tumor control. The past few years have seen a surge of interest in immunomodulatory agents capable of overwriting immune suppressive networks into favorable clinical outcome. Currently, a number of such combinations with anti-CD20 mAb is under evaluation and some have produced encouraging outcomes in rituximab refractory disease. In this review, we give an outline of anti-CD20 mAbs and explore the combinations with immunomodulatory agents that enhance antitumor immunity through targeting stimulatory or inhibitory pathways and have proven potential to synergize with anti-CD20 mAb therapy. These agents, primarily mAbs, target CTLA-4, PD-1/PD-L1, and CD40.

Significant progress in understanding and overcoming cardiac xenograft rejection using a clinically relevant large animal pig-to-baboon model has accelerated in recent years. This advancement is based on improved immune suppression, which attained more effective regulation of B lymphocytes and possibly newer donor genetics. These improvements have enhanced heterotopic cardiac xenograft survival from a few weeks to over 2 years, achieved intrathoracic heterotopic cardiac xenograft survival of 50 days and orthotopic survival of 57 days. This encouraging progress has rekindled interest in xenotransplantation research and refocused efforts on preclinical orthotopic cardiac xenotransplantation.

A major challenge in translational research is to reduce the currently high proportion of new candidate treatment agents for neuroinflammatory disease, which fail to reproduce promising effects observed in animal models when tested in patients. This disturbing situation has raised criticism against the currently used animal models in preclinical research and calls for improvement of these models. This seems a difficult task as the cause of failure is often not known. Here we propose a potentially useful strategy for investigating why a promising strategy fails as a guidance for improving the validity of the animal model(s). (C) 2015 Elsevier B.V. All rights reserved.

Background Rituximab (RTX) has been shown to be successful in the treatment of rheumatoid arthritis (RA), indicating that B cells have an important role in this disease. Objectives The present study was undertaken to investigate the mechanisms of action of RTX on the immune and endothelial cells (EC) of the vascular system in the setting of RA. Methods Purified lymphocytes from five RA patients with high disease activity were treated with RTX (1ug/mL) for 24 hours. Then, the depletion of B cells was assessed by flow cytometry, and the changes occurred in the inflammatory profile of T-lymphocytes was analysed by RT-PCR. In a second set of experiments, to evaluate the influence of B-cell depletion on the inflammatory/prothrombotic profile of cells belonging to the vascular system, supernatants from cultured lymphocytes of RA patients in the presence or in the absence of RTX were added to isolated monocytes from AR patients and to cultured endothelial cells. The response to RTX was then examined. Results As expected, RTX promoted a significant depletion of B-cells. In parallel, the inflammatory profile of T lymphocytes from RA patients was downregulated, as shown by a significant drop of IL-1, IL-6, IL-17, IFN and TNF expression levels, thus suggesting that the anti-inflammatory effects of RTX might be related to B cell depletion. Supernatants from RTX-treated lymphocytes further abridged the prothrombotic profile of RA-monocytes, promoting a significant inhibition of TF, MCP-1, IL-8, IL-1 and VEGF-A gene expression. Moreover, endothelial cells, activated after treatment with supernatants from cultured RA-lymphocytes, showed reduced expression of cell-adhesion molecules (i.e. V-CAM, I-CAM, E-Selectin) and pro-thrombotic factors (i.e. TF, VEGF, IL-8) after treatment with supernatants from cultured RA-lymphocytes in the presence of RTX. Conclusions Overall, these results reveal that depletion of B-cells by RTX in RA influences the inflammatory profile of T lymphocytes, as well as their interaction with monocytes and ECs, thus modulating the inflammatory and prothrombotic shape of vascular cells in the setting of RA. Acknowledgements Supported by CTS-794, ISCIII (PI15/01333; RIER RD16/0012/0015) Disclosure of Interest None declared

Primary Sjogren's Syndrome (pSS) is a systemic inflammatory autoimmune of unknown aetiology affecting exocrine glands, particularly the lacrimal and salivary glands. Growing evidence that B-cell depletion therapies are remarkably efficacious in the disorder indicate a major role for B-cell in the immunopathogenesis of pSS. B cell-targeted therapies have raised new therapy promise for they interact with B-cell homeostasis. Anti-CD20 therapy is the unique effective non-symptomatic therapy used in pSS. Growing data suggest Rituximab a promising candidate for pSS therapy. We performed a search for publications on Rituximab in the treatment of pSS to explicate pathogenetic function of B cells and assesse the efficacy in glandular symptoms, systemic manifestations and laboratory parameters in pSS patients. However, the efficiency on glandular manifestations is rather disappointing and controversial. Whether pSS patients with a reasonable residual salivary flow and/or with shorter disease duration will benefit most from Rituximab treatment still remains unclear. Fatigue is the symptom that responds best to Rituximab therapy compared with other systematical involvements. The efficiency in laboratory parameters is unsatisfactory.

The Editors of Blood retract the 24 February 2011 paper cited above. Concerns regarding the data underlying Figures 3A, 3B, 3C, 4A, and 5C were brought to the attention of Stanford University. The university investigated the issue, conducting a search for any original sources of these data. The search was unsuccessful; the experiments, data, and figure preparation for these figures were overseen by Holbrook E. Kohrt, who passed away before the university became aware of the concerns. As a result, the data underlying these figures cannot be validated. Holbrook E. Kohrt is deceased and cannot consent to the retraction. Kipp Weiskopf, Ash A. Alizadeh, Josh Brody, Debra Czerwinski, Steven Coutre, Mark P. Chao, Thomas F. Tedder, and Ronald Levy approve the retraction. Roch Houot, Matthew J. Goldstein, Antonia M.S. Muller, Russell Pachynski, and Lieping Chen could not be reached for a response.

Rituximab is a monoclonal therapeutic anti-CD20 antibody that has been approved for use in lymphoma and rheumatoid arthritis. Over the past decade several reports based on case series and observational studies have recorded the benefits of rituximab in particular groups of dermatological patients. Off-label use of rituximab in many dermatological indications is not uncommon in many countries in the world. This article reviews the available data that may be of use to the practicing dermatologist. Because of its potential complications, paucity of clinical data, and cost considerations, rituximab is favoured only when standard systemic therapies fail or corticosteroids are absolutely contraindicated. Further research is required in this field.

Rituximab was introduced into clinical practice as a medication with considerable potential. Its use in patients with B-cell lymphoma and rheumatoid arthritis revealed numerous indications in autoimmune diseases, many of which involve the skin, thus requiring dermatologists to become familiar with both the characteristics of anti-CD20 antibodies and the role of B cells in multiple skin diseases. Thanks to these developments, we will be able to use rituximab more frequently and appropriately in our patients and draw up consensus guidelines based on large case series. In other words, establishing the indications for rituximab will make it possible to shorten disease course and reduce morbidity due to more specific drugs.

Introduction:CD20 a cell surface protein selectively expressed in mature B cells is involved in regulation of B cell differentiation and is a well-established target for anti-CD20 therapy in the treatment of B cell malignancies. However, therapeutic resistance to anti-CD20 antibodies, including rituximab and obinutuzumab, continues to remain a major obstacle in the treatment for NHL patients. Known mechanisms of anti-CD20 resistance include loss of CD20 expression, apoptotic dysfunction and/or poor immunoreactivity. Further mechanisms, including potential biologic etiologies, which engender resistance to anti-CD20 antibodies remain largely unclear. We sought to delineate the immuno-biological landscape and mechanisms associated with anti-CD20 resistance via systems biology analyses and immune functional studies with rituximab and obinutuzumab resistant (RR & OR) NHL models in a novel single-cell microfluidics platform. Methods:RR or OR cells (SUDHL4 and SUDHL10) were developed by repeated culturing with chronic low dose exposure to antibody (Ab) drugs. Anti-CD20 resistance was biologically characterized by CD20 immunostaining-flow cytometry, gene expression profiling and systems biology analysis (with Ingenuity Pathway Analysis (IPA) and Gene Set Enrichment Analysis (GSEA). Immunological characterization was performed using NK mediated ADCC activity (AcellaTox-Glo), real-time analysis of NK cell-NHL interaction kinetics by microfluidics and cytokine/immune factor secretion using proximity extension assay (Olink immuno-oncology panel). Ionomycin induced release of Calcium assay was performed using Fluo-4 cell-based assay and plate reader. Results: Flow cytometric studies and ADCC assays using anti-CD20 Abs and primary NK cells, exhibited prominent downregulation of CD20 cell surface expression and markedly decreased NK mediated ADCC activity in RR (11%, P=0.0002) and OR (17%, P=0.001) compared with 10mg/ml of rituximab (51%) or obinutuzumab (56%), respectively, in the parental SUDHL4 cells. The basal NK mediated Furthermore, microfluidic analyses revealed decreased cell-cell interactions among NK cells and anti-CD20 resistant NHL cells in the presence of either antibody. Systems biology analysis of the transcriptome with these RR and OR cells showed downregulation of immune signaling mechanisms closely related MAPK, NFkB, mTOR and JAK/STAT pathways, with partial upregulation of PLCγ, B-cell receptor (BCR) signaling (via western blot). Using the Olink 92-plex cytokine assay, we observed hyposecretion of the majority of cytokines including IL-2, IL-6, IL-8, IL-10, TNFα, IFNγ and FASL all CD20 resistant cells (Fig. 1A). Based in part on these biological changes, we hypothesized that loss of CD20 associated with decreased calcium signaling could be the master regulator observed with anti-CD20 resistance. Assessment of ionomycin-induced releasable calcium showed lack of ionomycin releasable calcium in anti-CD20 resistant cells (Fig. 1B). Treatment with the depolarizing agent, veratridine, restored ionomycin releasable calcium levels, reversed BCR signaling, and it was accompanied with significantly decreased cell viability (60%, P Conclusions: RR and OR NHL cells were associated with downregulation of immune signaling pathways, cytokine hyposecretion, and upregulation of BCR signaling. Furthermore, these observed biological changes were associated with decreased intracellular calcium suggesting its role as a master regulator in anti-CD20 resistance. Utilizing depolarizing and hyperpolarizing pharmacologic agents, we were able to restore favorable signaling changes associated with anti-CD20 antibody sensitivity as well as mimic a resistant phenotype in sensitive cells. Additional investigation of the modulation of calcium signaling as a novel mechanism and target for the treatment of anti-CD20 resistant NHL is warranted. Disclosures Evens: Pharmacyclics International DMC: Membership on an entity's Board of Directors or advisory committees; Affimed: Consultancy; Bayer: Consultancy; Janssen: Consultancy; Seattle Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Consultancy; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy; Tesaro: Research Funding; Novartis: Consultancy.

Resume Les rejets aigus medies par anticorps sont une complication frequente et severe de la transplantation renale. De mauvais pronostic, ils sont souvent resistants aux traitements conventionnels, ce qui justifie une prise en charge avant transplantation pour en diminuer le risque, et apres, pour en ameliorer le diagnostic, le traitement et le suivi. Avant la greffe, la recherche d’anticorps anti-HLA donneur specifiques par des techniques sensibles (single antigen, ELISA) est essentielle pour quantifier le risque de rejet aigu medie par anticorps. Cela permet d’allouer les greffes en connaissance de cause, d’instaurer une surveillance et un suivi etroit post-transplantation des patients a risque et eventuellement de modifier les strategies d’immunosuppression. Post-transplantation, les strategies therapeutiques consistant a enlever ou bloquer les anticorps preexistants ou de novo par les IVIg a forte dose ou la plasmapherese, ou bien a inhiber ou depleter les cellules productrices d’anticorps par l’injection d’anticorps monoclonal anti-CD20 ou de thymoglobulines, ont montre leur efficacite pour traiter le rejet aigu medie par anticorps. La persistance d’anticorps anti-HLA donneur specifiques apres un episode de rejet aigu medie par anticorps etant un facteur de mauvaise evolution, elle rend leur suppression par ces traitements et leur suivi post-transplantation indispensables.

Rituximab is a chimeric anti-CD20 monoclonal antibody targeting B cells, which play numerous pathogenic roles in rheumatoid arthritis (RA). This review summarises the results of three controlled studies using rituximab in RA and the data regarding tolerance and repeated treatment in 1053 patients included in the clinical studies. These studies demonstrated the efficacy of rituximab in patients with RA, including those who had been unresponsive or intolerant to one or more TNF inhibitor therapies. Rituximab was globally well-tolerated. The current informations on the efficacy and the tolerance of rituximab led us to propose recommendations for the screening of patients, the use of rituximab, and the follow-up of patients. A longer follow-up duration and data from off-trial patients, included in registries, are now required.

Resume Le rituximab est un anticorps monoclonal chimerique anti-CD20. Il s’attaque donc aux lymphocytes B, qui exercent de nombreux effets pathogenes dans la polyarthrite rhumatoide (PR). Les trois etudes controlees du rituximab dans la PR, portant sur 1053 malades, sont passees en revue ici, en pretant une attention particuliere aux resultats concernant la tolerance et les traitements iteratifs. Ces etudes demontrent l’efficacite du rituximab dans la PR, meme lorsque les anti-TNFα sont inefficaces ou mal toleres. Le rituximab a ete bien tolere dans l’ensemble. Les donnees actuelles sur l’efficacite et la tolerance du rituximab ont conduit a proposer des recommandations concernant les indications du rituximab, ses modalites d’utilisation et le suivi des malades. Il est maintenant indispensable d’obtenir des informations a plus long terme et d’evaluer les malades qui sont traites en dehors des etudes cliniques, grâce a l’etablissement de registres.

Nehockinski limfomi danas predstavljaju kamen temeljac savremenoj onkohematologiji, s obzirom na mogucnost visokog procenta njihovog izlecenja. Najcesca podgrupa limfoma su DBKL koji su kod oko 30% bolesnika izlecivi primenom konvencionalne terapije, dok su FL neizlecivi ukoliko se lece samo konvencionalnom terapijom. Istina je da se kod bolesnika sa FL terapijski odgovor postize brzo, ali recidivi se gotovo po pravilu desavaju i bolesnike je u svakom sledecem recidivu sve teze leciti. Sredinom devedestih godina napravljeno je prvo monoklonsko antitelo u lecenju malignih bolesti, i to najpre za recidive ili refraktarne FL. Ovo anti CD20 monoklonsko antitelo, rituksimab, predstavlja krucijalan napredak u lecenju limfoma, jer je primenom kombinoivane imunohemioterapije izlecenje DBKL poraslo na oko 60%, a poslednje studije ukazuju na mogucnost dugotrajnih remisija i PFS za FL, sto moze biti ekvivalent izlecenju i ove podgrupe limfoma. U toku su brojne studije kojima se vrse uporedne analize za primenu ritoksimaba i kod drugih podtipova limfoma kao sto je limfom marginalne zone, mantle celijski limfom, Hockinova bolest, a uvode se indikacije i za pojedine sistemske bolesti vezivnog tkiva, kao sto je reumatoidni artritis.

The CD20 antigen characteristic for mature B-cell is also expressed on B-cell Non-Hodgkin lymphomas (NHL). It thus presents a possible target for immunotherapy. NHL respond readily to radio- and/or chemotherapy but this standard treatment bears a high risk of relapse. The specific monoclonal anti-CD20-antibody Rituximab, the first to be approved for clinical use, could be shown to improve response rates, response duration, and survival in NHL when combined with standard therapy. This review details the development, clinical application, and future perspectives of anti-CD20-antibody treatment of NHL, thereby proving the efficiency of immunotherapy via targeting of a tumor associated antigen.

Thrombotic thrombocytopenic purpura is a rare condition characterized by microangiopathic haemolytic anaemia, thrombocytopenia, altered neurology, renal impairment and fever. While plasma exchange has reduced mortality from more than 90% to between 10 and 30%, a proportion of cases fail to respond. Rituximab may be efficacious in the management of refractory cases of thrombotic thrombocytopenic purpura. We present two cases in which rituximab was used with successful outcomes. Treatment resulted in resolution of severe clinical and haematological abnormalities in both patients. There has been no relapse after 16 months follow up. Our experience supports the use of rituximab in difficult cases of TTP. Ongoing evaluation of its use is in progress at our institution.

In der Behandlung rheumatischer Erkrankungen kommt der selektiven Immunblockade eine zunehmende Bedeutung zu. Die Anti-TNFα-Therapie uberzeugt dabei durch eine hohe Effektivitat und Erfolge in bisher therapieresistenten Fallen bei unterschiedlichen Autoimmunerkrankungen. Diese neuen Ansatze versprechen neben den enormen klinischen Vorzugen Aufschluss uber die pathogenetische Rolle der beteiligten Mediatoren und bestimmter Immunzellen. Von besonderem Interesse sind aktuelle Entwicklungen in der Therapie der rheumatoiden Arthritis durch eine temporare BZell-Depletion mit einem Anti-CD20-Antikorper und deren deutliche klinische Effekte. Zweifelsohne wird es Aufgabe zukunftiger Studien sein, das Arsenal der verfugbaren Biologika, einschlieslich der B-Zell-Depletion, mit den herkommlichen DMARDs gezielt einzusetzen, um den individuellen Therapieerfordernissen der RA-Patienten durch Kombinationsals auch Eskalationsschemata besser gerecht zu werden.

e14548 Background: Chimeric Antigen Receptor T cells (CAR-Ts) targeting CD19 have shown very promising clinical outcomes in treatment of B-cell linage hematological malignancies. However, many patients with relapsed diseases were found to have down-regulated/loss of CD19 surface expression after CD19 CAR-T therapy. To solve this issue of CD19 single-targeting escape, we explored the application of another B-cell antigen, CD20, for targeted CAR-T therapy. Methods: We constructed four CD20 targeting CARs (all with 4-1BB co-stimulatory signaling) base on single-chain variable fragments (scFV) derived from four well-studied CD20 specific antibodies: Leu16, Rituximab, Obinutuzumab, and Ofatumumab. Leu16, Rituximab, and Obinutuzumab belong to the type I anti-CD20 antibody family and appear to bind to different epitopes located on the large loop of CD20, whereas Ofatumumab is the type II anti-CD20 antibody which has been shown to interact with the hydrophobic residues on the small loop surrounding a deep binding cleft. Results: All four CAR-T cells can specifically recognized CD20 positive target cells in our pre-clinical studies. They all showed up-regulated antigen-specific cell activation and high level of IFN-g release upon CD20 stimulation, and CAR-T20-Ofatumumab cells appeared to have significantly higher cell activation and more than 2-fold increase in IFN-g release compared to the other three CAR-T20 cells with their scFVs deriving from type I anti-CD20 antibodies. CAR-T20-Ofatumumab cells also showed higher degranulation upon stimulation, and it displayed ~50% of increase in ability to kill CD20 positive cells in cytotoxicity assays. Conclusions: Our data suggested that CAR-T20-Ofatumumab has better in vitro function and appears to be a CAR superior to those derived from other three antibodies. A possible explanation for this observation is that Ofatumumab interacts with the hydrophobic residues on the small loop, which is very close to cell membrane and confers more extensive binding to the small loop with striking slow off-rate. Our results suggest that CAR-Ts targeting CD20 with the scFVs from the type II anti-CD20 antibody may have superior cell killing effects.

金沢大学医学部附属病院眼科, 金沢大学大学院医学系研究科

To complete the existing treatment guidelines for all tumor types, ESMO organizes consensus conferences to better clarify open issues in each disease. In this setting, a consensus conference on the management of lymphoma was held on 18 June 2011 in Lugano, immediately after the end of the 11th International Conference on Malignant Lymphoma. The consensus conference convened ∼45 experts from all around Europe and selected six lymphoma entities to be addressed; for each of them three to five open questions were to be discussed by the experts. For each question, a recommendation should be given by the panel, supported by the strength of the recommendation based on the level of evidence. This consensus report focuses on the three most common lymphoproliferative malignancies: diffuse large B-cell lymphoma, follicular lymphoma and chronic lymphocytic leukemia. A second report will concentrate on mantle cell lymphoma, marginal zone lymphoma and T-cell lymphomas.

We report a successful treatment with rituximab in the case of rheumatoid vasculitis causing digital tips necrosis in exacerbated rheumatoid arthritis. The vasculitis lesions did not respond completely to intravenous methylprednisolone and cyclophosphamide but responded on rituximab treatment. Deep necrosis of a digital tip resolved entirely after completing a course of rituximab.

As infections are among the most important adverse events associated with the use of biological agents, patients should be aware of the increased risk and physicians should remain vigilant. Knowing...

7533Background: Hepatitis B reactivation can occur after hepatitis B virus (HBV) surface antigen (HBsAg) loss, especially in immunocompromised patients (pts).1,2A high rate of reactivation has been...