Tocilizumab In Combination Research Articles

COMPARATIVE EFFICACY OF METHYLPREDNISOLONE AND TOCILIZUMAB IN PATIENTS WITH A SEVERE FORM OF COVID-19

Background. Recently, we have again noted an increase in the incidence of COVID-19. The treatment of patients with severe coronavirus infection poses a significant medical challenge. Objectives. The purpose of this research was to compare the efficacy of standard therapy and pulses of methylprednisolone in combination with or without tocilizumab in patients with a severe form of COVID-19. Patients and methods. In a retrospective study, the medical charts of 220 patients with a severe course of COVID-19 were reviewed. Patients were divided into four groups: those on daily methylprednisolone at a dose of 32 mg enterally; patients who received methylprednisolone pulses (500 mg daily intravenously for three consecutive days, with a subsequent change to the 32 mg of methylprednisolone daily); patients who received a single dose of 400 mg tocilizumab in combination with a 32 mg of methylprednisolone daily; patients who received a single dose of 400 mg tocilizumab in combination with methyl­prednisolone pulse therapy. At the end of therapy, 28-day mortality and the number of intubations in each group one week after the end of therapy were analyzed. Results. Patients treated with a combination of tocilizumab and pulse methylprednisolone therapy had the lowest risk of death (p<0.001), OR=0.03 (95 % CI 0.01-0.16), compared to patients treated only with 32 mg of methylprednisolone. Conclusions. Methylprednisolone pulses therapy is more effective than therapy with methylprednisolone at a daily dose of 32 mg. The combination of methylprednisolone and tocilizumab is more effective than the isolated administration of methylprednisolone. The combination of tocilizumab with methylprednisolone pulse therapy had the highest therapeutic effect.

Primary observational study of tocilizumab in children with severe acute necrotizing encephalopathy

Objective: To investigate the efficacy and safety of tocilizumab in the treatment of critically ill children with acute necrotizing encephalopathy (ANE). Methods: It is a retrospective cohort study. The children with ANE admitted to the pediatric intensive care unit of 4 Chinese tertiary hospitals from December 2022 to November 2023 were divided into conventional treatment group and tocilizumab group, and the comparison between groups was performed by using Mann - Whitney U test or Chi-square test. Results: Among 21 cases of severe ANE, there were 11 males with the onset age of 65 (27, 113) months. The duration from onset to PICU admission was 2 (1, 2) days. There were 13 cases of ultra-high fever (greater than 40 ℃), including 18 cases of convulsions, and 19 cases with a GCS score of less than 8 points. The causative agent was novel coronavirus Omicron in 7 cases and influenza A in 14 cases. All cases had central respiratory failure requiring mechanical ventilation. Of the 21 cases, 18 were shock, 15 were coagulopathy, 10 were kidney injury and 13 were liver dysfunction. Of these hospitalized patients, 8 children with ANE were treated with tocilizumab. Eight cases received continuous blood purification (CBP) treatment, 5 of them were combined with plasmapheresis. Serum cytokine levels were elevated in 21 children with ANE, including (interleukin, IL)-6 and IL-8 (61 (22, 1 513) and 68 (5, 296) ng/L). There were 14 cases (67%) deaths, including 11 cases in the conventional treatment group and 3 cases in the tocilizumab group. There was no significant difference in the mortality rate between the two groups (P=0.056). Tocilizumab-related rash or other adverse events were not observed. Conclusions: The motality of critically ill ANE patients was high. The combination of Tocilizumab with conventional treatment did not reduce the motality of severe ANE patients, and no adverse reactions of tocilizumab were observed.

Systems medicine framework for repurposable drug combinations for COVID-19 comorbidities

Currently, vaccines have shown efficacy against new SARS-CoV-2 variants. This study aimed to develop a systems medicine framework that can predict and validate drug combinations that can be repurposed for treating COVID-19 and its comorbidities, specifically type 2 diabetes and hypertension. This study found that gut microbes could potentially influence the action of drugs, innate immune response, intestinal dysfunction, and susceptibility to the virus in individuals with these comorbidities. It was also discovered that the spike protein of the virus interacts with 57 human genes, many of which are linked to food-borne bacteria. An analysis of disease enrichment showed that arthritis and hypertension were frequently observed as comorbidities in patients infected with SARS-CoV-2. Several drugs, including Fluvoxamine, Donepezil, and Ifenprodil, have been identified as potentially repurposable drugs for treating COVID-19 in individuals with hypertension. Moreover, nitazoxanide and tocilizumab (antivirals), bacitracin (antibacterial), and gliclazide (antidiabetics) were also identified as potential repurposable drugs. Tocilizumab and gliclazide are effective drug combinations for treating COVID-19 in individuals with type 2 diabetes. A combination of tocilizumab and lidocaine has also been suggested for treating COVID-19 in individuals infected with food-borne bacteria.

Impact of Natural Killer Cell-Associated Factors on Acute Leukemia Outcomes after Haploidentical Hematopoietic Stem Cell Transplantation with αβ T Cell Depletion in a Pediatric Cohort

The technique of αβ T cell depletion (αβTCD) is a well-established method of hematopoietic stem cell transplantation (HSCT) for children with acute leukemia owing to the low rates of graft-versus-host disease and nonrelapse mortality (NRM). The graft-versus-leukemia effect is generally ascribed to natural killer (NK) cells conserved within the graft. It is not known whether NK-related factors affect the outcome of αβTCD HSCT, however. The aim of this retrospective study was to explore the impact of NK alloreactivity (based on donor-recipient killer immunoglobulin-like receptor [KIR] mismatch), graft NK cell dose, and blood NK cell recovery on day +30 post-HSCT on the incidences of leukemia relapse and NRM. The pediatric acute leukemia cohort comprised 295 patients who underwent their first HSCT from a haploidentical donor in complete remission. During post hoc analysis, the total cohort was divided into subcohorts by diagnosis (acute lymphoblastic leukemia [ALL]/acute myeloid leukemia [AML]), NK alloreactivity prediction (KIR match/KIR mismatch), graft NK cell dose (less than versus greater than the median value), and blood NK cell recovery on day +30 post-HSCT (less than versus greater than the median value). We also investigated the influence of serotherapy (antithymocyte globulin [ATG] group) versus abatacept + tocilizumab combination [aba+toci] group) on relapse risk in the context of KIR mismatch. The risks of relapse and NRM were calculated by the cumulative risk method, and groups were compared using the Gray test. Multivariate analysis revealed no apparent impact of predicted NK alloreactivity or any other studied NK cell-related factors for the entire cohort. For patients with AML, a significantly higher relapse risk associated with high NK cell graft content on the background of no predicted KIR mismatch (P = .002) was shown. Multivariate analysis confirmed this finding (P = .018); on the other hand, for the KIR-mismatched patients, there was a trend toward a lower risk of relapse associated with high NK cell dose. The use of ATG was associated with a trend toward reduced relapse risk (P = .074) in the AML patients. There was no significant impact of NK-related factors in the ALL patients. Overall, the evaluated NK-related factors did not show a clear and straightforward correlation with the key outcomes of HSCT in our cohort of children with acute leukemia. In practice, the data support prioritization of KIR-mismatched donors for patients with AML. Importantly, a potential interaction of KIR ligand mismatch and NK cell content in the graft was identified. Indirect evidence suggests that additional cellular constituents of the graft could influence the function of NK cells after HSCT and affect their role as graft-versus-leukemia effectors.

Therapeutic Impact of Tocilizumab in the Setting of Severe COVID-19; an Updated and Comprehensive Review on Current Evidence.

The COVID-19 pandemic caused by SARS-CoV-2 has been the major health concern in 2019 globally. Considering the severity and phase of the disease, various pharmacotherapy schedules were proposed. Here, we set out to provide close-up insights on the clinical utility of Tocilizumab (TCZ), a biologic monoclonal antibody in this regard. In this comprehensive review, various databases, including Scopus, PubMed Central, Medline, Embase, Google Scholar, and preprint publishers (med/bioRxiv) were searched until January 30, 2024, according to the keywords and search criteria. Besides the pros and cons, compelling evidence purported the safety and efficacy of TCZ and indicated that it exhibits great potential to reduce short-term and all-cause (28-30-day) mortality. TCZ significantly drops the adverse events if administered in the right time course (in the inflammatory phase) during critical/severe COVID-19 pneumonia. Despite contradictory results, the benefits of TCZ appear significant, especially in combination with add-on therapies, such as corticosteroids. Although the safety of TCZ is acceptable, solid data is lacking as to its benefits during pregnancy. There are limited data on TCZ combination therapies, such as hemoperfusion, intravenous immunoglobulin (IVIG), simple O2 therapy, vasopressor support, convalescent plasma therapy, and even in vaccinated patients and COVID-19 reinfection, especially in elderly persons. In addition, the impact of TCZ therapy on the long-lasting COVID-19 is unclear. Personalized medicine based on individual characteristics and pertinent clinical conditions must be considered in the clinicians' decision-making policy. Finally, to mitigate the risk-to-benefit ratio of TCZ, a treatment algorithm, based on available literature and updated national institute of health (NIH) and Infectious Diseases Society of America (IDSA) guidelines, is also proposed.

Study of various therapeutic strategies for the treatment of rapidly progressive periodontitis in experimental models

Rapidly progressive periodontitis is a serious disease that leads to rapid degradation of periodontal tissues and can lead to tooth loss at a relatively young age. The purpose of this article is to study the effectiveness of various modern methods in the treatment of this disease on an experimental model. A model of the studied pathology was created – a rat with a destroyed circular ligament of the tooth and a ligature applied to the base of the teeth. 5 study groups were formed, where various treatment methods were used: the appointment of soft food, the combination of intramuscular administration of vitamin C and prednisolone, the combination of tocilizumab and dexamethasone, and the combination of photodynamic therapy and tocilizumab. Histological material was taken from experimental animals and evaluated. The best results were noted in the group of photodynamic therapy and tocilizumab, where there was a better histological picture with minimal signs of the inflammatory process and satisfactory indicators of clinical dynamics, this approach showed high efficiency in resolving inflammation in the area of the affected foci. The 2nd place was taken by the combination of tocilizumab and dexamethasone, in this group, accelerated positive dynamics were noted compared to other groups, but the results of histological examination were worse than in group 1. In 3rd place – the combination of ascorbic acid with dexamethasone and the appointment of soft food, where there were almost no differences in terms of histological results and clinical picture compared to the control group. The combination of tocilizumab with photodynamic therapy is promising in the treatment of patients with rapidly progressive periodontitis, but additional human studies are required to include this type of treatment in clinical guidelines.

Treatment for giant cell arteritis with 8 weeks of prednisone in combination with tocilizumab: a single-arm, open-label, proof-of-concept study

Even after the approval of tocilizumab, substantial glucocorticoid exposure (usually ≥6 months) and toxicity continue to be important problems for patients with giant cell arteritis. We aimed to assess the outcomes of a group of patients with giant cell arteritis treated with tocilizumab in combination with 8 weeks of prednisone. This prospective, single arm, proof-of-concept study was conducted at Massachusetts General Hospital (Boston, MA, USA). Individuals aged 50 years or older who had new-onset or relapsing giant cell arteritis with active disease were eligible for inclusion. Participants received 12 months of tocilizumab 162 mg weekly subcutaneously in combination with 8 weeks of prednisone. The primary endpoint was sustained prednisone-free remission at week 52. Adverse events were also evaluated. This trial is registered with ClinicalTrials.gov (NCT03726749), and is complete. Between Nov 28, 2018, and Nov 2, 2020, we enrolled 30 patients (mean age 73·7 years [SD 8·1], 18 [60%] women and 12 [40%] men, 30 [100%] White race, 15 [50%] new-onset disease, 23 [77%] temporal artery biopsy-proven, 14 [47%] imaging-proven). The initial prednisone doses were 60 mg (n=7), 50 mg (n=1), 40 mg (n=7), 30 mg (n=6), and 20 mg (n=9). All patients entered remission within 4 weeks from baseline. 23 (77%) of 30 patients were in sustained prednisone-free remission at week 52 and seven (23%) patients relapsed, with a mean time to relapse of 15·8 weeks (SD 14·7). Overall, four (13%) participants developed a serious adverse event, including one related or probably related to prednisone exclusively, two related or probably related to tocilizumab exclusively, and one related or probably related to prednisone, tocilizumab, or both. Two of the non-responder patients stopped tocilizumab and withdrew from the study prematurely after having a second disease relapse. No cases of giant cell arteritis-related permanent vision loss occurred during the study. These results suggest that 12 months of tocilizumab in combination with 8 weeks of prednisone could induce and maintain remission in patients with giant cell arteritis. Confirmation of these findings in a randomised controlled trial is required. Genentech.

Excellent Safety Profile of a Low-Cost Novel Humanized CD19 CAR T-Cell Therapy, Actalycabtagene Autoleucel : Potential Impact on Access and Feasibility

Background: A high incidence of severe toxicities especially grade 3/4 immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS), need for hospitalization, and the cost of supportive care is an hindrance to the implementation of CAR-T cell therapy for low and middle income countries (LMICs). To address these limitations, we designed a novel humanized CD19 CAR and demonstrated a favorable balance of efficacy to toxicity in the preclinical model and in the first-in-human Phase I study (Dwivedi et al. Mol Cancer Ther. 2021, Karulkar et al. ASH 2022). Here, we quantified the healthcare resource utilization (HCRU) and associated cost of clinical management of Actalycabtagene autoleucel (Actaly-cel) in India from an ongoing Phase I/II study in B-cell malignancies. Methods: This is a retrospective analysis of the HCRU costs of patients with r/r B-cell malignancies treated on Phase I/II study with Actaly-cel at 3 centers in India between June 2021 through July 2023. The key components of HCRUs are defined in Table 1 and were quantified from the electronic records from the time of enrolment till their last follow-up. Once enrolled, bridging therapy was allowed at investigator's discretion. After lymphodepletion (LD) with a fludarabine plus cyclophosphamide (FC) regimen for 3 days, patients received Actaly-cel at a target dose ≥ 5 million CAR-T cells/kg (upper limit; total 2 x10 9). The patients were monitored for toxicities particularly CRS, ICANS and cytopenias, as inpatient (non-HEPA filtered rooms) for at least a week. CRS and ICANS were graded as per ASTCT grading system and cytopenias as per CTCAE v5. Results: Total 59 patients were enrolled in this study and 47 patients received the infusion. Thirty seven patients (r/r lymphoma; n=28, r/r B-ALL; n=9) who completed 28 days post-infusion were evaluable for HCRU analysis. The median age was 37 years (16-71). The median follow-up of the cohort was 60 days (21-644); 19% (7/36) and 11% (4/36) patients completed 6 months and 12 months follow-up respectively. Among all patients (n=37) who received LD therapy, 46% of lymphoma patients received LD in the outpatient setting while 78% of B-ALL patients required hospitalization for LD. The median hospitalization period post Actaly-cel infusion was only 8 days (range: 7-17 days) in the lymphoma cohort, and 13 days (range: 7-19 days) for B-ALL patients. Importantly, none of the lymphoma patients required ICU admission, and only one B-ALL patient required ICU admission for management of adverse events. In the lymphoma cohort, 54% (15/28) of patients developed Grade 1/2 CRS and none had grade >/=3. A single dose of tocilizumab was given to 36% (10/28) of patients and only 4% (1/28) received tocilizumab plus corticosteroids. None of the patients required vasopressor support. Majority of B-ALL patients developed CRS. The incidence and severity of CRS was as follows: G1; 44% , G2; 11% and G3; 22%. There were no grade 4/5 CRS events. While 11% (1/9) of patients received a single dose of tocilizumab, 44% (4/9) received tocilizumab in combination with corticosteroids. Vasopressors were required in 22% of patients. None of the patients developed ICANS of any grade . Most patients (lymphoma and B-ALL) developed hematological toxicities(Table 1). The severity of Grade 3-4 was more prevalent in the B-ALL cohort. IVIG was administered to 25% of lymphoma and 22% of B-ALL patients. The induction and severity of the above toxicities were not dependent on the Actaly-cel dosage (median: 9 x 10 6 ;range: 2 x 10 6-21 x 10 6 CAR-T cells/kg). The projected production cost of Actaly-cel in the regional decentralized manufacturing model at the scale of 300 patients/year is ~15,000 USD per patient. The mean cost of HCRU for clinical management (until last follow-up) per patient was ~ 4,400 USD in an academic centre (lymphoma; ~4,000 USD, B-ALL; ~5,565 USD) and interestingly, only about 14% of these costs were incurred due to inpatient management (Figure 1). Conclusions: Actaly-cel was efficacious, with no incidence of ICANS and manageable CRS across a wide dose range. More importantly, this study reported low HCRUs due to negligible ICU admission and shorter duration of hospitalization, ensuring potential usage of Actaly-cel in outpatient settings, and ultimately improving the access and feasibility of CD19 CAR-T cell therapy in resource constrained settings such as LMICs.

Tocilizumab in combination with a standard induction chemotherapy in acute myeloid leukaemia patients (TOCILAM study): a single-centre, single-arm, phase 1 trial

In acute myeloid leukaemia (AML), interleukin-6 (IL-6) promotes chemo-resistance and its levels correlate with poor prognosis. IL-6 blockade may represent a promising therapeutic strategy. We aimed to test, tocilizumab, an anti-IL-6 receptor (R) monoclonal antibody in combination with standard intensive AML induction chemotherapy. This investigator-initiated single-centre phase 1 trial was conducted at Nantes University Hospital in France. According to a continual reassessment method, three escalating doses were tested of intravenous (IV) tocilizumab (4, 6, and 8mg/kg) administered at day (d) 8 of a standard AML induction chemotherapy (IV idarubicine 8mg/m2 d1 to d5+IV cytarabine 100mg/m2 d1 to d7). All adults (aged ≥ 18 years) with an Eastern Cooperative Oncology Group performance status of 0-2 and with a newly diagnosed (excluding patients with a favourable risk according to ELN-2017 classification if<60 year-old) or a relapsed/refractory AML were eligible. The primary objective was to determine the maximum tolerated dose of tocilizumab to administrate with a standard intensive AML induction. Safety outcomes were continuously monitored for at each participant contact. This trial is registered with ClinicalTrials.gov, NCT04547062. Between Dec 29, 2020 and Dec 1, 2022, 12 patients were enrolled, of whom 75% had an ELN-2017 high-risk profile, and were treated with tocilizumab- two patients at 4mg/kg, two at 6mg/kg and eight at 8mg/kg of tocilizumab. No dose-limiting toxicity related to tocilizumab was documented. There were nine serious adverse events, none of which were related to tocilizumab, and there was no treatment-related deaths. MTD was thus not reached. Two deaths occurred during induction. In the remaining ten evaluable patients, nine responded to treatment. The combination of tocilizumab with standard AML intensive induction appears to be safe and resulting responses are encouraging. A dose of 8mg/kg of tocilizumab given at day 8 of induction could be used for further phase 2/3 studies. The Leucémie Espoir Atlantique Famille (LEAF)-"Tous avec Fabien" association.

First-in-human trial of tocilizumab in combination with a standard induction chemotherapy in newly diagnosed acute myeloid leukemia patients: The phase 1 TOCILAM study.

7028 Background: Numerous studies have pointed out the pathological role of deregulated expression of Interleukin-6 (IL-6) in cancers. In acute myeloid leukemia (AML), IL-6 promotes chemo-resistance and correlates with poor prognosis. One explanation is that AML cells express IL-6 receptor (R) and self-produce IL-6 at once, favouring blast proliferation and survival. Therefore, IL-6 blockade may represent a new promising therapeutic strategy for AML. Here, we have tested Tocilizumab (Toci), an anti-IL-6R antibody, in combination with a standard AML induction chemotherapy. Methods: This was a monocentric Phase 1 study testing three escalating doses of Toci (4, 6 and 8 mg/kg) administered at day (d) 8 of a standard AML induction chemotherapy (Idarubicine 8 mg/m² d1 to d5 + cytarabine 100 mg/m² d1 to d7). All adults ( &gt; = 18 yo) with a newly diagnosed (excluding patients (pts) with a favorable risk according to ELN-2017 classification if &lt; 60 yo) or a relapsed/refractory AML were eligible. The main objective was to determine the maximum tolerated dose of Toci for further phase 2/3 studies. Patients had to be included 2 by 2, according to a continual reassessment method while targeting a related-experimental drug toxicity level &lt; 30%. A maximum of 12 pts had to be included. Toxicity was evaluated using NCI version5 criteria. Responses were evaluated according to ELN-2017 criteria between d30/d45 of induction. Also, IL-6 and Toci plasma levels were assessed. All pts gave informed consent and the trial was registered at Clinical trials under NCT04547062. Results: Between Dec/2020 and Dec/2022, 12 pts were treated, including 2 pts at 4 mg/Kg, 2 at 6 mg/kg and 8 at 8 mg/kg of Toci. The median age was 66 yo (range: 56-73), all pts had a newly diagnosed AML, ELN risk was intermediate: 25%; unfavorable: 75%. No dose limiting toxicity related to Toci was documented. Two pts died during induction, 1 of infection and 1 of cerebral haemorrhage. Complete remission (CR) rate for evaluable pts was 90% (n = 9/10). After induction, 7 received a consolidation and 7 were allo-transplanted. With a median follow-up of 600d, 4 patients have relapsed and 7 have died, 1-y OS and LFS were estimated at 43% (21-88%) and 39% (19-82%), respectively. Dosages of IL-6 (pg/mL) showed a significant increase after Toci injection (median 23,2 (2.6-53.5) vs 202,9 (21.1-6189.2) after 8d and 481,5 (53.8-7327.4) after 15d), suggesting a good saturation of the targets (IL6-R) on AML cells and a potential anti-leukemic effect. Median dosages of Toci (µg/ml) were higher 8d and 15d after injection at L2 (34.8; 17.2) and L3 (38.5; 12.9) compared to L 1 (10.9; 1.4). Conclusions: The combination of Toci to a standard AML intensive induction appears to be very safe providing both high CR rate and the expected biological effect. We now recommend a dose of 8 mg/kg of Toci given at d8 of induction for further phase 2/3 studies. Clinical trial information: NCT04547062 .

Artificial intelligence assessment of the potential of tocilizumab along with corticosteroids therapy for the management of COVID-19 evoked acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS), associated with high mortality rate, affects up to 67% of hospitalized COVID-19 patients. Early evidence indicated that the pathogenesis of COVID-19 evoked ARDS is, at least partially, mediated by hyperinflammatory cytokine storm in which interleukin 6 (IL-6) plays an essential role. The corticosteroid dexamethasone is an effective treatment for severe COVID-19 related ARDS. However, trials of other immunomodulatory therapies, including anti-IL6 agents such as tocilizumab and sarilumab, have shown limited evidence of benefit as monotherapy. But recently published large trials have reported added benefit of tocilizumab in combination with dexamethasone in severe COVID-19 related ARDS. In silico tools can be useful to shed light on the mechanisms evoked by SARS-CoV-2 infection and of the potential therapeutic approaches. Therapeutic performance mapping system (TPMS), based on systems biology and artificial intelligence, integrate available biological, pharmacological and medical knowledge to create mathematical models of the disease. This technology was used to identify the pharmacological mechanism of dexamethasone, with or without tocilizumab, in the management of COVID-19 evoked ARDS. The results showed that while dexamethasone would be addressing a wider range of pathological processes with low intensity, tocilizumab might provide a more direct and intense effect upon the cytokine storm. Based on this in silico study, we conclude that the use of tocilizumab alongside dexamethasone is predicted to induce a synergistic effect in dampening inflammation and subsequent pathological processes, supporting the beneficial effect of the combined therapy in critically ill patients. Future research will allow identifying the ideal subpopulation of patients that would benefit better from this combined treatment.

Efficacy and safety of Tocilizumab, plasmapheresis and their combination in severe COVID-19: A randomized clinical trial

This study sought to evaluate and compare the effectiveness of plasmapheresis, Tocilizumab, and Tocilizumab with plasmapheresis treatment on the removal of inflammatory cytokines and improvement clinically of patients with severe COVID-19 in Intensive Care Units (ICU) due to the association between increased cytokine release and the severity of COVID-19. This clinical trial study was conducted in three treatment arms in Iran. All patients received standard care and randomization into one of three treatment groups; Tocilizumab (TCZ) alone, plasmapheresis alone, or a combination of Tocilizumab and plasmapheresis. Demographics, clinical evaluation, oxygenation status, laboratory tests and imaging data were evaluated in the three groups and re-checked 48h after the end of treatment trials. Primary outcomes were oxygenation status, the need for mechanical ventilation and the rate of death. Ninety-four patients were included in the trial after meeting the eligibility requirements. Twenty-eight patients received Tocilizumab alone, 33 had plasmapheresis alone, and 33 received both Tocilizumab and plasmapheresis. Baseline characteristics did not differ between three groups that included demographic, clinical and laboratory parameters. Following therapy, there was no difference between the three groups for CRP, ferritin, d-dimer, IL-6, pro-calcitonin and neutrophil to lymphocyte ratio (NLR) (P>0.05). While a significant reduction was found in CRP levels within each group (32.04±42.43 to 17.40±38.11, 51.28±40.96 to 26.36±33.07 and 41.20±34.27 to 21.56±24.96 in the tocilizumab, plasmapheresis, and combined group, respectively) (p<0.05), procalcitonin levels were elevated significantly in the Tocilizumab group (0.28±0.09 to 0.37±0.11) (p<0.05). Clinically there was no difference between the three groups following treatment for O2 saturation levels with supplementary oxygen at discharge, endotracheal intubation rate, use of NIVPP, mortality, mean hospital and ICU length of stay (p>0.05). Study results showed that the reduction of serum inflammatory markers, the rate of intubation and therapeutic complications including death were no different between the three groups; however, CRP levels were significantly reduced in all three groups, indicating that the interventions reduced inflammation likely through a reduction in the cytokine storm, though clinical outcomes were unaffected.

Tocilizumab in Combination with Corticosteroids in COVID-19 Pneumonia: A Single-Centre Retrospective Controlled Study.

Introduction: Interleukin 6 receptor inhibition by tocilizumab (TCZ) has been effectively used worldwide for the treatment of multisystem inflammatory syndrome (MIS) associated with COVID-19. In this single centre study, we compared the outcome of COVID-19 pneumonia in TCZ-treated vs. untreated (control) patients. We wished to compare TCZ administration in the general ward vs. in the intensive care unit (ICU). We also studied the role of a consulting rheumatologist in the management of severe COVID-19 pneumonia. Patients and methods: In our patients, COVID-19 pneumonia was confirmed by SARS-CoV-2 PCR, chest X-ray, and CT. We compared patients selected for TCZ treatment with TCZ-untreated age- and sex-matched controls. All patients received corticosteroids. In the TCZ-treated group, patients received one or two doses of TCZ 8 mg/kg IV in combination with corticosteroids. We recorded age, sex, symptom duration, oxygen saturation (SaO2), partial arterial oxygen pressure (PaO2), total white blood cell (WBC), absolute neutrophil, absolute lymphocyte and platelet counts, CRP, ferritin, IL-6, LDH, procalcitonin (PCT), and D-dimer. The primary outcome parameters were the need for ICU, ventilation, death, and time of hospitalisation. Results: Altogether, 104 patients, 52 TCZ-treated and 52 TCZ-untreated, were included in this study. At baseline, the TCZ-treated patient group indeed had more pronounced COVID-19-related MIS compared to controls. Consultation with a rheumatologist was performed in 60% vs. 40% of cases. Nineteen patients (37%) received one, while 33 (63%) received two TCZ doses. TCZ was administered to 28 patients (54%) in the general ward and to 24 (46%) in the ICU. TCZ treatment was found to be safe in our COVID-19 pneumonia patients. TCZ treatment favourably influenced MIS biomarkers, and was associated with better clinical outcomes compared to controls. Patients receiving TCZ treatment in combination with corticosteroids already in the general ward exerted much better outcomes than those treated in the ICU. Consultation with a rheumatologist also improved outcome. Conclusions: We successfully used TCZ in combination with corticosteroids in Hungarian COVID-19 pneumonia patients. We pointed out the importance of early treatment already in the general ward, and the involvement of a rheumatologist in making treatment decisions.

Effect of tocilizumab treatment in mildly-obese patients with coronavirus disease 2019: a case series

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is an increasingly widespread international medical problem. Several randomized trials and observational studies in patients with COVID-19 have been performed. However, the standard treatment strategy has not yet been established. The purpose of this study is to report effect of tocilizumab treatment combined with remdesivir, dexamethasone, and heparin on obese Japanese patients with COVID-19. Tocilizumab is a monoclonal antibody against the interleukin-6 (IL-6) receptor. Obesity, characterized by systemic enlarged adipocytes, promotes proinflammatory cytokine expression in adipose tissue. More specifically, obesity induces detrimental adipocytokine production including tumor necrosis factor-α (TNF-α), monocyte chemoattractant protein-1 (MCP-1), and IL-6. In addition, its production in the adipose tissue is associated with body mass index (BMI) and adipocyte size. IL-6 can promote inflammation not only in the adipose tissues but also in endothelial cells and triggers systemic inflammation. A cross-sectional observational study was conducted. The study sample consisted of 96 patients between August 2020 and January 2021 at Showa University Fujigaoka Hospital. Overall, 56.3% (54 of 96) were administered with remdesivir, 54.2% (52 of 96) with dexamethasone, 19.8% (19 of 96) with anticoagulant therapy with heparin. Of the patients, nine were administered tocilizumab with remdesivir, dexamethasone, and heparin. The current study indicated that single-dose treatment of tocilizumab in combination with remdesivir, dexamethasone, and heparin is beneficial for obese Japanese patients with COVID-19. We believe that the severity of obesity is related to the anti-IL-6 treatment sensitivity in patients with COVID-19.

151P Clinical outcome and preliminary immune analysis of phase II clinical trial of combination of tocilizumab with ipilimumab and nivolumab for patients with treatment naïve metastatic melanoma

Immune related adverse events (irAEs) can possess a major challenge in patient symptom burden and risk of fatalities. In addition, it is a barrier for the development of multi-agent immunotherapy regimen. Management of these irAEs using corticosteroids as first-line therapy may have detrimental impact on cancer outcomes and worsen survival. We have previously demonstrated that interleukin-6 (IL-6) plays a role in the pathogenesis of irAEs in tumor resistance. Based on this data, we conducted this trial to assess the safety and efficacy of IL-6 blockade, using Tocilizumab, in combination with ipilimumab and nivolumab in melanoma patients.

Is Tocilizumab Effective and Safe in Polymyalgia Rheumatica and Giant-Cell Arteritis With Polymyalgia Rheumatica?

Polymyalgia rheumatica (PMR) and giant-cell arteritis (GCA) with symptoms of PMR share some pathophysiologic features. Interleukin 6 (IL-6) levels are elevated in both groups. We investigated the effect of tocilizumab (TCZ), an IL-6 inhibitor, in both populations and whether there were any differences regarding effectiveness and safety between them.We conducted a systematic review following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines by searching the following databases: PubMed, PMC, Medline, Scopus, Cochrane Library, and ClincalTrials.gov.We found eight articles including one systematic review, one randomized controlled trial (RCT), one posthoc analysis of an RCT, and five observational studies. A total of 668 patients were included in this study. After a comprehensive analysis, we can only infer that there is insufficient evidence to suggest TCZ as monotherapy. Nevertheless, using TCZ in combination with glucocorticoid can be an effective therapeutic option.

Tocilizumab in combination with ipilimumab and nivolumab in solid tumors.

TPS9600 Background: Immune checkpoint inhibitors (ICIs) are approved for multiple malignancies, however, durable remission rates with ICI monotherapy remains low. Combined treatment with anti-CTLA-4 and anti-PD1 has shown higher response rates in several cancers but is associated with up to 60% grade 3/4 immune-related adverse events (irAEs) leading to frequent treatment discontinuation. The need for corticosteroids to control irAEs may further diminish anti-tumor activity. A multi-disciplinary approach using clinical, preclinical, and translational analyses implicated the IL-6/Th17 axis in both ICI-related autoimmunity and resistance. Further, preliminary data showed that targeting interleukin 6 (IL-6) could be an effective approach to reduce irAEs while maintaining and possibly boosting the antitumor immune response. Methods: We are conducting a phase II, open-label, single center study to evaluate the use of combination treatment with tocilizumab (toci; anti-IL6), ipilimumab (ipi; anti-CTLA4) and nivolumab (nivo; anti-PD1) as a front-line therapy for patients (pts) with treatment-naïve advanced cutaneous melanoma (cohort 1), urothelial carcinoma (cohort 2), and EGFR mutant non-small cell lung cancer after tyrosine kinase inhibitors failure (cohort 3) (NCT04940299). Ten pts per disease site will be enrolled, plus an additional 25 melanoma pts in an expansion cohort. Key inclusion criteria are age ≥18 years (yrs) and histologically confirmed locally advanced or metastatic disease, with specific eligibility criteria defined for each cohort. Patients with interstitial lung diseases, autoimmune diseases, infection, or conditions requiring immunosuppressive therapies are not eligible, but stable asymptomatic brain mets are allowed. Ipi/Nivo dosing is as per approved disease indications: in cohort 1 &amp;2, ipi 3 mg/kg + nivo 1 mg/kg is administered intravenously (IV) every 3 weeks (wks) for 4 doses then nivo 480 mg/4 wks up to 2 yrs. In cohort 3, IV ipi 1 mg/kg/6 wks + nivo 3 mg/kg/2 wks is administered up to 2 yrs. In all 3 cohorts, subcutaneous (SQ) toci 162 mg/2wks is administered up to 12 wks. Imaging is every 12 wks up to 2 yrs or until dose-limiting toxicities or progression. The primary outcome is safety/tolerability of the triple therapy. The secondary outcomes are antitumor efficacy and overall survival. Additionally, tumor and blood samples are being collected for longitudinal immune analysis, including gene expression and multiplex histochemistry to identify predictive biomarkers of response, resistance, and toxicity. The trial opened in October 2021 and has enrolled 14 patients to date. Clinical trial information: NCT04940299.

Combined IL-6 and IL-8 inhibition to overcome mesenchymal stem cell (MSC)-induced resistance to antimetastatic drugs in osteosarcoma.

10037 Background: Mesenchymal stem cells (MSCs) play a key role in the progression of osteosarcoma (OS). In response to tumor-associated signals, including tumor-secreted extracellular vesicles (EVs), MSCs increase the expression of inflammatory cytokines promoting tumor cell aggressiveness. Previous data has demonstrated that IL-6 and IL-8 signaling mediate metastasis in OS. The aim of this study was to evaluate tumor EV-induced alterations of MSCs and identify combination therapies that can counteract MSC-induced resistance to antimetastatic drugs. Methods: Tumor EV-induced alterations of the MSC transcriptome were analyzed by RNA-seq. Gene set enrichment analysis (GSEA) was applied to discriminate TGFβ-dependent and independent pathways. EV RNA-induced expression changes were identified by transfecting purified EV-RNA in MSCs and by using a selective dsRNA antagonist. We selected candidate targets to block MSC-induced drug resistance and evaluated their effect in an orthotopic xenograft model of OS. Ladarixin (an allosteric inhibitor of the CXCL8/IL-8 receptors CXCR1 and CXCR2; 30 mg/kg 6x per week i.p.) and tocilizumab (anti-IL6 receptor antibody; 100 µg/mouse every other day i.p.) were administered starting from day one until the experimental endpoint. Metastasis were quantified by histological examination. This study was funded by the Dutch Cancer Society (KWF), POR FESR Campania 2014‐2020 and Dompé Farmaceutici SpA. Results: EVs from aggressive cancer cell lines induced an inflammatory MSC (iMSC) phenotype, characterized by increased expression of chemokines, including IL-8 as the most upregulated. Apart from IL-6, these alterations were mostly independent from TGFβ signaling and related to pattern recognition receptor (PRR) activation. We demonstrated that tumor EV-associated non-coding RNAs trigger TLR3 signaling in MSCs activating an innate immune response leading to high induction of IL-8 and other chemokines. Ladarixin and tocilizumab combination significantly reduced metastasis formation in a spontaneous metastasis model and overcame iMSC-induced resistance observed with single antimetastatic treatments. No effect was observed on primary tumor growth. Conclusions: EV-associated TGFβ together with EV-RNA induce iMSCs development in OS. Ladarixin in combination with tocilizumab reduced metastasis formation in a xenograft mouse model of OS, and, importantly, may prevent the occurrence of iMSC-induced tumor resistance to antimetastatic drugs.

OP0185 TOCILIZUMAB IN COMBINATION WITH 8 WEEKS OF PREDNISONE FOR GIANT CELL ARTERITIS

BackgroundEven with the use of tocilizumab (TCZ), significant glucocorticoid exposure (usually ≥ 6 months) continues to be an important problem in giant cell arteritis (GCA).ObjectivesWe aimed to evaluate the efficacy and safety of tocilizumab (TCZ) in combination with 2 months of prednisone in a group of patients with GCA.MethodsWe conducted a prospective, single arm, open-label study of TCZ in combination with 2 months of prednisone for new-onset and relapsing GCA patients with active disease (ClinicalTrials.gov Identifier NCT03726749). GCA diagnosis required confirmation by temporal artery biopsy or vascular imaging. Active disease was defined as presence of cranial or polymyalgia rheumatica symptoms necessitating treatment within 6 weeks of baseline. All patients received TCZ 162 mg subcutaneously every week for 12 months and an 8-week prednisone taper starting between 20 mg and 60 mg daily (Figure 1). The primary endpoint, sustained prednisone-free remission, was defined as absence of relapse from induction of remission up to week 52 while adhering to the prednisone taper. Relapse was defined as the recurrence of symptoms of GCA requiring treatment intensification regardless of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels. Safety was also evaluated.Figure 1.Clinical Trial SchemaResultsBetween 11/2018 and 11/2020 we enrolled 30 patients (mean age 74 years, 60% females, 50% new-onset disease, 77% temporal artery biopsy-proven, 47% imaging-proven). The mean ESR and CRP at screening were 45 mm/hour and 48 mg/L, respectively. The initial prednisone dose was 60 mg (n = 7), 50 mg (n = 1), 40 mg (n = 7), 30 mg (n = 6) and 20 mg (n = 9). All patients entered remission within 4 weeks of baseline. The primary endpoint was achieved by 23 (77%) patients (Table 1). The mean (SD) cumulative prednisone dose in these 23 patients was 1052 (390) mg. After a mean period of 16 weeks, 7 (23%) patients relapsed (Table 1). All relapses but one occurred after the completion of the study prednisone taper. Overall, 6 of the 7 patients with relapse received a second prednisone taper over 8 weeks. Of these 6 patients, 4 achieved and maintained remission for the remainder of the trial period, and 2 withdrew from the study after having a second relapse. One patient with relapse received a second prednisone taper over 26 weeks and stayed in remission until the end of the study. The mean (SD) cumulative prednisone dose in the 7 patients with relapse was 1883 (699) mg (Table 1). Overall, 4 (13%) participants developed a serious adverse event (Table 1). No cases of ischemia-related visual symptoms including permanent vision loss occurred during the study.Table 1.Efficacy and Safety OutcomesGCA patients(n = 30)Efficacy Sustained, prednisone-free remission by week 5223.0 (76.7) Cumulative prednisone dose (mg) at week 52, mean (SD)1051.5 (390.3) Relapse7.0 (23.3) Time to relapse, weeks: mean (SD)15.8 (14.7) Prednisone dose (mg/day) at relapse, mean (SD)2.1 (5.2) Cumulative prednisone dose (mg), mean (SD)1883.1 (699.2) Clinical manifestations at relapse Cranial symptoms4 out of 7 patients Ischemic visual symptoms0 out of 7 patients PMR symptoms4 out of 7 patientsSafety Serious adverse events4.0 (13.3) Cellulitis1 COVID-191 Fragility fracture1 Cholecystitis1Values represent number and (%) unless otherwise specified. SD, standard deviation; PMR, polymyalgia rheumaticaConclusionThese results suggest that 12 months of TCZ in combination with 8 weeks of prednisone could be efficacious for inducing and maintaining disease remission in patients with GCA. Confirmation of these findings in a randomized controlled trial is required.Disclosure of InterestsSebastian Unizony Consultant of: Kiniksa, Sanofi, Janssen, GSK, Grant/research support from: Janssen, Genentech, Mark Matza: None declared, Adam Jarvie: None declared, Ana Fernandes: None declared, John H. Stone Consultant of: Roche/Genentech, Grant/research support from: Roche/Genentech

Efficacy and Outcome of Remdesivir and Tocilizumab Combination Against Dexamethasone for the Treatment of Severe COVID-19: A Randomized Controlled Trial.

Objective: In this study, we investigated the efficacy and safety of remdesivir and tocilizumab combination therapy against dexamethasone for the management of severe COVID-19 patients. Methods: This was a multicenter study. Cases were randomly chosen and divided into two groups using an odd–even ratio of 1:1 applied to the hospital registration number. Group A received remdesivir [5 mg/kg (<40 kg) or 200 mg (>40 kg) on day 1 and then 2.5 mg/kg (<40 kg) or 100 mg (>40 kg) daily] + tocilizumab [8 mg/kg up to 800 mg highest 12 h apart], and group B was the control and received dexamethasone 6 mg/day. In addition, a broad-spectrum antibiotic and other essential treatments were received by all patients. To evaluate the mortality risk, the sequential organ failure assessment (SOFA) score was calculated on day-1. Treatment outcomes were measured as time to clinical improvement; mortality rate; duration of ICU stay; total period of hospitalization; the rate of (Supplementary Material) oxygen use; time to clinical failure; National Early Warning Score-2 (NEWS), and the percentage of lung recovery on CT of chest on discharge. Clinical trial registration ID: NCT04678739. Results: Remdesivir-Tocilizumab group had a lower mortality rate (25.49%) than the control (30.77%). The time to clinical improvement (Group A-9.41; B-14.21 days), NEWS-2 on discharge (Group A-0.89; B-1.2), duration of ICU stay (Group A-7.68; B-10.58), and duration of hospitalization (Group A-9.91; B-14.68) were less in the treatment group. Group A had a better percentage of lung recovery on chest CT than the control (Group A-22.13; B-11.74). All these differences were statistically significant (p= <0.05) in a t-test. However, no significant survival benefit was found among the study groups in Kaplan–Meier survival analysis, p = 0.739. Conclusion: The remdesivir–tocilizumab combination had preferable outcomes compared to the dexamethasone therapy for the treatment of severe COVID-19 concerning mortality rate and clinical and pulmonary improvement, although it did not demonstrate a significant survival benefit. Clinical Trial Registration: https://clinicaltrials.gov, NCT04678739.