Azoximer bromide and hydroxyapatite: promising immune adjuvants in cancer.

Immune adjuvants are immune modulators that have been developed in the context of infectious vaccinations. There is currently a growing interest in immune adjuvants due to the development of immunotherapy against cancers. Immune adjuvant mechanisms of action are focused on the initiation and amplification of the inflammatory response leading to the innate immune response, followed by the adaptive immune response. The main activity lies in the support of antigen presentation and the maturation and functions of dendritic cells. Most immune adjuvants are associated with a vaccine or incorporated into the new generation of mRNA vaccines. Few immune adjuvants are used as drugs. Hydroxyapatite (HA) ceramics and azoximer bromide (AZB) are overlooked molecules that were used in early clinical trials, which demonstrated clinical efficacy and excellent tolerance profiles. HA combined in an autologous vaccine was previously developed in the veterinary field for use in canine spontaneous lymphomas. AZB, an original immune modulator derived from a class of heterochain aliphatic polyamines that is licensed in Russia, the Commonwealth of Independent States, and Slovakia for infectious and inflammatory diseases, is and now being developed for use in cancer with promising results. These two immune adjuvants can be combined in various immunotherapy strategies.

Clinical and Serological Follow-Up of 216 Patients with Hematological Malignancies after Vaccination with Pfizer-BioNT162b2 mRNA COVID-19 in a Real-World Study.

Hematological malignancies (HMs) have heterogeneous serological responses after vaccination due to disease or treatment. The aim of this real-world study was to analyze it after Pfizer-BioNT162b2 mRNA vaccination in 216 patients followed up for 1 year. The first 43 patients had an initial follow-up by a telemedicine (TM) system with no major events reported. The anti-spike IgG antibodies were checked 3-4 weeks post-first vaccination and every 3-4 months, by two standard bioassays and a rapid serological test (RST). Vaccine boosts were given when the level was <7 BAU/mL. Patients who did not seroconvert after 3-4 doses received tixagevimab/cilgavimab (TC). Fifteen results were discordant between two standard bioassays. Good agreement was observed between the standard and RST in 97 samples. After two doses, 68% were seroconverted (median = 59 BAU/mL) with a median of 162 BAU/mL and 9 BAU/mL, respectively, in untreated and treated patients (p < 0.001), particularly for patients receiving rituximab. Patients with gammaglobulin levels < 5 g/L had reduced seroconversion compared to higher levels (p = 0.019). The median levels were 228 BAU/mL post-second dose if seroconverted post-first and second, or if seroconverted only post-second dose. A total of 68% of post-second dose negative patients were post-third dose positive. A total of 16% received TC, six with non-severe symptomatic COVID-19 within 15-40 days. Personalized serological follow-up should apply particularly to patients with HMs.

Optimisation of anti-interleukin-6 therapy: Precision medicine through mathematical modelling.

Background: Dysregulated interleukin (IL)-6 production can be characterised by the levels present, the kinetics of its rise and its inappropriate location. Rapid, excessive IL-6 production can exacerbate tissue damage in vital organs. In this situation, therapy with an anti-IL-6 or anti-IL-6 receptor (IL-6R) monoclonal antibody, if inappropriately dosed, may be insufficient to fully block IL-6 signalling and normalise the immune response. Methods: We analysed inhibition of C-reactive protein (CRP) - a biomarker for IL-6 activity - in patients with COVID-19 or idiopathic multicentric Castleman disease (iMCD) treated with tocilizumab (anti-IL-6R) or siltuximab (anti-IL-6), respectively. We used mathematical modelling to analyse how to optimise anti-IL-6 or anti-IL-6R blockade for the high levels of IL-6 observed in these diseases. Results: IL-6 signalling was insufficiently inhibited in patients with COVID-19 or iMCD treated with standard doses of anti-IL-6 therapy. Patients whose disease worsened throughout therapy had only partial inhibition of CRP production. Our model demonstrated that, in a scenario representative of iMCD with persistent high IL-6 production not controlled by a single dose of anti-IL-6 therapy, repeated administration more effectively inhibited IL-6 activity. In a situation with rapid, high, dysregulated IL-6 production, such as severe COVID-19 or a cytokine storm, repeated daily administration of an anti-IL-6/anti-IL-6R agent, or alternating daily doses of anti-IL-6 and anti-IL-6R therapies, could neutralise IL-6 activity. Conclusion: In clinical practice, IL-6 inhibition should be individualised based on pathophysiology to achieve full blockade of CRP production. Funding: EUSA Pharma funded medical writing assistance and provided access to the phase II clinical data of siltuximab for analysis.

Open-label use of an aliphatic polyamine immunomodulator in patients hospitalized with COVID-19.

Background: Evidence-based therapies used to treat coronavirus disease (COVID-19) remain limited. Azoximer bromide (AZB; Polyoxidonium®) is an immunomodulating molecule frequently used in the Russian Federation. It offers demonstrable therapeutic benefit in upper respiratory tract infections. This study evaluated the safety and efficacy of AZB when used in combination with standard of care treatment in patients hospitalized with COVID-19. Methods: Hospitalized patients with COVID-19 (n=81; nine sites) received AZB 12 mg intravenously once daily for 3 days then intramuscularly every other day until day 17. The primary endpoint included clinical status at day 15 versus baseline. Historical control data of 100 patients from a randomized, controlled, open-label trial conducted in China were included to serve as a direct control group. Results: Notable clinical improvement, assessed by seven-point ordinal scale (OS) score and National Early Warning Score, was observed. Mean duration of hospitalization was 19.3 days. Indicators of pneumonia and lung function showed gradual recovery to normalization. No patients died but, by day 28, one patient still required respiratory support; this patient died on day 34. A higher proportion of patients receiving AZB required invasive or non-invasive ventilation (OS 5 or 6) at baseline compared with the historical control group. Improvement in mean OS score by day 14/15 was not notable in the control group (OS 3.99-3.87) but was clear in the AZB group (OS 4.36-2.90). Mean duration of hospitalization was similar in the control group (16.0 days); however, day 28 mortality was higher, at 25.0% (n=25). Conclusion: AZB combined with standard of care was safe and well tolerated. An apparent clinical improvement could not be fully evaluated due to the lack of a direct control group; further assessment of AZB for the treatment of COVID-19 in a randomized, placebo-controlled study is warranted.

The effect of azoximer bromide (Polyoxidonium®) in patients hospitalized with coronavirus disease (COVID-19): an open-label, multicentre, interventional clinical study.

A clinical need for aetiotropic coronavirus disease (COVID-19) treatments is required. The immune modulator azoximer bromide (AZB; Polyoxidonium®) is indicated in Russia for use against acute viral infections and during remission. In this study, adults hospitalized with COVID-19 (n=32) received AZB and standard of care in an open-label, multicentre, interventional study. All patients were symptomatic; 22 had severe disease (National Early Warning Score ≥5) and required mechanical ventilation or oxygen saturation (SpO2) and 19 patients had co-morbidities. Patients received AZB 12 mg intravenously once daily for 3 days, then intramuscularly every other day (approximately ten injections) until discharge. The primary endpoint was the patient's clinical status (7-point Ordinal Scale; OS) on day 15 versus that at baseline. The mean duration of hospitalization was 20 days. All patients were alive and discharged with normal SpO2 with no secondary infections or delayed mortality reported by the end-of-study visit (on day 28-72). A decrease in the mean OS and National Early Warning Score values was observed following treatment with AZB. A decrease in OS score was marked in patients identified as severe. Both sets of patients achieved similar scores, which can be classified as an improvement by day 9-10; SpO2 levels trended to normalization over time. By day 11-12, all patients had a normal body temperature. Serum C-reactive protein levels decreased in patients with severe and mild disease. Most patients had signs of pneumonia at baseline (n=27), with the majority recovering by days 10-12. No major toxicities were observed. AZB was safe and well tolerated when administered in addition to standard of care treatment for COVID-19. Further randomized, placebo-controlled studies are needed to elucidate any potential therapeutic effect in COVID-19.

Dynamic Immune/Inflammation Precision Medicine: The Good and the Bad Inflammation in Infection and Cancer.

Normal or "good" inflammation process starts from a local cellular response against injury or any infectious agent, with the activation of neutrophils, macrophages, Langerhans cells, dendritic cells, and innate immune cells. Cytokines and chemokines are produced to amplify the local inflammatory process followed by the migration of immune cells to the regional lymph nodes where adaptive immune response is initiated. Systemic inflammation enhances the biological response to mobilize additional cells from central and peripheral immune/hematopoietic system. Local mechanisms to limit inflammation are initiated and lead to healing. During the normal inflammatory process, there is a balance between the production of inflammatory chemokines/cytokines such as Tumor Necrosis Factor (TNF)-α, interleukin (IL)-6 and IL-1 and the production of compounds that limit inflammation and have an immune suppressive effect, such as IL-10 and Transforming Factor (TGF) ß. IL-6 and IL-6/soluble IL-6 Receptor (R) complex stimulate liver cells to produce inflammatory proteins, which represents the systemic inflammation response. The magnitude and the duration of the systemic inflammatory response are linked to the cause, under genetic and epigenetic control. Significant inflammation as seen in septic shock, in severe forms of infections or in certain active cancers, represents the "bad inflammation", correlated with a poor prognosis. In addition, the persistence of a chronic smoldering inflammation may lead to pathological situations which are observed in the majority of inflammatory, degenerative, dysmetabolic, or dysimmune diseases and cancer. Chronic smoldering inflammation is a cross between different pathological situations possibly linked. In addition, within the tumor microenvironment, inflammatory process results from different cellular mechanisms modulated by metabolic and vascular changes. On the contrary, a limited and balanced inflammation initiates the normal immune response, including the adaptive response which amplifies any immunotherapy, including vaccines. Immune checkpoint inhibitors and chimeric antigen receptor (CAR) T-cells are associated with cytokine release syndrome, a clinical risk leading to the use of anti-cytokine drugs. Nowadays, it is time to monitor the dynamic inflammatory process for a better immune precision medicine in both infections and cancer.

Polyoxidonium® Activates Cytotoxic Lymphocyte Responses Through Dendritic Cell Maturation: Clinical Effects in Breast Cancer.

Immunotherapy, which is seen as a major tool for cancer treatment, requires, in some cases, the presence of several agents to maximize its effects. Adjuvants can enhance the effect of other agents. However, despite their long-time use, only a few adjuvants are licensed today, and their use in cancer treatment is rare. Azoximer bromide, marketed under the trade name Polyoxidonium® (PO), is a copolymer of N-oxidized 1,4-ethylenepiperazine and (N-carboxyethyl)-1,4-ethylene piperazinium bromide. It has been described as an immune adjuvant and immunomodulator that is clinically used with excellent tolerance. PO is used in the treatment and prophylaxis of diseases connected with damage to the immune system, and there is interest in testing it in antitumor therapy. We show here that PO treatment for 1 week induced positive pathological changes in 6 out of 20 patients with breast cancer, including complete response in a triple-negative patient. This correlated with an increased tumor CD4+ T-lymphocyte infiltration. The immune effects of PO are associated with myeloid cell activation, and little is known about the action of PO on lymphocyte lineages, such as natural killer (NK) and T cells. We reveal that PO increases T-cell proliferation in vitro without negative effects on any activation marker. PO does not affect dendritic cell (DC) viability and increases the expansion of immature DC (iDC) and mature DC (mDC) at 100 µg/ml, and it stimulates expression of several DC co-stimulatory molecules, inducing the proliferation of allogeneic T cells. In contrast, PO decreases DC viability when added at day 5 post-expansion. PO is not toxic for NK cells at doses up to 100 µM and does not affect their activation, maturation, and cytotoxicity but tends to increase degranulation. This could be beneficial against target cells that show low sensitivity to NK cells, e.g., solid tumor cells. Finally, we have found great variability in PO response between donors. In summary, our in vitro results show that PO increases the number of costimulatory molecules on DC that prime T cells, favoring the production of effector T cells. This may support the future clinical development of PO in cancer treatment.

Immune precision medicine for cancer: a novel insight based on the efficiency of immune effector cells.

Cancer cell growth is associated with immune surveillance failure. Nowadays, restoring the desired immune response against cancer cells remains a major therapeutic strategy. Due to the recent advances in biological knowledge, efficient therapeutic tools have been developed to support the best bio-clinical approaches for immune precision therapy. One of the most important successes in immune therapy is represented by the applicational use of monoclonal antibodies, particularly the use of rituximab for B-cell lymphoproliferative disorders. More recently, other monoclonal antibodies have been developed, to inhibit immune checkpoints within the tumor microenvironment that limit immune suppression, or to enhance some immune functions with immune adjuvants through different targets such as Toll-receptor agonists. The aim is to inhibit cancer proliferation by the diminishing/elimination of cancer residual cells and clinically improving the response duration with no or few adverse effects. This effect is supported by enhancing the number, functions, and activity of the immune effector cells, including the natural killer (NK) lymphocytes, NKT-lymphocytes, γδ T-lymphocytes, cytotoxic T-lymphocytes, directly or indirectly through vaccines particularly with neoantigens, and by lowering the functions of the immune suppressive cells. Beyond these new therapeutics and their personalized usage, new considerations have to be taken into account, such as epigenetic regulation particularly from microbiota, evaluation of transversal functions, particularly cellular metabolism, and consideration to the clinical consequences at the body level. The aim of this review is to discuss some practical aspects of immune therapy, giving to clinicians the concept of immune effector cells balancing between control and tolerance. Immunological precision medicine is a combination of modern biological knowledge and clinical therapeutic decisions in a global vision of the patient.

International, evidence-based consensus treatment guidelines for idiopathic multicentric Castleman disease.

Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8-negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti-interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

International, evidence-based consensus diagnostic criteria for HHV-8-negative/idiopathic multicentric Castleman disease.

Human herpesvirus-8 (HHV-8)-negative, idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening disorder involving systemic inflammatory symptoms, polyclonal lymphoproliferation, cytopenias, and multiple organ system dysfunction caused by a cytokine storm often including interleukin-6. iMCD accounts for one third to one half of all cases of MCD and can occur in individuals of any age. Accurate diagnosis is challenging, because no standard diagnostic criteria or diagnostic biomarkers currently exist, and there is significant overlap with malignant, autoimmune, and infectious disorders. An international working group comprising 34 pediatric and adult pathology and clinical experts in iMCD and related disorders from 8 countries, including 2 physicians that are also iMCD patients, was convened to establish iMCD diagnostic criteria. The working group reviewed data from 244 cases, met twice, and refined criteria over 15 months (June 2015 to September 2016). The proposed consensus criteria require both Major Criteria (characteristic lymph node histopathology and multicentric lymphadenopathy), at least 2 of 11 Minor Criteria with at least 1 laboratory abnormality, and exclusion of infectious, malignant, and autoimmune disorders that can mimic iMCD. Characteristic histopathologic features may include a constellation of regressed or hyperplastic germinal centers, follicular dendritic cell prominence, hypervascularization, and polytypic plasmacytosis. Laboratory and clinical Minor Criteria include elevated C-reactive protein or erythrocyte sedimentation rate, anemia, thrombocytopenia or thrombocytosis, hypoalbuminemia, renal dysfunction or proteinuria, polyclonal hypergammaglobulinemia, constitutional symptoms, hepatosplenomegaly, effusions or edema, eruptive cherry hemangiomatosis or violaceous papules, and lymphocytic interstitial pneumonitis. iMCD consensus diagnostic criteria will facilitate consistent diagnosis, appropriate treatment, and collaborative research.

Differential effects of lenalidomide during plasma cell differentiation.

Thalidomide, lenalidomide and pomalidomide have greatly improved the outcome of patients with multiple myeloma. However, their effects on plasma cells, the healthy counterpart of myeloma cells, are unknown. Here, we investigated lenalidomide effects on normal human plasma cell generation using an in vitro model. Lenalidomide inhibited the generation of pre-plasmablasts and early plasma cells, while it moderately affected plasmablast production. It also reduced the expression level of Ikaros, Aiolos, and IRF4 transcription factors, in plasmablasts and early plasma cells. This suggests that their differential sensitivity to lenalidomide is not due to a difference in Ikaros or Aiolos degradation. Lenalidomide also inhibited long-lived plasma cell generation, but did not impair their long-term survival once generated. This last observation is in agreement with the finding that lenalidomide treatment for 3-18 months did not affect the bone marrow healthy plasma cell count in allografted patients with multiple myeloma. Our findings should prompt to investigate whether lenalidomide resistance in patients with multiple myeloma could be associated with the emergence of malignant plasmablasts or long-lived plasma cells that are less sensitive to lenalidomide.

CD45 Isoform Profile Identifies Natural Killer (NK) Subsets with Differential Activity.

The leucocyte-specific phosphatase CD45 is present in two main isoforms: the large CD45RA and the short CD45RO. We have recently shown that distinctive expression of these isoforms distinguishes natural killer (NK) populations. For example, co-expression of both isoforms identifies in vivo the anti tumor NK cells in hematological cancer patients. Here we show that low CD45 expression associates with less mature, CD56bright, NK cells. Most NK cells in healthy human donors are CD45RA+CD45RO-. The CD45RA-RO+ phenotype, CD45RO cells, is extremely uncommon in B or NK cells, in contrast to T cells. However, healthy donors possess CD45RAdimRO- (CD45RAdim cells), which show immature markers and are largely expanded in hematopoietic stem cell transplant patients. Blood borne cancer patients also have more CD45RAdim cells that carry several features of immature NK cells. However, and in opposition to their association to NK cell progenitors, they do not proliferate and show low expression of the transferrin receptor protein 1/CD71, suggesting low metabolic activity. Moreover, CD45RAdim cells properly respond to in vitro encounter with target cells by degranulating or gaining CD69 expression. In summary, they are quiescent NK cells, with low metabolic status that can, however, respond after encounter with target cells.

Identification of Anti-tumor Cells Carrying Natural Killer (NK) Cell Antigens in Patients With Hematological Cancers.

Natural killer (NK) cells, a cytotoxic lymphocyte lineage, are able to kill tumor cells in vitro and in mouse models. However, whether these cells display an anti-tumor activity in cancer patients has not been demonstrated. Here we have addressed this issue in patients with several hematological cancers. We found a population of highly activated CD56(dim)CD16(+) NK cells that have recently degranulated, evidence of killing activity, and it is absent in healthy donors. A high percentage of these cells expressed natural killer cell p46-related protein (NKp46), natural-killer group 2, member D (NKG2D) and killer inhibitory receptors (KIRs) and a low percentage expressed NKG2A and CD94. They are also characterized by a high metabolic activity and active proliferation. Notably, we found that activated NK cells from hematological cancer patients have non-NK tumor cell antigens on their surface, evidence of trogocytosis during tumor cell killing. Finally, we found that these activated NK cells are distinguished by their CD45RA(+)RO(+) phenotype, as opposed to non-activated cells in patients or in healthy donors displaying a CD45RA(+)RO(-) phenotype similar to naïve T cells. In summary, we show that CD45RA(+)RO(+) cells, which resemble a unique NK population, have recognized tumor cells and degranulate in patients with hematological neoplasias.

Targeted Therapies in Adult B-Cell Malignancies.

B-lymphocytes are programmed for the production of immunoglobulin (Ig) after antigen presentation, in the context of T-lymphocyte control within lymphoid organs. During this differentiation/activation process, B-lymphocytes exhibit different restricted or common surface markers, activation of cellular pathways that regulate cell cycle, metabolism, proteasome activity, and protein synthesis. All molecules involved in these different cellular mechanisms are potent therapeutic targets. Nowadays, due to the progress of the biology, more and more targeted drugs are identified, a situation that is correlated with an extended field of the targeted therapy. The full knowledge of the cellular machinery and cell-cell communication allows making the best choice to treat patients, in the context of personalized medicine. Also, focus should not be restricted to the immediate effects observed as clinical endpoints, that is, response rate, survival markers with conventional statistical methods, but it should consider the prediction of different clinical consequences due to other collateral drug targets, based on new methodologies. This means that new reflection and new bioclinical follow-up have to be monitored, particularly with the new drugs used with success in B-cell malignancies. This review discussed the principal aspects of such evident bioclinical progress.

The presence of wild type p53 in hematological cancers improves the efficacy of combinational therapy targeting metabolism.

Manipulation of metabolic pathways in hematological cancers has therapeutic potential. Here, we determined the molecular mechanism of action of the metabolic modulator dichloroacetate (DCA) in leukemic cells. We found that DCA induces the AMP-activated protein kinase (AMPK)/p53 pathway with increased efficacy in tumors expressing wild type (wt p53). Clinically relevant, low concentrations of doxorubicin synergize in vitro and in vivo with DCA to further enhance p53 activation and to block tumor progression. Leukemia cell lines and primary leukemic cells containing mutant p53 are resistant to the above-described combination approach. However, DCA synergized with the Hsp90 inhibitor 17-AAG to specifically eliminate these cells. Our studies strongly indicate that depending on the p53 status, different combination therapies would provide better treatment with decreased side effects in hematological cancers.

Interleukin-6 as a therapeutic target.

Human IL6 is a cytokine produced by many cell types that has pleiotropic effects. In agreement, anti-IL6 therapy reduces inflammation, hepatic acute phase proteins, and anemia and has antiangiogenic effects. Blocking IL6 has demonstrated therapeutic efficacy with drug registration in Castleman disease and inflammatory diseases (rheumatoid arthritis) without major toxicity. Interestingly, the inhibition of C-reactive protein (CRP) production is a trustworthy surrogate marker of anti-IL6 therapy efficacy. Clinically registered IL6 inhibitors include siltuximab, an anti-IL6 mAb, and tocilizumab, an anti-IL6R mAb. In various cancers, in particular plasma cell cancers, large randomized trials showed no efficacy of IL6 inhibitors, despite a full inhibition of CRP production in treated patients in vivo, the numerous data showing an involvement of IL6 in these diseases, and initial short-term treatments demonstrating a dramatic inhibition of cancer cell proliferation in vivo. A likely explanation is the plasticity of cancer cells, with the presence of various subclones, making the outgrowth of cancer subclones possible using growth factors other than IL6. In addition, current therapeutic strategies used in these cancers already target IL6 activity. Thus, anti-IL6 therapeutics are able to neutralize IL6 production in vivo and are safe and useful in inflammatory diseases and Castleman disease.

Siltuximab for multicentric Castleman's disease: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Multicentric Castleman's disease is a rare lymphoproliferative disorder driven by dysregulated production of interleukin 6. No randomised trials have been done to establish the best treatment for the disease. We assessed the safety and efficacy of siltuximab-a chimeric monoclonal antibody against interleukin 6-in HIV-negative patients with multicentric Castleman's disease. METHODS: We did this randomised, double-blind, placebo-controlled study at 38 hospitals in 19 countries worldwide. We enrolled HIV-negative and human herpesvirus-8-seronegative patients with symptomatic multicentric Castleman's disease. Treatment allocation was randomised with a computer-generated list, with block size six, and stratification by baseline corticosteroid use. Patients and investigators were masked to treatment allocation. Patients were randomly assigned (2:1) to siltuximab (11 mg/kg intravenous infusion every 3 weeks) or placebo; all patients also received best supportive care. Patients continued treatment until treatment failure. The primary endpoint was durable tumour and symptomatic response for at least 18 weeks for the intention-to-treat population. Enrolment has been completed. The study is registered with ClinicalTrials.gov, number NCT01024036. FINDINGS: We screened 140 patients, 79 of whom were randomly assigned to siltuximab (n=53) or placebo (n=26). Durable tumour and symptomatic responses occurred in 18 (34%) of 53 patients in the siltuximab group and none of 26 in the placebo group (difference 34·0%, 95% CI 11·1-54·8, p=0·0012). The incidence of grade 3 or more adverse events (25 [47%] vs 14 [54%]) and serious adverse events (12 [23%] vs five [19%]) was similar in each group despite longer median treatment duration with siltuximab than with placebo (375 days [range 1-1031] vs 152 days [23-666]). The most common grade 3 or higher were fatigue (five vs one), night sweats (four vs one), and anaemia (one vs three). Three (6%) of 53 patients had serious adverse events judged reasonably related to siltuximab (lower respiratory tract infection, anaphylactic reaction, sepsis). INTERPRETATION: Siltuximab plus best supportive care was superior to best supportive care alone for patients with symptomatic multicentric Castleman's disease and well tolerated with prolonged exposure. Siltuximab is an important new treatment option for this disease. FUNDING: Janssen Research & Development.