Sylvant (siltuximab)

P1, N=20, Recruiting, Paolo Caimi, MD | Not yet recruiting --> Recruiting

P1, N=6, Active, not recruiting, H. Lee Moffitt Cancer Center and Research Institute | Recruiting --> Active, not recruiting | N=20 --> 6

P=N/A, N=65, Recruiting, IRCCS Azienda Ospedaliero-Universitaria di Bologna

P2, N=215, Recruiting, Memorial Sloan Kettering Cancer Center

P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2024 --> Oct 2025 | Trial primary completion date: Oct 2024 --> Oct 2025

Sixteen patients had CRS previously treated with tocilizumab and 17 patients had ICANS previously treated with steroids. Siltuximab appeared to be effective for both CRS and ICANS, including previously treated toxicities. These data support the use of siltuximab in CRS and ICANS as well as provide rationale for future prospective studies.

Optimizing the formulation, for example, enriched fish oil that meets drug concentration standards for EPA and DHA, a continuous infusion rate, reductions in long-chain saturated fatty acids concentrations, and addition of medium-chain triglycerides to improve EPA + DHA utilization and physical stability are key pharmaceutical factors. This may result in a safer and more effective option than targeted abrogation of cytokines and consequent risks of adverse drug reactions, but will require formal study in randomized control trials in humans.

P1, N=20, Not yet recruiting, Paolo Caimi, MD | Initiation date: Aug 2024 --> Dec 2024

This study presents a case of a 6-year-old girl with DOCK8 deficiency, characterized by severe, treatment-resistant herpetic infections who was successfully treated with siltuximab and glucocorticoids. The successful use of siltuximab in achieving remission highlights the pivotal role of interleukin-6 (IL-6) in DOCK8 deficiency pathogenesis and suggests that IL-6 modulation can be critical in managing DOCK8 deficiency-related viral infections, which may inform future therapeutic strategies for DOCK8 deficiency and similar immunodeficiencies.

This study aimed to evaluate the clinical efficacy and safety of siltuximab in combination with pemetrexed and platinum-based chemotherapeutic agents for treating non-small cell lung cancer (NSCLC) through a randomized trial. A nuanced understanding of limitations is crucial for future research and application. This study prompts further research in NSCLC, advocating for larger cohorts and long-term follow-ups to explore sustained efficacy and potential biomarkers, guiding improvements in patient care.

P1, N=20, Not yet recruiting, Case Comprehensive Cancer Center

P2, N=20, Not yet recruiting, Case Comprehensive Cancer Center

P1, N=20, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial completion date: Sep 2025 --> Jan 2025 | Trial primary completion date: Sep 2025 --> Jan 2025

This result is encouraging and demonstrates the potential of siltuximab as treatment of CD. As earlier published, this case confirms that significantly elevated inflammatory markers in a patient with CD predict a good response to siltuximab.

P2, N=24, Recruiting, University of Pennsylvania | Trial completion date: Dec 2023 --> Jun 2025 | Trial primary completion date: Dec 2023 --> Jun 2024

Moreover, potential drugs like CILOBRADINE for MALAT1 and SILTUXIMAB for IL6 were identified. This research underscored MALAT1 and IL6's potential value as targets in diagnosis and treatment for IBD patients.

Axicabtagene ciloleucel (42%) was the most common cellular therapy product...Prior to siltuximab, 52% of pts received tocilizumab with the majority (59%) receiving more than 1 dose, 69% of pts received corticosteroids, and 10 pts received additional treatments: anakinra (7/10 pts), LP with intrathecal (IT) chemo (3/10 pts), LP with IT steroids (2/10 pts), ruxolitinib (1/10 pt)... To our knowledge, this is the largest cohort of pts treated with siltuximab for CRS and/or ICANS following CAR-T therapy. Half of the pts had CRS or ICANS refractory to tocilizumab and/or steroids. Siltuximab appeared to be effective for both CRS and ICANS, including refractory toxicities.

The top three novel predicted treatments for iMCD included two TNF inhibitors, adalimumab and certolizumab pegol, and the B cell depleting agent, rituximab, the second most prescribed drug for iMCD after siltuximab. We utilized a translational research approach including experimental and unbiased machine learning approaches to identify TNF as a novel therapeutic target that we inhibited to treat a highly refractory iMCD patient. Together, our data suggest that over-production of TNF, in part by activated T cells, promotes iMCD pathogenesis and highlight that further research is needed into TNF inhibition as a potential treatment strategy for iMCD.

1L regimens were grouped into one of the following mutually exclusive categories in hierarchical order: siltuximab-containing regimen, rituximab-containing regimen, and primary chemotherapy-containing regimen. This may be due to the inclusion of other CD subtypes in the cohort or sicker patients not being seen in an outpatient oncology setting. Future work should explore the drivers of poor outcomes for patients as well as the factors associated with lack of receipt of siltuximab.

While anti-interleukin-6 (IL-6) therapy with siltuximab is effective in 34-50% of iMCD patients, disease pathophysiology remains largely unknown... IgG autoantibodies associated with CTDs, such as anti-Mi2, anti-SRP54, anti-La, anti-Ro, and anti-Histone 3; and ACAs, such as anti-OSM, anti-TNF, and anti-ITM2B were common in iMCD patients. While autoantibodies suggest autoimmune involvement, the presence of autoantibodies does not directly implicate autoimmunity as a pathological mechanism. For example, Hodgkin's disease and other post-infectious etiologies can present with elevated autoantibodies.

P2, N=30, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Oct 2023 --> Oct 2024 | Trial primary completion date: Oct 2023 --> Oct 2024

P2, N=40, Recruiting, Massachusetts General Hospital | Not yet recruiting --> Recruiting | Initiation date: Mar 2023 --> Aug 2023

Treatment with high-dose steroids and siltuximab was started, and it improved the symptoms. Although iMCD-TAFRO is a rare disease, this case emphasizes the importance of a comprehensive workup for appropriate and timely recognition of this entity and highlights the diagnostic challenges that it may present.

Current treatment using immunosuppressive doses of methotrexate, cyclophosphamide, or cyclosporine A has modest efficacy, and the responses are usually not durable. No new safety signal was observed. The study is actively recruiting at Moffitt Cancer Center, Tampa, FL.

Sixteen patients (66.6%) received tocilizumab, 10(41.6%) steroids, 6(25.0%) anakinra, and 5(20.8%) siltuximab. Supportive treatment allowed effective management and high survival. Some patients presenting with carHLH, can suffer a fulminant course.

It seems that the use of anti-IL6/IL6R in CRS secondary to bsAb administration in solid tumors patients does not significantly increase the risk of infection, as opposed to DLBCL patients where secondary infection might be a concern.

P1, N=20, Recruiting, H. Lee Moffitt Cancer Center and Research Institute | Trial primary completion date: Sep 2024 --> Sep 2025

P1, N=12, Recruiting, Nantes University Hospital | Not yet recruiting --> Recruiting

He was started on methylprednisolone, tocilizumab, and later baricitinib and etoposide...Treatment with the anti-IL-6 monoclonal antibody, siltuximab, has demonstrated improved survival... This case illustrates rapidly deteriorating nature of the iMCD-TAFRO syndrome. Early diagnosis is challenging but essential to improving outcomes. An intensivist must have high suspicion when blood cultures are negative but new lymphadenopathy is present

Background: CD19 CAR-T tisagenlecleucel has been proved to be effective in B-cell precursor acute lymphoblastic leukemia (B-ALL)...Bridging therapy was individualised in each patient, and lymphodepletion regimen consisted on fludarabine and cyclophosphamide...Two (40%) suffered disease progression and received palliative treatment.PATIENT IDP1P2P3P4P5AGE (years)136111710GENDERMFFMMDISEASErB-ALLrB-ALLrB-ALLRB-ALLrB-ALLPREVIOUS HSCTMonths to relapseNOYES1.3YES14.8NONOPREVIOUS CD19 CAR-TMonths to relapseYES7YES7YES6.5NONOOTHER PREVIOUSTHERAPY-InotuzumabCarfilzomib(NCT02303821)--IMMUNOPHENOTYPECD19-CD22+CD19-CD22lowCD19-CD22+CD19lowCD22+CD19+CD22lowCD19+CD22+BRIGDE THERAPYITTSteroidsVCRARA-CMCPHUDexaTUMOR BURDEN (%) PRE-LYMPHODEPLETION0.014.55.328775LYMPHODEPLETIONFluCy600FluCy600FluCy600FluCy900FluCy500DAYS OF PRODUCTION911101110DOSE (cells/kg)FRESH INFUSSION3x1e6NO3x1e6NO3x1e6NO1.5x1e6YES7.5x1e5YESCRSMax...grade (ASBMT)Day of onsetTreatmentNONONOYES36SiltuximabDexaYES37DexaHLHDay of onsetTreatmentNONONOYES6AnakinraDexaYES7AnakinraDexaRuxoPICU ADMISSION (days)NONONOYES (5)YES (6)RESPONSE DAY +28CR, MRD-PDCRi, MRD+CR, MRD-CR, MRD-RELAPSE &TREATMENTYESHSCT-Palliative-ReinfussionNOHSCTNOHSCTSTATUS &FOLLOW-UP (months)A28PA2PA4.5A5A1 The manufacturing of dual CD19/22 CAR-T therapy is feasible and reproducible under GMP conditions... The manufacturing of dual CD19/22 CAR-T therapy is feasible and reproducible under GMP conditions. The infusion of the product seems to be well tolerated without severe toxicities in the majority of patients, with an adequate safety profile. Data from our experience suggest the efficacy of its use.

Patient characteristicsTisa-celN=18Axi-celN=32Sex, male, n (%)11 (61)14 (44)Age, median (range)63 (41-73)63 (33-79)Bridging therapy, n (%)12 (67)31 (97)ECOG, n (%) 0-1 2-3 18 (100)0 (0)32 (100)0 (0)Histology, n (%) DLBC Transformed FL Primary mediastinal lymphoma16 (89)2 (11)0 (0)26 (81)2 (6)4 (13)Disease status at apheresis, n (%) Progressive disease Stable disease Partial response Complete response8 (44)6 (33)2 (11)2 (11)19 (60)4 (13)6 (19)3 (10)Primary refractory, n (%)8 (44)20 (63)Previous lines, median (range)2 (2-4)2 (2-5)Prior ASCT, n (%)9 (50)11 (34)Prior Allo-SCT, n (%)1 (6)0 (0)CRS 2, n (%) Tocilizumab Corticosteroids2 (11)2 (11)0 (0)12 (38)12 (38)10 (31)ICANS, n (%) Corticosteroids Siltuximab Anakinra1 (6)1 (6)0 (0)0 (0)6 (19)6 (19)4 (13)4 (13) Infections after CAR-T cell therapy are frequent and may be severe. Infections after CAR-T cell therapy are frequent and may be severe. Low rates of total T cell counts and CD8 T cells are associated to an increase risk of infections after day +90 after commercial CAR-T cell therapy. Tisa-cel shows a better CD4 T cell reconstitution although this does not seem to influence in presenting significant higher infection rates compared to axi-cel.

P1, N=12, Not yet recruiting, Nantes University Hospital

1 day post-infusion on the ward, he developed CRS and ICANS, with fever and altered mental status, for which he received tocilizumab, dexamethasone, and anakinra, in addition to empiric antibiotics. He progressed with worsening hypotension and encephalopathy and was admitted to the ICU and required vasopressors, pulse-dose steroids, and siltuximab...Effective and timely treatment of bleeding associated with DIC and severe CRS can be life-saving. It behooves the intensivist to recognize the toxicities of CAR-T as therapeutic applications broaden in the coming years.

A 63-year-old patient with relapsed/refractory mantle cell lymphoma received conditioning with fludarabine/cyclophosphamide and then, 2.5×108 CAR-T cells/kg...Due to persistent fever, tocilizumab was commenced...Oral levetiracetam, administered prophylactically since infusion day, was replaced with increased dose of intravenous levetiracetam due to bedside EEG alterations, with dexamethazone...High dose intravenous methylprednisolone and anakinra were administered...Siltuximab was also added, along with supportive treatment. After 34 days, he was extubated without neurologic deficits, but with myopathy and colonization of resistant Gram-negative bacteria. One month post CAR-T cell therapy, complete remission (CR) was achieved, and the patient was discharged.

P1, N=10, Recruiting, Timothy Voorhees | Not yet recruiting --> Recruiting

P1, N=10, Not yet recruiting, Timothy Voorhees

Median CRS duration was 3 (1-7) days and peak C-reactive Protein 10.5 (2.4-38.3), for which 9 (47.4%) received siltuximab, 4 (21%) tocilizumab and 2 (10.5%) dexamethasone. All patients received routine prophylaxis with ciprofloxacin and acyclovir, while 23 (88.5%) received trimethoprim-sulfamethoxazole and 3 (11.5%) received pentamidine for PCJ prophylaxis... Infectious complications after anti Myeloma CAR-T therapy are rare, non-fatal and easily manageable. Larger studies are needed to confirm the role of CRS, older age, male sex and other patient, disease or therapy-related variables in predicting infections post CAR-T.

Tocilizumab, an anti-interleukin – 6 receptor (IL-6R) monoclonal antibody used for the treatment of CRS, can lead to a paradoxical increase in circulating IL-6 levels (Nishimoto et al...2 pts received axicabtagene ciloleucel, 2 pts received idecabtagene vicleucel, 1 pt each received lisocabtagene ciloleucel and tisagenlecleucel, respectively... In this interim analysis, siltuximab appears to have demonstrated safety and efficacy for managing CRS and ICANS in pts receiving CAR T-cell therapy. Only 1 of 6 pts did not respond to siltuximab, therefore, the study will continue accrual to a target of 20 pts.

Siltuximab which binds to site I of IL-6 receptor and prevents IL-6 binding to it, is not FDA approved, however used in selective tocilizumab resistance cases or as an alternative therapy (Riegler et al., 2019). Anakinra is an IL-1 receptor antagonist, which was found to improve CRS in association with tocilizumab when compared to tocilizumab alone (Jatiani et al., 2020). Lenzilumab, is a monoclonal antibody that neutralizes granulocyte-monocyte colony stimulating factor (GM CSF), was also used in preclinical studies and found to be lessening the severity of CRS without dampening CAR-T cell function (Sterner et al., 2019).Infections: The factors which increase the risk of infection in MM patients post-BCMA therapy are >3 prior lines of therapy, B-cell aplasia, infections 30-days before CAR-T, and post CAR-T lymphopenia...In most cases cytopenia would improve over a period of 12-months.Conclusion : Given the recent use of BCMA therapy in RRMM, there is no standard guideline on how to manage the complications associated with it. Larger studies with longer follow up needs to be conducted, to address the safety of the therapy for better patient outcome

Tocilizumab with or without corticosteroid (e.g., dexamethasone) is the current standard management for moderate to severe CRS (Brudno JN & Kochenderfer JN, 2020 Blood Rev.)...The usage of siltuximab (anti-IL6 antibody) was observed in one patient with high CRS grade alone (2.2%, wo anakinra) and one patient with co-occurring ICANS (2.2% w anakinra)...Etanercept (TNF antagonist) was also used after tocilizumab, methylprednisolone, and anakinra in one patient with severe CRS complication and co-occurring ICANS. Conclusion s : In this study, we provided a real-world clinical pattern for patients with tocilizumab non-responding CRS or patients with co-occurring ICANS. Gaining a better understanding of toxicity management in those groups can help guiding the treatment of CAR-T cell therapy toxicity and improving quality of life for patients with cancer.

The only FDA-approved drug for iMCD, siltuximab, blocks IL-6 and is effective in treating a portion of patients suggesting other key cytokines may contribute to iMCD pathogenesis...Finally, previously published single-cell RNA sequencing data from our group showed that IFNƔ signaling was up-regulated in every circulating cell population profiled in iMCD during active disease suggesting that IFNƔ signaling is activated in immune cells in the blood, likely from high levels of IFNƔ. Herein, we present evidence that increased IFNƔ activity is characteristic of iMCD and propose IFNƔ signaling as an underappreciated pathway and key mechanism underlying iMCD and potential therapeutic target.