tbuckley/cabot-search huggingface dataset:
Preclinical assessment of IPH6501, a first-in-class IL2v-armed tetraspecific NK cell engager directed against CD20 for R/R B-NHL, in comparison with a CD20-targeting T cell engager.
Authors: Olivier Demaria, Marie Vetizou, Romain Remark, Laura Chiossone, Constance Vagne, Rachel Courtois, Caroline Denis, Aurélie Maguer, François Le Floch, Agnès Represa, Audrey Blanchard Alvarez, Laurent Gauthier, Sonia Quaratino, Carine Paturel, Eric Vivier
Journal: Journal of Clinical Oncology (2024)

7030 Background: The therapeutic landscape for relapsed or refractory (R/R) B-cell non-Hodgkin lymphoma (B-NHL) is evolving to include targeted T-cell based immunotherapies, including CD19-targeted CAR-T and CD3xCD20 T-cell engaging (TCE) bispecific antibodies. Yet, there remains an unmet medical need for patients who are refractory to, or ineligible for these treatments. Leveraging natural killer (NK) cells emerges as a promising strategy in hematological malignancies, as shown in a Phase 1 study with IPH6101/SAR’579 in R/R AML (Stein, ASCO 2023; Bajel, ASH 2023). Methods: We developed IPH6501, a tetraspecific antibody-based NK cell engager that simultaneously targets on NK cells the CD16a and NKp46 receptors, the IL-2 receptor with an engineered IL-2 variant (IL2v) and on B-NHL cells the CD20 antigen. This approach boosts NK cell activation and proliferation, cytotoxicity against tumor cells, and cytokine production. The IL-2 variant is designed with mutations that prevent binding to CD25 (IL-2Rα), limiting Treg activation and potential IL-2-related side effects. IPH6501 has been evaluated in mouse, non-human primate, and human-derived models, including cells from R/R B-NHL patients. Results: In vivo studies in non-human primates and tumor mouse models revealed that IPH6501, at well-tolerated doses, significantly boosted peripheral NK cell proliferation, drove their accumulation at tumor locations, and effectively eradicated CD20+ cells in blood and tissues. In human derived-models, IPH6501 significantly induced NK cell proliferation and cytotoxicity. Notably, IPH6501 showed potent activity against a range of B-NHL cell lines, including those with low CD20 expression. In addition, IPH6501 upregulated the expression of activating receptors on NK cells, such as NKG2D, essential for the recognition and killing of malignant cells, thereby introducing another mode of action enabling the elimination of CD20-negative tumor cells. In a comparative analysis with a CD3xCD20 TCE, IPH6501 induced lower cytokine secretion, suggesting a potentially safer profile. Additionally, IPH6501 showed higher killing efficacy compared to the TCE in samples from healthy individuals as well as R/R B-NHL patients, underscoring its therapeutic potential. Conclusions: The preclinical demonstrations of IPH6501 activities across various in vivo models and its effectiveness in ex vivo assays using cells from R/R B-NHL patients provide compelling evidence of its therapeutic potential and tolerability. IPH6501 is emerging as a promising new candidate within the treatment landscape for R/R B-NHL and is currently being investigated in a global, first-in-human phase 1/2 study (NCT 06088654).
AB1703 ANALYSIS OF SLCO1B1 VARIANTS AS PREDICTORS OF METHOTREXATE TOLERANCE IN MEXICAN CHILDREN WITH JUVENILE IDIOPATHIC ARTHRITIS
Authors: J. Garcia-Silva, B. Silva-Ramirez, A. K. Leos-Leija, V. Mata-Tijerina, A. Villarreal-Trevino, N. Rubio, F. García-Rodriguez
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Methotrexate (MTX) is the disease-modifying drug of choice for most clinical forms of juvenile idiopathic arthritis (JIA). The most frequent adverse events (AEs) of MTX are gastrointestinal alterations and hepatotoxicity, which can affect adherence to treatment, leading to the activation of the disease. The SLCO1B1 gene codes for a liver protein (OATP1B1) that is responsible for drug transportation. Genetic variation within the SLCO1B1 gene locus impact drug transport, which can lead to altered pharmacokinetic profiles, delayed MTX clearance and increased toxicity. <h3>Objectives:</h3> Our aim was to determine the association between Single Nucleotide Polymorphisms (SNPs) in the SLCO1B1 gene (rs4149056, rs2306283) with the presence of AEs in patients with JIA being treated with MTX. <h3>Methods:</h3> This is an observational study to analyze the relationship between SNPs of the SLCO1B1 gene and the AEs reported in the clinical record during therapy with MTX in patients with JIA. The SNPs were determined with Real Time-PCR using TaqMan®SNP Assays. The haplotypes were conformed of the two SNPs at *1A, *1B, *5, and *15. Allele frequencies, genotypes and haplotypes were compared using the following programs: https://www.snpstats.net/ and Epi Info V7 https://www.cdc.gov/epiinfo/esp/es_index.html. <h3>Results:</h3> Twenty-three Mexican children diagnosed with JIA participates in the study, 17 girls and 6 boys, with a mean age of 11.26 (3-17) years. Fourteen patients (60.86%) presented any AEs, being gastrointestinal alterations the most frequent (13, 92.85%). The distribution of genotypes was found in Hardy-Weinberg equilibrium. The SLCO1B1*1B was associated with the presence of more AEs in the response to MTX in patients with JIA (OR=4.22, 95% CI=1.19 -18.89, p=0.03). <h3>Conclusion:</h3> Patients with allele *1B may benefit from lower doses of MTX. SLCO1B1 genotyping is a promising way to identify patients at higher risk of getting AEs during treatment with MTX, allowing individualization of the treatment. Due to the sample size, the results should be interpreted as preliminary and further confirmatory studies in a larger cohort are needed. <h3>REFERENCES:</h3> [1] J Roszkiewicz, D Michałek, A Ryk, Z Swacha, B Szmyd &amp; E Smolewska (2020): SLCO1B1 variants as predictors of methotrexate-related toxicity in children with juvenile idiopathic arthritis, Scandinavian Journal of Rheumatology, DOI: 10.1080/03009742.2020.1818821. <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>
AB1607-HPR DEVELOPMENT OF PATIENT-REPORTED QUALITY INDICATORS FOR HAND OSTEOARTHRITIS CARE USING THE RAND/UCLA METHOD – A EUROPEAN CONSENSUS STUDY
Authors: D. H. Bordvik, Y. Prior, A. T. Tveter, I. K. Haugen, B. Christensen, F. Berenbaum, H. Laheij, J. Edwards, K. Dziedzic, M. Ritt, M. Kloppenburg, M. Bjork, N. Osteras, R. Bamford, T. Stamm, T. Blanck, T. Borgen, C. Graham, N. Gilanliogullari, I. Kjeken
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Hand osteoarthritis (OA) is a prevalent rheumatic disease, yet access to recommended treatments is often poor for those affected. To enhance care quality, sets of quality indicators (QIs) grounded in current treatment guidelines are crucial. They serve as tools to guide clinical practice and evaluate care quality. While validated QI sets exist for OA, i.e., OA-QI v.2., none specifically tailor hand OA. This gap underlines the need for developing hand OA-specific QIs. <h3>Objectives:</h3> We aimed to adapt the OsteoArthritis Quality Indicator (OA-QI) v.2 questionnaire, making it suitable for assessing the patient-reported quality of hand OA care. <h3>Methods:</h3> The adaptation began with the existing OA-QI set, augmented by a literature review to identify potential QIs for hand OA, following the Rand/UCLA Appropriateness Method. A European multidisciplinary expert panel, including researchers, clinicians, and patient research partners, engaged in meetings and anonymous ratings to reach a consensus. They evaluated each QI on importance, validity, usefulness, and feasibility using a 9-point Likert scale. Cognitive debriefing interviews with hand OA patients are ongoing to ensure clarity of the questionnaire items. This study was funded by a EULAR health professional research grant <h3>Results:</h3> An initial search yielded 1670 articles, with none relevant for our QI set, necessitating 4 voting rounds to finalise 16 QI items (Table 1). These items align with international hand OA care standards and are presented in English and Norwegian, targeting users in the UK and Norway. Preliminary feedback from cognitive interviews suggests minor amendments for clarity <h3>Conclusion:</h3> We successfully adapted the OA-QI v.2 into a 16-item QI set, reflecting the international care standards for hand OA. This tool can quantify the care quality for hand OA. Future studies will evaluate the psychometric properties of the new QI set. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>
Mosunetuzumab with polatuzumab vedotin: Subgroup analyses in patients (pts) with primary refractory or early relapsed large B-cell lymphoma (LBCL).
Authors: Sarit Assouline, Lihua Elizabeth Budde, Julio C. Chavez, Catherine S. Diefenbach, Kathleen Anne Dorritie, Nilanjan Ghosh, Adam J Olszewski, Izidore S. Lossos, Amitkumar Mehta, Dipenkumar Modi, Seema Naik, Stephen Douglas Smith, Sneha Makadia, Song Pham, Hao Wu, Connie Lee Batlevi, Iris To, Michael C. Wei, Manali Kamdar
Journal: Journal of Clinical Oncology (2024)

7021 Background: The primary analysis of mosunetuzumab with polatuzumab vedotin (mosun-pola) in the Phase Ib/II study (NCT03671018) demonstrated durable responses and manageable safety in pts with relapsed or refractory (R/R), transplant-ineligible LBCL (Budde et al. Nat Med 2023). Here, we present results for primary refractory (refr) or early relapse (rel) subgroups from this study after a median follow-up of 23.9 months. Methods: Pts with R/R LBCL (diffuse LBCL not otherwise specified [NOS], high-grade B-cell lymphoma [HGBCL], transformed follicular lymphoma (FL), and FL grade 3b) and who received ≥1 prior line of therapy (including an anti-CD20 antibody) were treated with mosun-pola. Refr was defined as SD, PD, PR, or CR with relapse &lt;3 months after first-line (1L) therapy. Rel was defined as CR with relapse ≥3 and ≤12 months after 1L therapy. The primary endpoint was best overall response rate (ORR) by IRC using Lugano 2014 response criteria. Key secondary endpoints included CR rate, duration of response (DOR), duration of CR (DOCR), progression-free survival (PFS), overall survival (OS), and safety. Results: As of July 6, 2023, of the 98 pts in the overall population, 45 (46%) and 27 (28%) pts had refr or rel LBCL, respectively. At baseline, the median age in the refr and rel subgroups was 68 and 70 years respectively; 23/45 pts (51%) and 6/27 pts (22%) were treated with mosun-pola as second-line, respectively. The majority of refr/rel pts had DLBCL NOS (71%; 78%) or HGBCL (24%; 19%), Ann Arbor stage III/IV (80%; 89%), elevated LDH (55%; 48%), and extranodal involvement (67%; 59%). In refr pts, the ORR was 49%, which was generally consistent with the overall population (59%); although the sample size was limited, higher responses (ORR: 74%) were observed in rel pts. Additional clinical outcomes are reported (Table). The safety profile was consistent with the overall population. Grade 3 CRS occurred in one pt in each subgroup. Treatment-related ICANS-like events occurred in 2/45 pts (4%; refr) and 3/27 pts (11%; rel). Conclusions: Mosun-pola demonstrated durable benefits in ORR and CR rates irrespective of a poor response to 1L treatment. Outcomes for pts with refr or rel LBCL are encouraging. Clinical trial information: NCT03671018 . [Table: see text]
POS1185 IRON DEFICIENCY IN FAMILIAL MEDITERRANEAN FEVER: A STUDY ON 211 ADULT PATIENTS FROM THE JIR COHORT
Authors: I. DI Cola, L. Savey, M. Delplanque, R. Bourguiba, A. Bartoli, Z. Aknouche, F. Bensalek, I. Koné-Paut, L. Rossi-Semerano, I. Melki, B. Bader-Meunier, B. Neven, P. Quartier, G. Boursier, I. Giurgea, L. Cuisset, G. Grateau, V. Hentgen, S. Georgin-Lavialle
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide [1]. Fatigue is known to trigger attacks of the disease [2]. So far, no association has been reported between iron deficiency and fatigue in FMF patients <h3>Objectives:</h3> Our aim was to evaluate the prevalence of iron deficiency in FMF patients and its association with clinical and laboratory parameters, disease activity and outcomes over time. <h3>Methods:</h3> A retrospective evaluation of prospectively followed homozygous FMF patients at the French National Reference Centre for Adult Autoinflammatory Diseases was performed. All patients consented to the anonymous collection of their medical data via the JIR cohort. <h3>Results:</h3> Of 211 patients, 67 (31.8%) had a serum ferritin level &lt; 27 ng/mL and were defined as iron deficient. Of these, 61 (91%) were female with a mean age of 36.81 (± 17.03) years. FMF patients with iron deficiency had lower levels of hemoglobin (p &lt; 0.001) and body mass index (p=0.023) and were significantly younger than those without iron deficiency (p=0.004), but they did not have more elevated inflammatory biomarkers. Female gender (p=0.0015) was associated with lower ferritin levels. <h3>Conclusion:</h3> Iron deficiency, which mainly affects young women regardless of their level of inflammation, may be secondary to excessive gynaecological losses. Iron-deficient FMF patients may be more tired, which may lead to an increase in FMF attacks. Thus, it may be important to correct iron deficiency because this condition alone can cause asthenia, even in the absence of anaemia. Interestingly, ferritin doesn't seem to have pro-inflammatory properties in FMF. In conclusion, this work highlights the importance of measuring ferritin levels in FMF patients to detect iron deficiency in the absence of anaemia. <h3>REFERENCES:</h3> [1] L. Savey, G. Grateau, S. Georgin-Lavialle, Fièvre méditerranéenne familiale en 2020, Nephrol Ther. 17 (2021) S119–S125. https://doi.org/10.1016/j.nephro.2020.02.013. [2] M.T. Duruoz, C. Unal, D.K. Bingul, F. Ulutatar, Fatigue in familial Mediterranean fever and its relations with other clinical parameters, Rheumatol Int. 38 (2018) 75–81. https://doi.org/10.1007/s00296-017-3882-3. <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>
POS1284 A NOMOGRAM FOR THE PREDICTION OF CO-INFECTION IN MDA5 DERMATOMYOSITIS: A RAPID CLINICAL ASSESSMENT MODEL
Authors: Y. Wu, Y. LI, C. Tan, Y. Liu
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Patients with anti-melanoma differentiation-associated gene 5-positive dermatomyositis (MDA5 DM) are prone to infections, but there is a lack of rapid methods to assess infection risk, which greatly affects patient prognosis. <h3>Objectives:</h3> The aim of this study is to establish a rapid prediction model for the risk of co-infection based on the clinical characteristics of patients with MDA5 dermatomyositis. <h3>Methods:</h3> Retrospective analysis was performed on clinical data from 118 hospitalized patients with MDA5 DM. According to the results of pathogen detection and clinical manifestations, the patients were divided into infected group and non-infected group. LASSO analysis and multivariate logistic regression were used to establish the prediction model of infection in MAD5 DM patients. The resulting model was visualized using a Nomogram. We used methods such as ROC curve analysis, AUC calculation to evaluate the model. <h3>Results:</h3> Cough, rapidly progressive interstitial lung disease, and elevated hydroxybutyrate dehydrogenase were significantly associated with infection risk in MDA5 DM patients. A prediction model was developed using these three risk factors, achieving an AUC of 0.773 in determining co-infection status. Further analysis based on infection site and pathogen classification demonstrated improved performance of the model in identifying pulmonary infection (AUC: 0.817) and fungal infection (AUC: 0.901). <h3>Conclusion:</h3> This study aimed to develop a clinical prediction model and visualize it using Nomogram to assess the risk of infection in MDA5 DM. The model provides an effective tool for determining infection status in patients and serves as a reference for formulating clinical medication regimens. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>
POS1024 EARLY DYNAMICS OF B CELL SUBSETS FOLLOWING TELITACICEPT AND STANDARD TREATMENT IN SYSTEMIC LUPUS ERYTHEMATOSUS: A 6-MONTH LONGITUDINAL FOLLOW-UP
Authors: L. Zhu, X. Chen, J. Tu, J. Gui, M. Fang, L. Sun
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Systemic lupus erythematosus (SLE) is an autoimmune disorder characterized by aberrant B cell activation and heightened autoantibody production. Targeting B cells constitutes a pivotal therapeutic strategy in managing SLE. Telitacicept, a novel biologic drug, specifically inhibits B lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), demonstrating promising efficacy in SLE treatment. <h3>Objectives:</h3> This study aims to investigate the early impact of telitacicept in combination with standard treatments on B cell subsets in SLE patients within the first 6 months. <h3>Methods:</h3> Twenty active SLE patients (SLEDAI-2K≥6) were enrolled, and B cell subset analyses were conducted at 0, 4, 12, and 24 weeks after initiating Telitacicept treatment. Flow cytometry was used to quantify B cell subset dynamics. The SLE Responder Index-4 (SRI-4) response rate at 6 months and changes in clinical and laboratory parameters were assessed. <h3>Results:</h3> After 6 months of treatment, the SRI-4 response rate was remarkable at 95% (19/20). In comparison to the baseline, significant improvements were observed in SLEDAI-2K scores (12.00 ± 3.28 VS. 1.78 ± 2.29, p&lt; 0.001), anti-dsDNA levels, and complement C3 and C4 levels (p&lt;0.05). A notable decrease in 24-hour urine protein (p=0.004) was recorded. B cell subset analysis in 15 patients completing four follow-ups revealed a decrease in the proportions of total B cells (14.03%± 6.87% VS. 4.44%± 2.63%, p&lt; 0.001), naive B cell(54.985± 17.96% VS. 25.78 %± 10.72, p&lt; 0.001), and short-lived plasma cells(0.10% ± 0.11% VS. 0.04% ± 0.04%, p=0.027), along with an increase in transitional B cells (T1) (0.10% ± 0.22% VS. 0.74% ± 1.11%, p=0.046), switched memory B cells(12.09%±15.39% VS. 24.68%±10.57%, p=0.020), double-negative B cells(8.73%± 8.46% VS. 15.8%±9.26%, p=0.001), and Breg cells (10.56% ± 10.61% VS. 19.33%±10.03%, p=0.002). <h3>Conclusion:</h3> The combination of Telitacicept with standard treatment led to significant improvements in disease activity, renal parameters, and B cell subset dynamics. These findings underscore the potential of Telitacicept in modulating the B cell landscape and achieving favorable treatment responses in active SLE patients. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> Thanks to all the follow-up patients and the doctors involved in the follow-up. <h3>Disclosure of Interests:</h3> <b>None declared.</b>
POS0452 1,25(OH)2D3 REINFORCES IL-10 INDUCTION UNDER DUAL INHIBITION OF TNFα AND IL-17A IN CCR6+ MEMORY Th17 CELLS MEDIATED SYNOVIAL INFLAMMATION
Authors: Y. He, A. M.C. Mus, N. Davelaar, B. Van Heeswijk, E. Lubberts
Journal: Annals of the Rheumatic Diseases (2024)

<h3>Background:</h3> Pro-inflammatory cytokines are therapeutic targets in the treatment of inflammatory arthritis. Blockade of TNFα has been registered for many immune-mediated inflammatory diseases, including the treatment of rheumatoid arthritis (RA). Also, specific antibodies against IL-17A are approved for the treatment of patients with psoriatic arthritis (PsA). However, these monotherapies do not reach sufficient response in all patients. Active vitamin D (1,25(OH)<sub>2</sub>D<sub>3</sub>) has potent anti-inflammation property for many immune cells, including Th17 cells. <h3>Objectives:</h3> We aim to assess the effects of dual application of anti-TNFα and IL-17A in a T cell-derived synovitis model and evaluate whether 1,25(OH)<sub>2</sub>D<sub>3</sub> could provide additive value. <h3>Methods:</h3> CCR6<sup>+</sup> CD25<sup>-/low</sup> memory Th17 cells were sorted from peripheral mononuclear cells (PBMCs) of healthy donors and co-cultured with synovial fibroblasts (SF) derived from rheumatoid arthritis (RA) or psoriatic arthritis (PsA) patients for 3 days, with or without adalimumab (anti-TNFα antibody), secukinumab (anti-IL-17A antibody), or 1,25(OH)<sub>2</sub>D<sub>3</sub>. Treatment effects were evaluated by measuring cytokine levels in the supernatant. <h3>Results:</h3> Compared to single treatments, dual blockade of TNFα and IL-17A did not provide additional value compared to individual treatment in suppressing IL-17A, IL-22, and TNFα in contrast to IL-8. However, when combined with 1,25(OH)<sub>2</sub>D<sub>3</sub>, a comprehensive regulatory effect on controlling the interplay between CCR6<sup>+</sup> memory Th17 cells and SF was noted. This triple treatment demonstrated better suppression of T cell-derived cytokines (IL-17A and IFN-γ). Also, IL-22 was downregulated, which could not be achieved by inhibition of the cytokines alone. Furthermore, triple therapy showed stronger inhibition of fibroblasts producing cytokines, such as IL-6 and IL-8. Interestingly, the application of 1,25(OH)<sub>2</sub>D<sub>3</sub> together with TNFα and IL-17A blockade strongly and significantly induced the production of the anti-inflammatory cytokine IL-10, which was higher compared to treatment with anti-TNFα and/or anti-IL-17A, or 1,25(OH)<sub>2</sub>D<sub>3</sub> alone. <h3>Conclusion:</h3> The combination of 1,25(OH)<sub>2</sub>D<sub>3</sub> with dual blockade of TNFα and IL-17A showed not only suppression of the targeted proinflammatory cytokine(s) but also the induction of IL-10. This suggests a more comprehensive regulatory effect on T cell-derived synovitis which may be a promising therapeutic strategy to improve therapy in patients with inflammatory arthritis. <h3>REFERENCES:</h3> <b>NIL.</b> <h3>Acknowledgements:</h3> <b>NIL.</b> <h3>Disclosure of Interests:</h3> <b>None declared.</b>