PARIS LA DÉFENSE, France, Oct. 13, 2025 /PRNewswire/ — Nexans announces that its Board of Directors has resolved to appoint Julien Hueber as the new Chief Executive Officer and to part ways with Christopher Guérin. These decisions will take effect immediately; Christopher will be available to Julien until October 31st, 2025.
The Board of Directors wishes to create a new momentum to further optimize performance while executing the roadmap which was presented during the last Capital Market Day. The Appointments & Corporate Governance Committee has conducted a comprehensive process to propose a successor for the role of Chief Executive Officer, in line with its established succession plan approach and with the support of a leading executive search firm.
Julien Hueber, Executive Managing Director of Power Grid & Connect Europe, oversees a €2.6 billion business spanning 23 manufacturing plants. A member of Nexans’ Executive Committee since 2018, he joined the company in 2002. Julien brings extensive expertise in supply chain and procurement, as well as deep regional knowledge of Asia-Pacific, particularly China and South Korea, where he spent several years leading operations. He later headed Nexans’ global “Industrial Cables – Industry Solutions & Projects” business.
Jean Mouton, Chairman of the Board of Directors, stated: “Over the past 23years,Julienhas demonstrated exceptional leadership and a profound understanding of Nexans’ business, operating model, and culture. He combines a strategic vision for future technologies with a strong record of operational excellence, as evidenced by the remarkable acceleration of the PWR Grid & Connect Europe segment under his leadership. I have complete confidence in his ability to lead Nexans in this new phase of focused acceleration, in line with the goals announced during the last Capital Markets Day.”
The Board concluded that Julien Hueber’s extensive experience, proven leadership, and deep understanding of Nexans made him the ideal choice to lead the Company. His strong track record in shaping vision, defining strategy, and driving successful execution further reinforced this decision. The Board of Directors unanimously and enthusiastically endorsed his appointment.
The Board would like to express its deep gratitude to Christopher Guérin for his exceptional contribution to Nexans during his seven years as Chief Executive Officer. Beyond the strong financial results, Christopher has profoundly transformed Nexans into a focused leader in sustainable electrification, giving meaning and direction to its mission. He has brought innovation, responsibility, and simplicity to the heart of the company, while restoring confidence across teams worldwide. His leadership and passion have left a lasting mark on the Group and its people.
Jean Mouton, Chairman of the Board of Directors, said: “I would like to warmly thank Christopher for his remarkable commitment and his essential contribution to the transformation of Nexans. He has restored a sentiment of pride to be part of the Nexans family. We wish him every success in his future endeavours.”
About Nexans
Nexans is the global pure player in sustainable electrification, building the essential systems that power the world’s transition to a connected, resilient, and low-carbon future. From offshore and onshore renewable energies to smart cities and homes, Nexans designs and delivers advanced cable solutions, accessories and services that electrify progress safely, efficiently, and sustainably.
With over 140 years of history, through three core businesses: PWR Transmission, PWR Grid, and PWR Connect, Nexans blends deep industry expertise with cutting-edge innovation to accelerate the energy transition and better meet its customers’ needs. Its unique E3 model, focused on Environment, Economy and Engagement, drives every action, aligning performance with purpose.
Nexans operates in 41 countries with 28,500 people and generated €7.1 billion in standard sales in 2024. As recognized climate action leader, Nexans is committed to Net-Zero emissions by 2050 aligned with the Science Based Targets initiative (SBTi) and expanding energy access through the Foundation Nexans.
Nexans is listed on Euronext Paris, Compartment A. www.nexans.com | #ElectrifyTheFuture
The wait is almost over. The 2025 ESMO Congress is only days away.
As the global oncology community turns its focus to Berlin, Germany, for the start of the 2025 ESMO Congress on Friday, October 17, the meeting is again primed to deliver practice-changing data across various tumor types and specialties.
With this year’s program shaping up to be one of the most comprehensive yet, OncLive® is here to help you navigate a crowded agenda featuring key updates and research across the lung, breast, gastrointestinal (GI), genitourinary (GU), gynecologic, and hematologic cancer spaces.
In anticipation of the congress, we gathered insights from experts in their respective fields, and we also invited the oncology community to vote in a series of preview polls highlighting the most-anticipated abstracts and topics in each tumor type.
Before experts from across the field of oncology converge at the 2025 ESMO Congress, there’s still time to prepare and preview some of the biggest presentations and data that shape the next era of oncology care.
Below, take a look at all of our previews for the 2025 ESMO Congress. Be sure to dive in before the congress kicks off on Friday.
Breast Cancer Experts: Key ADC Developments and CDK 4/6 Inhibitor Updates Set to Dominate ESMO 2025
There will be no shortage of anticipated data in the breast cancer space during the 2025 ESMO Congress, with a smattering of late-breaking abstracts and other oral presentations set to dominate the meeting.
“A lot of incredible abstracts and late-breakers will be [presented during] ESMO 2025, [but] there are 2 main categories [of research driving the conversation],” Paolo Tarantino, MD, a research fellow in the Department of Medicine at the Dana-Farber Cancer Institute in Boston, Massachusetts, shared with OncLive. “One, as it often happens, is antibody-drug conjugates [ADCs]. The other hot [topic] is new drugs for hormone receptor–positive breast cancer…[including] CDK 4/6 inhibitors combined with PI3K/mTOR inhibitors.”
Our preview featured insights from Tarantino and the following breast cancer experts:
Kelly McCann, MD, PhD, an associate clinical professor of medicine in the Division of Hematology/Oncology at the University of California, Los Angeles Health
Jason A. Mouabbi, MD, an assistant professor in the Department of Medical Breast Oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston
Erika P. Hamilton, MD, director of Breast Cancer Research at Sarah Cannon Research Institute in Nashville, Tennessee
Inside the Most Anticipated Lung Cancer Abstracts at ESMO 2025
“The 2025 ESMO Congress will feature multiple late-breaking abstracts that could reshape the lung cancer treatment landscape,” Amol Akhade, MD, MBBS, a senior consultant at Fortis Hospitals Mumbai, consultant medical oncologist at Suyog Cancer Clinics in Thane, and the honorary in-charge consultant medical oncologist at Topiwala National Medical College in Mumbai, India, told OncLive. “Among them, the [trials] that stand out as particularly important [are the phase 3] HARMONi-6 [NCT05840016] and OptiTROP-Lung04 [NCT05870319] trials, as well as the [the phase 1] Beamion LUNG-1 trial [NCT04886804] and [the phase 1/2] SOHO-01 trial [NCT05099172] in the HER2-mutant setting.”
Along with Akhade, our preview featured expert insights from:
Sagus Sampath, MD, a radiation oncologist at City of Hope in Duarte, California.
Balazs Halmos, MD, a professor in the Department of Oncology (Medical Oncology) and Department of Medicine (Oncology and Hematology) and associate director of clinical science at Montefiore Einstein Comprehensive Cancer Center in the Bronx, New York.
D. Ross Camidge, MD, PhD, a professor in medicine-medical oncology and director of the Thoracic Oncology Clinical and Clinical Research Programs at the University of Colorado Cancer Center/Anschutz Medical Campus in Aurora.
Edward B. Garon, MD, MS, a thoracic medical oncologist and a professor of medicine at the David Geffen School of Medicine at UCLA in Los Angeles, California.
Advances in Targeted Therapies and ADCs in Gynecologic Cancer Are Highly Anticipated at ESMO 2025
“[Something] we have to keep track of as we’re hearing the new data is what trials are currently opening up [for enrollment],” Brian Slomovitz, MD, the director of Gynecologic Oncology and cochair of the Cancer Research Committee at Mount Sinai Medical Center in New York, told OncLive. “We have a whole slew of trials opening up in endometrial cancer, about 9 or 10 randomized, phase 3 trials that were opening up…These are all potentially practice-changing trials. We need to really keep an eye on where the data is going and what the new studies are that are coming out that’ll help us do what’s better for our patients.”
Our expert-led gynecologic cancer preview also featured insights from:
Premal H. Thaker, MD, MS, the David G. and Lynn Mutch Distinguished Professor of Obstetrics and Gynecology and director of Gynecological Oncology Clinical Research, and interim chief of the Division of Gynecologic Oncology at Siteman Cancer Center in Saint Louis, Missouri
Dana M. Chase, MD, a professor of Clinical Obstetrics and Gynecology in the Division of Gynecologic Oncology at the University of California, Los Angeles
ESMO 2025 Will See Novel Agents Emerge and Standard Strategies Shift in GI Oncology
“We’re all looking forward to data with immuno-oncology [IO] and VEGF [inhibitor] combinations that might be coming out,” Kanwal P. S. Raghav, MBBS, MD, a professor in the Department of Gastrointestinal Medical Oncology in the Division of Cancer Medicine, associate vice president of the Department of Ambulatory Medical Operations, and executive medical director of the Department of Ambulatory Treatment Centers at The University of Texas MD Anderson Cancer Center in Houston, told OncLive. “There are data on multiple antibody-drug conjugates with colorectal expansions that are coming forward, [including] data on HER2 and the long-term outcomes for the now FDA-approved fam-trastuzumab deruxtecan-nxki [Enhertu] in CRC. It’s going to be an exciting ESMO.”
Along with Raghav, our exclusive expert preview featured insights from:
Tanios S. Bekaii-Saab, MD, the David F. and Margaret T. Grohne Professor of Novel Therapeutics for Cancer Research I at the Mayo Clinic College of Medicine and Science, chairman for the Division of Hematology/Medical Oncology at Mayo Clinic, and co-leader of the Advanced Clinical and Translational Science Program and the Disease Group leader for Gastrointestinal Cancers for the Mayo Clinic Cancer Center in Phoenix, Arizona
Suneel Kamath, MD, an assistant professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, as well as a gastrointestinal (GI) medical oncologist at Cleveland Clinic in Ohio
Inside the Most Anticipated Genitourinary Cancer Abstracts at ESMO 2025
“[At the 2025 ESMO Congress,] there will be many exciting abstracts in [GU oncology], so it is difficult to pick just a handful. In the frontline settings, we are in need of novel agents to improve the rate of durable responses. Kidney cancer is still in need of predictive and prognostic biomarkers, and there is much interesting work being done in this space,” David A. Braun, MD, PhD, an assistant professor of medicine (medical oncology) and Louis Goodman and Alfred Gilman Yale Scholar at Yale Medical School in New Haven, Connecticut, explained.
For the GU oncology preview, Braun’s insights were accompanied from perspectives from:
Alan Tan, MD, an associate professor of medicine, Division of Hematology Oncology at Vanderbilt University Medical Center in Nashville, Tennessee.
Axel Merseburger, MD, PhD, a professor and chair of the Department of Urology at University Hospital Schleswig-Holstein in Lübeck, Germany.
Hematologic Oncology Abstracts to Watch at the 2025 ESMO Congress
Although the 2025 ESMO Congress program is driven primarily by data, abstracts, and presentations surrounding solid tumor management, the congress will feature a spread of updates and data emerging from the hematologic oncology landscape.
Read our preview and poll results above to see what hematologic oncology topics made the cut for ESMO 2025 before this field turns its attention to the 2025 ASH Annual Meeting and Exposition in December.
Ratio of high-density lipoprotein cholesterol (HDL-C) to low-density lipoprotein cholesterol (LDL-C) (HDL-C/LDL-C) can be used to predict the prognosis of individuals at high risk for cardiovascular disease (CVD) without type 2 diabetes (T2D), with a ratio between 0.3 and 0.5 being the most helpful range for patients in this population, according to new data published by investigators in Chronic Diseases and Translational Medicine.1
What is the HDL-C/LDL-C Ratio?
Lipid management is a hallmark of CVD prevention and can improve patient prognosis. Patients with T2D have an especially heightened risk of CVD morbidity and mortality and has been directly linked to lipid metabolism. It is essential to identify more valuable lipid indicators for prognosis improvement and primary prevention.1,2
Accordingly, studies have affirmed that extremely high HDL-C and excessively low LDL-C can increase the risk of adverse prognoses, highlighting the potential role of the HDL-C/LDL-C ratio as a marker of cholesterol control. Controlling HDL-C/LDL-C ratio can be used to prevent coronary heart disease and stroke, with studies indicating that mortality from such diseases is lowest when HDL-C/LDL-C ratio is between 0.4 and 0.6. Critically, the ratio has been shown to be a more accurate predictor of clinical disease compared with individual lipoprotein levels.3-5
There is a lack of existing research on the HDL-C/LDL-C ratio, especially in populations at high CVD risk. Furthermore, there is limited data on whether such a ratio could be a reliable prognostic biomarker in populations with high CVD risk who both do and do not have T2D. The current authors aimed to address the association between HDL-C/LDL-C ratio and adverse prognoses in populations at high risk for CVD, while comparing its usefulness between populations with and without T2D.1
This analysis was based on the Fujian Cardiometabolic Diseases and Comorbidities Cohort trial (NCT06102187), which was an observational study conducted between 2017 and 2021 to assess CVD risk. Associations between HDL-C/LDL-C ratio and all-cause mortality were analyzed using restricted cubic spline curves (RCSs), and the investigators then categorized patients into 3 groups using thresholds of 0.3 and 0.5 for low HDL-C/LDL-C (less than 0.3), middle (HDL-C/LDL-C, between 0.3 and 0.5), and high HDL-C/LDL-C (more than 0.5).1
What is the Ideal HDL-C/LDL-C Ratio for CVD Prevention?
A total of 32,609 participants were included in the cohort. Based on the RCS analysis, a nonlinear U-shaped relationship between HDL-C/LDL-C and the participants’ all-cause mortality was identified. Compared with the other groups, the RCS analysis indicated that the middle group had the lowest all-cause mortality risk. Kaplan-Meier survival analysis revealed that cumulative all-cause mortality rate was higher in the low and high groups than in the middle group (P < .05), which was verified by a Cox proportional analysis.1
Additionally, the risk of all-cause mortality (hazard ratio [HR] = 1.40 [95% CI, 1.08—1.82], P < .05 for low; HR = 1.41 [95% CI, 1.15—1.71], P < .01 for high) was greater in the low and high groups than in the middle group in the univariate analysis. When the investigators controlled for covariates, the risk of all-cause mortality (HR = 1.48 [95% CI, 1.14—1.93], P < .01 for low; HR = 1.30 [95% CI, 1.06—1.58], P < .05 for high) was elevated in both groups.1
The investigators specifically examined associations between HDL-C/LDL-C and all-cause mortality in individuals with and without type 2 diabetes. Kaplan-Meier analyses revealed that the middle group without T2D presented the lowest cumulative all-cause mortality, while no statistically significant differences in all-cause mortality were observed across subgroups in populations at high CVD risk with T2D. Concurrently, Cox proportional hazards regression analysis demonstrated greater risk of all-cause mortality in the low and high ratio groups than in the middle group.1
Because HDL-C and LDL-C are widely available and simple-to-measure biomarkers, pharmacists and clinicians can easily calculate the ratio necessary to determine patient CVD prognosis. It is critical that the authors noted a range of a ratio of 0.3 to 0.5 was the most beneficial for patients, allowing pharmacists to specifically tailor treatment strategies and help patients reach their goals. Above all, another indicator that can provide early intervention in populations at high CVD risk is critical for primary prevention.1
“Maintaining HDL-C/LDL-C ratios within the range of 0.3–0.5 may have clinical significance for cohorts without T2D, whereas its prognostic implications in individuals with T2DM necessitate further exploration,” the study authors wrote in their conclusion.1
REFERENCES
1. Lin B, Ling Y, Zhou G, et al. HDL-C/LDL-C ratio and all-cause mortality in populations at high CVD risk: A prospective observational cohort study. Chronic Dis Transl Med. 2025;11(3):213-223. doi:10.1002/cdt3.70013
2. Haas ME, Attie AD, Biddinger SB. The regulation of ApoB metabolism by insulin. Trends Endrocrinol Metab. 2013;24(8):391-397. doi:10.1016/j.tem.2013.04.001
3. You S, Zhong C, Zu J, et al. LDL-C/HDL-C ratio and risk of all-cause mortality in patients with intracerebral hemorrhage. Neurol Res. 2016;38(10):903-908. doi:10.1080/01616412.2016.1204797
4. Zimmer F, Riebeling V, Benke B, Schuster J, Roskamm H. The LDL-HDL ratio in patients with coronary arteriosclerosis. Z Kardiol. 1980;69(3):149-153. PMID: 7456590. https://pubmed.ncbi.nlm.nih.gov/7456590/
5. Sun T, Chen M, Shen H, et al. Predictive value of LDL/HDL ratio in coronary atherosclerotic heart disease. BMC Cardio Disord. 2022;22(273). doi:10.1186/s12872-022-02706-6
6. Cohort study in Fuijan province. ClinicalTrials.gov Identifier: NCT06102187. Last Updated November 3, 2023. Accessed October 13, 2025. https://clinicaltrials.gov/study/NCT06102187
Comprehensive bridging therapy administered prior to anti-BCMA CAR T-cell therapy exhibited safety and tolerability as treatment in a small cohort of patients with relapsed/refractory multiple myeloma from a single institution, according to findings from a retrospective analysis exhibited in a poster presentation at the 2025 American Society of Radiation Oncology (ASTRO) Annual Meeting.
Data from the trial revealed that among 19 patients treated with bridging radiotherapy prior to CAR T-cell therapy, no grade 3 or higher toxicities were observed related to the use of bridging therapy. Additionally, 2 patients experienced grade 2 cytokine release syndrome (CRS), and 2 had developed grade 2 immune effector cell-associated neurotoxicity syndrome (ICANS); no grade 3 CRS or ICANS events were observed.
Additionally, efficacy data revealed that the median progression-free survival (PFS) among all patients treated with bridging therapy was 6.8 months after a median follow-up of 8.2 months. The median overall survival (OS) had not been reached. Furthermore, among those who experienced progression, 60% showed no evidence of bone marrow involvement, and all 10 patients developed distant plasmacytopenias.
Among patients who did not have extramedullary disease (EMD), a statistically significant improvement in PFS was observed: the median PFS was 10.4 months vs 6.6 among patients with EMD (P = .006) in a Kaplan-Meier analysis of PFS for EMD. In patients with EMD who received comprehensive vs focal bridging radiation therapy, a nonsignificant trend for PFS favored those who received comprehensive bridging radiotherapy in a Kaplan-Meier analysis of PFS between both modalities. The median PFS was 6.7 months vs 4.4 months in those who received focal bridging therapy (P = .055).
“[Bridging radiotherapy] prior to anti-BCMA CAR T therapy appears to be a safe and tolerable treatment strategy, with no grade [3 or higher] toxicities,” Preston Perez, BA, of the University of South Florida Morsani School of Medicine and the Moffitt Cancer Center, wrote in the presentation with study coinvestigators. “EMD continues to be associated with inferior clinical outcomes. Comprehensive [bridging radiotherapy] to all sites of EMD prior to CAR T may be associated with improved PFS.”
The retrospective analysis included patients with relapsed/refractory multiple myeloma who received bridging radiation therapy within 90 days of CAR T-cell infusion. PFS and OS outcomes were treated using the Kaplan-Meier method from the time of CAR T infusion.
Local failure was defined as recurrent disease within a previously irradiated site, and comprehensive bridging radiotherapy encompassed radiation to all sites of EMD. Toxicities were graded using CTCAE v.5.0 criteria. ASTCT criteria were used for all CRS and ICANS events.
The most common dose and fractionation was 20 Gy in 5 fractions among 6 patients and 8 Gy in 1 fraction among 8 patients.
The investigators sought to ascertain the role of bridging radiation therapy prior to anti-BCMA CAR T cell-therapy by evaluating its efficacy and safety in that indication. They also assessed the local control of EMD and its impact on survival outcomes.
According to the study authors, a phase 2 single arm trial is ongoing to evaluate comprehensive bridging therapy for patients with multiple myeloma with EMD prior to CAR T-cell therapy. A total of 26 patients have been enrolled, all of whom are receiving bridging therapy to all sites of EMD, with a primary end point of 12-month PFS; specifically, an improvement from 25% to 50%. Bridging radiation therapy will be given at 20 Gy in 5 fractions.
Reference
Perez PE, Nakashima JY, Peterson J, et al. Clinical outcomes following bridging radiotherapy in relapsed/refractory multiple myeloma patients prior to chimeric antigen receptor T-cell therapy. Presented at: 2025 American Society of Radiation Oncology (ASTRO) Annual Meeting; September 27 – October 1, 2025; San Francisco, CA. Abstract 3705.
Data published in the Journal of Clinical Investigation demonstrated that patients with asthma have significantly elevated levels of cyclic adenosine monophosphate (cAMP), a certain molecule within the blood. With this discovery, the researchers determined that a simple blood test may be able to diagnose asthma and its severity, which could be significant when identifying and monitoring patients with asthmatic symptoms.1,2
The authors wrote that β2-agonists are cornerstone treatments of asthma when attempting to prevent or reverse the shortening of human airway smooth muscle (HASM), the pivotal cell regulating bronchomotor tone. β2-agonists act upon β2-adrenoceptor (β2AR) and activate adenylyl cyclase, which generates 3′,5′-cAMP. An increase in intracellular cAMP levels stimulates protein kinase A, which modulates multiple downstream targets to promote HASM relaxation and reverse airflow obstruction.1
To further explore the clinical utility of detecting circulating cAMP, the authors conducted their study to measure cAMP levels in a serum biobank from the Severe Asthma Research Program 3 (SARP-3). The investigators obtained 87 serum samples of patients with asthma, of whom 39 were diagnosed with severe disease, as well as 273 serum samples of participants without a known history of asthma or other lung diseases.1
“What we discovered is a specific transporter, a protein on the membrane of airway smooth muscle cells, allows cAMP to leak into the blood,” senior study author Reynold Panettieri, vice chancellor and director of translational medicine and science at Rutgers University, said in a news release. “For decades, we believed that an enzyme called phosphodiesterase was the critical factor in decreasing cAMP. We now refute that and say this transporter simply leaks it out.”2
A high variability—or a wide spread of cAMP levels—was detected in the 87 serum samples of patients with asthma, ranging from about 0.291 to 563.9 picomoles. Conversely, the range of cAMP levels in the 273 serum samples of individuals without asthma was markedly smaller (0–27.72 picomoles), and compared with the nonasthma group (median: 0.520 picomole), serum cAMP levels were significantly higher in patients with asthma (median: 6.220 picomoles).1
“We would anticipate maybe in the next 6 months, we’ll have nailed the fidelity of it, get it into our intellectual property and patent the test itself, and then in a year to 2, it could become available,” Panettieri said. “Every disease we study or treat is not one disease. There are different aspects and attributes within a disease entity.”2
To further test the hypothesis that cAMP levels can differentiate asthma severity (severe vs nonsevere) in Severe Asthma Research Program 3 (SARP-3) samples, the investigators applied linear regression models with age and sex as covariates across clinical groups. They observed no significant difference of serum cAMP levels between the 2 severities; however, each asthma group showed significantly higher cAMP levels (adjusted P < .00001) than the nonasthma group.1
The SARP-3 data were also leveraged to assess whether measured serum cAMP levels are associated with any clinical traits of asthma, such as asthma endotypes, poor control indicators, and postbronchodilator airflow reversibility. There were no significant differences in cAMP levels among or between groups stratified by eosinophilic or neutrophilic asthma nor any of the poor control indicators. In addition, the investigators reported they did not detect significant differences in serum cAMP levels with maximum FEV1 reversibility with albuterol. Also of note, serum cAMP levels increased with the number of inhaled corticosteroid puffs and controllers used, and in the nonsevere asthma group, increased with the increases of postbronchodilator lung function.1
The authors explained that lung function tests in kids under the age of 5 years are difficult; therefore, pinprick or blood tests may be more feasible options in this age group.2 Future research is needed to further confirm the link between serum cAMP levels in asthma severity and other disease characteristics.1
“Further studies are necessary to explore the link between serum cAMP levels with bronchodilator or treatment responses by asthma severity; ABCC1 expression and activity in health and disease, including specific cell types of origin; and, whether these physiological outcomes and clinical phenotypes are affected by variations in ABCC1 genotypes in a large cohort of patients with and without asthma,” the authors concluded.1
REFERENCES
1. An SS, Cao G, Ahn K, et al. Serum cAMP levels are increased in patients with asthma. J Clin Invest. 2025;135(5):e186937. doi.org/10.1172/JCI186937
2. Rutgers University. Scientists discover potential blood test for asthma diagnosis and severity. News release. September 29, 2025. Accessed October 13, 2025. https://www.rutgers.edu/news/scientists-discover-potential-blood-test-asthma-diagnosis-and-severity
Llama immunization and nanobody library construction
For nanobody generation, a recombinant murine LYVE1 protein, consisting of 288 amino acids, fused to a His10 tag, was expressed in human embryonic kidney 293 cells. The recombinant protein was injected alongside Adjuvant P (3111, GERBU Biotechnik GmbH, Heidelberg, Germany) weekly on six consecutive occasions into a Ilama (Lama glama). Forty days after the initial immunization, 100 mL of anticoagulated blood were collected from the Ilama, 5 days after the final antigen injection. Peripheral blood lymphocytes were isolated and total RNA extracted for cDNA first-strand synthesis using oligo(dT) primers. Sequences encoding variable nanobodies were subsequently amplified by PCR, digested with the restriction enzyme SapI, and cloned into the SapI site of the phagemid vector pMECS. Electrocompetent E. coli TG1 cells (60502, Lucigen, Middleton, WI, USA) were then transformed with the variable domain of heavy-chain-only antibody (VHH) sequence harbouring pMECS vectors, resulting in a nanobody library comprising 109 independent transformants. This process has previously been described in detail [34].
Biopanning and identification of anti-mouse nanobodies specific to LYVE1
Phage enrichment and biopanning were carried out as described [34]. Briefly, the previously constructed nanobody library was panned for 3 rounds on solid phase coated with mouse LYVE1 (100 µg/mL in 100 mM NaHCO3, pH 8.2) yielding a 400-fold enrichment of antigen-specific phages after the 3rd round of panning. A total of 380 colonies were randomly selected and assayed for mouse LYVE1-specific antigens by ELISA, again using mouse LYVE1 and additionally mouse LYVE1 fused to human IgG1 Fc at the C-terminus (50065-M02H, Sino Biological, Beijing, China). To exclude potential nanobody clones binding to human IgG1 Fc, human IgG1 Fc (10702-HNAH, Sino Biological) was utilized as a control, as well as blocking buffer only (100 mM NaHCO3, pH 8.2). After comparing binding specificity of different clones with the control values, 278 colonies were identified as positive for mouse LYVE1 binding. Using the sequence data, the number of possible nanobody candidates was further narrowed down to 98, of which 96 were able to specifically bind both mouse LYVE1-His10 and mouse LYVE1 fused to human IgG1 Fc. The remaining unique clones derived from 21 different B cell lineages according to their complementary determining region (CDR) 3 groups. Considering the different B cell linages and robustness of ELISA screening data, 6 clones were selected for further experiments.
Cloning of nanobody sequences in expression vector
To generate 6xHis-tagged nanobodies, nanobody sequences were cloned from the pMECS phagemid vector into the pHEN6c expression vector. Initially, nanobody sequences were amplified by PCR using the following primers:
(1) 5’ GAT GTG CAG CTG CAG GAG TCT GGR GGA GG 3’.
(2) 5’ CTA GTG CGG CCG CTG AGG AGA CGG TGA CCT GGG T 3’.
PCR products were purified (28104, QIAquick PCR Purification Kit,, Qiagen, Hilden, Germany) and digested for 20 min at 37 °C with PstI-HF (R3140, New England Biolabs, Ipswich, MA, USA) and BstEII-HF (R3162, New England Biolabs) restriction enzymes, while empty pHEN6c plasmids were concurrently digested with the same restriction enzymes. The empty pHEN6c plasmids, however, were supplemented by 5 units of heat-inactivated (5 min at 80 °C) FastAP™ alkaline phosphatase (EF0651, Thermo Fisher Scientific, Waltham, MA, USA). Digestion products were purified (28104, QIAquick PCR Purification Kit, Qiagen) and subjected to T4 DNA ligase-mediated ligation reactions. The ligation reaction was performed at 16 °C for 16 h using 2.5 units of T4 DNA ligase (M0202, New England Biolabs). Subsequently, newly generated nanobody sequence harbouring pHEN6c plasmids were transformed into WK6 E. coli cells (C303006, Thermo Fisher Scientific) and analysed to determine correct nanobody sequence integration by Sanger DNA sequencing using the following primers:
(1) 5’ TCA CAC AGG AAA CAG CTA TGA C 3’.
(2) 5’ CGC CAG GGT TTT CCC AGT CAC GAC 3’.
Production and purification of anti-LYVE1 nanobodies
WK6 E. coli carrying pHEN6c-Nanobody plasmid were cultivated at 37 °C, shaking in 1 L `Terrific Broth` medium (2.3 g/L KH2PO4, 16.4 g/L K2HPO4-3H2O, 12 g/L tryptone, 24 g/L yeast extract, 0.4% (v/v) glycerol) complemented with 100 µg/mL ampicillin, 2 mM MgCl2, and 0.1% (w/v) glucose. Nanobody expression was induced at an OD600 of 0.6–0.9 by adding 1 nM isopropyl ß-D-1-thiogalactopyranoside (IPTG). After an incubation period of 16 h, the nanobodies were extracted by centrifugation (8000× g, 8 min, RT). 18 mL of TES/4 buffer (0.05 M Tris [pH 8.0], 0.125 mM EDTA, 0.125 M sucrose) were added for 1 h of shaking on ice. The cell suspension was then centrifuged (8000× g, 30 min, 4 °C), and periplasmic protein-containing supernatant collected. For 6xHis-tagged nanobody extraction, HIS-Select® nickel affinity gel (P6611, Sigma-Aldrich, Darmstadt, Germany) was applied according to the manufacturer’s instructions. The solution was loaded on a PD-10 column (17-0435-01, GE healthcare, Chicago, IL, USA) and nanobodies eluted via 3 × 1 mL 0.5 M imidazole in phosphate-buffered saline (PBS) (I2399, Sigma-Aldrich). An overnight dialysis (3 kDa MWCO, 66382, Thermo Fisher Scientific) against PBS was carried out to remove undesirable imidazole from the nanobody solution.
Coomassie-blue stained SDS PAGE and Western blotting
To verify nanobody production and pureness, sample protein was separated by molecular weight using established sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE). For each clone, 5 µg of denatured protein with 0.04% (w/v) OrangeG in ddH2O) were loaded onto the gel alongside a pre-stained protein ladder (ab116029, Abcam, Cambridge, UK). For protein visualisation, gels were treated with Coomassie staining solution (0.1% (w/v), Coomassie Brilliant Blue R-250 (1610400, Bio-Rad Laboratories Inc., Hercules, CA, USA), 50% (v/v) methanol, and 10% (v/v) glacial acetic acid in ddH2O for 1 h, followed by incubation with Coomassie destaining solution (50% ddH2O, 40% methanol, 10% acetic acid (v/v/v)). Alternatively, gels were blotted onto a nitrocellulose membrane (1620112, Bio-Rad Laboratories Inc.) and nanobodies identified using a primary anti-His antibody (12698, Cell Signaling Technology, Danvers, MA, USA) and a secondary anti-rabbit antibody (926-32211, LI-COR Biosciences, Lincoln, NE, USA). Subsequently, blots were analysed by an Odyssey® Fc Imaging System (LI-COR Biosciences).
Mouse husbandry and acquisition of mouse tissues
C57BL/6 wildtype mice, or Lyve1Cre − eGFP mice [35] on the C57BL/6 background were utilised in this study. All animal experiments were carried out under a UK Home Office project license (PPL: PP1776587) in compliance with the UK Animals (Scientific Procedures) Act 1986 or approved by German federal authorities (LaGeSo Berlin) under the licence number ZH120. Nutrition and water were available to animals ad libitum. Mouse embryos were staged by time-matings, considering embryonic day (E) 0.5 to be the morning a copulation plug was detected. Adult mice or pregnant mice were sacrificed using CO2 inhalation and cervical translocation as a Schedule 1 procedure. The desired organs were obtained from embryonic, juvenile, or adult mice, washed in PBS, and subsequently fixed in 4% (w/v) paraformaldehyde (PFA) in PBS for 4 h at 4 °C to preserve tissue integrity. After fixation, samples were thoroughly washed in three changes of PBS and stored at 4 °C in PBS containing 0.03% (w/v) sodium azide until further processing.
Antibodies for Immunofluorescence
The following commercially available antibodies were used: rabbit monoclonal anti-His antibody (12698, Cell Signaling Technologies) [1:200], donkey polyclonal anti-rabbit IgG Alexa Fluor™ 647 antibody (A31573, Invitrogen, Waltham, MA, USA) [1:1000], donkey polyclonal anti-rabbit IgG Highly-Cross-Absorbed Alexa Fluor™ 647 antibody (A32795, Invitrogen) [1:1000], goat polyclonal anti-mLYVE1 (AF2125, R&D Systems, Minneapolis, MN, USA) [1:100], donkey polyclonal anti-goat IgG Alexa Fluor™ 568 antibody (A11057, Invitrogen) [1:1000], donkey polyclonal anti-goat IgG Highly cross-absorbed Alexa Fluor™ 488 + antibody (A32814, Invitrogen) [1:1000], hamster monoclonal anti-Podoplanin (14-5381-82, Invitrogen) [1:200], goat polyclonal anti-Syrian hamster IgG Cross-Absorbed Alexa Fluor™ 546 antibody (A-21111, Invitrogen) [1:1000], chicken polyclonal anti-GFP (ab13970, Abcam) [1:200], donkey anti-chicken Highly cross-absorbed Alexa Fluor™ 488 + antibody (A32931TR, Invitrogen) [1:1000], rat monoclonal anti-mF4/80 antibody (MCA497G, BioRad) [1:50], donkey anti-rat Highly cross-absorbed Alexa Fluor™ 488 + antibody (A48269, Invitrogen) [1:1000]. Nanobodies were detected by anti-His staining in combination with an Alexa Fluor™ dye-conjugated secondary antibody. An overview of antibody combinations used for each experiment including concentration and incubation time can be found in Table S1.
Zenon labelling of IgG antibodies
Anti-His antibodies were labelled using the Zenon™ Rabbit IgG Labeling Kit (Z25306, Thermo Fisher Scientific) by incubating the antibody with Component A for 5 min, followed by blocking with Component B for another 5 min. The labelled antibody was used within 30 min.
Direct labelling of nanobodies
Anti-mouse LYVE1 nanobodies were directly labelled with Alexa Fluor™ 647 NHS-Ester (A20006, Invitrogen) by reacting 1 mg of nanobody with 1 mg of dye in NaHCO₃ buffer (pH 8.0) for 1 h at room temperature. Labelled nanobodies were purified using a NAP™-10 column (Sephadex™ G-25, Thermo Fisher) and stored in PBS with 0.03% (w/v) sodium azide.
Immunofluorescence staining of cryosections
Snap-frozen 5 μm sections of E14.5 wildtype mice were stained with nanobodies (0.1 µg/mL) and appropriate control antibodies as previously described [36]. Visualisation of representative regions was accomplished using an Axioscope5 fluorescence microscope (Zeiss, Oberkochen, Germany) equipped with a Plan-NEOFLUAR 40x/0.75 objective (Zeiss).
Wholemount Immunofluorescence staining and optical clearing
Mouse organs were either cut into smaller sections measuring 0.5–2 mm thickness (for studies in Figs. 2A, 3 and 4, Fig. S3B) using a scalpel at room temperature or processed as whole specimens (for studies in Figs. 2B and 4A (E18.5-P5), Fig. S3A, Fig. S4). Tissues were dehydrated using an ascending methanol series and bleached overnight at 4 °C in a solution containing 5% H2O2 (VWR Chemicals, Radnor, PE, USA) in methanol. Wholemount staining was performed as previously described [22]. For optical clearing, samples were treated with methanol for dehydration followed by BABB (1:2 benzyl alcohol and benzyl benzoate) immersion, as described in [22]. Intestine samples were not optically-cleared, but mounted in fluorescent medium (S3023, Agilent Technologies, Santa Clara, CA, USA). Details on antibodies used, incubation periods and concentrations are outlined in Table S1.
Wholemount Immunofluorescence staining and optical clearing of embryonic and postnatal day one specimens
Embryonic and early postnatal (P) kidneys were initially dehydrated and bleached as described above. Following rehydration, samples were permeabilized overnight in a 5% solution of 3-((3-cholamidopropyl) dimethylammonio)-1-propanesulfonate in ddH2O and blocked in PBS supplemented with 0.2% (v/v) Triton X100, 10% (v/v) DMSO, and 6% (v/v) goat serum. Nanobodies (10 µg/mL) and antibodies were diluted in antibody solution (PBS + 0.2% v/v Tween20 + 0.1% v/v heparin solution + 5% v/v DMSO + 3% v/v goat serum + 0.1% w/v saponin) and incubated for a duration between 4 (nanobodies) and 24 h (IgG antibodies) at 4 °C. Between staining steps, samples were washed in PBS-Tween20. Clearing was performed with BABB as previously described for embryonic kidneys [37].
Confocal and light sheet imaging
Specimens were imaged using two different microscopy systems. For confocal imaging, an LSM 880 Upright Confocal Multiphoton microscope (Zeiss) equipped with a 20x/NA 1.0 W-plan Apochromat water immersion objective was utilized. A comprehensive description of the setup specific to BABB-cleared specimens for this microscope can be found in previously published work [37]. Intact mouse organs were imaged by LaVision Ultramicroscope II with a LaVison BioTec MVPLAPO 2x OC OBE objective. Various magnifications were employed, and image acquisition utilized a step size of 2 μm. Imaging thresholds were set individually for each channel during image acquisition and post-processing. This approach was chosen to accommodate the variability in autofluorescence and other factors, and to ensure optimal signal detection for each channel.
Image processing and 3D rendering
2D immunofluorescence images were subjected to post-processing using ZEN 3.4 (blue edition) software from Zeiss. Single channels were extracted and saved in TIFF format. Z-stack datasets were processed and 3D-rendered using Imaris (version 9.8, Oxford Instruments Abingdon, UK). To reduce non-specific background signal, single channels were subjected to the Isosurface Render function. Images of the 3D-rendered data were captured using the Snapshot function and saved in TIFF format. Videos were captured using the Animation function.
Quantification of signal-to-background ratio
Signal-to-background ratio was quantified using ImageJ 2.24/1.54f (https://github.com/imagej/ImageJ [38]), . Ten intensity values were randomly selected in vessel areas and areas that showed no specific staining. The mean values for signal and background areas were calculated and the signal-to-background ratio was determined using the formula: Signal-to-background ratio = mean signal/mean background.
Calculation of correlation coefficients
Pearson’s correlation coefficients r were calculated using the Imaris Coloc function. For very large microscopy files, colocalization analysis was performed on representative regions of interest, as full-volume analysis was not computationally feasible on the available hardware. For colocalization of nuclear GFP staining and endothelial nanobody staining, an object-based approach was applied. Spots were segmented independently for GFP and LYVE1 signals using the Imaris Spots function. For each LYVE1 spot, the shortest distance to the nearest GFP spot was determined. LYVE1 spots within 25 μm of a GFP spot were classified as colocalized, and the coefficient was calculated as the proportion of colocalized LYVE1 spots relative to the total number of LYVE1 spots.
Quantitative analysis of 3D imaging volumes
The quantitative analysis of three-dimensional volumes commenced with the binarization of single channels using Imaris. The binarization process was conducted using the Isosurface Render function, and for E18.5 and P1 samples, 3D cropping was applied to exclude regions with high podoplanin (PDPN) intensity at the kidney surface, thus enhancing binarization accuracy. During surface rendering, the threshold was set to absolute intensity, with manual adjustments to ensure the inclusion of all relevant structures. To eliminate smaller non-specific signals, structures were filtered based on the number of voxels. Following surface generation, PDPN channel-derived non-lymphatic structures, such as glomeruli, were manually removed using the selection function. Subsequently, the channel of interest was masked using specific settings: constant inside/outside, setting voxels outside the surface to 0.00, and inside the surface to the maximum intensity of the prepared channel. All channels except the newly created masked channel were then deleted, and the single channel was saved in TIFF format. With the binarized files prepared, TIFF files were imported into the VesselVio application [39]. The analysis settings were configured as follows: unit µm, resolution type anisotropic with individual sizes of samples, analysis dimensions 3D, image resolution 1.0 µm3, and filters applied to isolate segments shorter than 10.0 µm and purge end-point segments shorter than 10.0 µm. Analysis results were automatically saved in Microsoft Excel files by VesselVio. Among the parameters offered by VesselVio, vessel volume was selected as the parameter for further analysis, as it considers both vessel length and width. To account for variability in sample size and volume, vessel volumes (LYVE1 and PDPN) were normalized by dividing the measured vessel volume by the total sample volume, calculated based on the Imaris output for the x, y, and z dimensions. This normalized value was referred to as ‘relative volume’ [40].
Single-cell RNA sequencing analysis
The generation of the mouse kidney scRNA-seq data used in this study has been described [41]. In brief, a regional enrichment strategy was used to isolate hilum, cortex and medulla separately from 12-week-old C57Bl/6 mouse kidneys (n = 14), before single-cell droplet capture using the 10X Genomics platform (10x Genomics, Pleasanton, USA) and sequencing using an Illumina HiSeq X system (San Diego, USA). The count matrix corresponding to the lymphatic cluster was isolated and re-processed, applying a standard workflow using Seurat (v5) in R [42]. The Harmony package [43] was used for integration, using the mouse identifier as a batch variable. Differential expression analysis was performed using the FindAllMarkers function, utilising Wilcoxon rank sum tests. Marker genes are presented with average log-fold change (log2FC) values and an adjusted p value of < 0.05 was considered as statistically significant. Gene ontology (GO) analysis was applied using the Panther database [44], using statistical overrepresentation tests and calculating the false discovery rate (FDR) for each GO term.
Sample size Estimation and statistical analysis
Sample size was estimated based on prior publications of developmental studies of kidney lymphatic vessels [40] and studies investigating lymphatics in adult mice organs [9, 16]. These indicated that 6–8 animals per experiment would be sufficient to power statistical analyses. Statistical analysis was conducted using Prism (v8, GraphPad by Dotmatics, Boston, MA, USA) and RStudio version 12.0 (Posit, Boston, MA, USA). To determine the significance of differences in volume between LYVE1 and PDPN at individual time points and individual organs, a paired student’s t-test was carried out. For comparisons of Pearson correlation coefficients r, one-way ANOVA followed by Tukey’s post hoc test was applied. To assess statistical significance across different time points a rank-based approach using the R package nparcomp [45] with the function mctp1 (multiple comparisons for relative contrast effect testing) was chosen. This approach allows for nonparametric multiple comparisons to evaluate relative contrast effects. A p value of less than 0.05 was considered statistically significant for all tests. Quantitative data was visualised using Prism. All graphical representations present individual data points either by region of interest or by animal, along with the mean and standard error of the mean.
Preparation of figures and videos
The graphical abstract was created in BioRender.com. The figures presented in this paper were prepared using the free software tool Inkscape 1.1.0 (Inkscape Project, 2020) for graphic design and layout. Any modifications made to the images, such as adjustment of brightness and contrast, were applied consistently throughout one panel to maintain uniformity across all coherent single and merged channel images. Videos were edited in Clipchamp (Microsoft, Redmond, WA, USA).
The Chinese online marketplace Temu’s EU operations more than doubled pre-tax profits last year to just below $120m (£90m) despite employing just eight people, accounts show.
They rose 171% in the 12 months to December 2024 compared with the $44.1m the year before, as shoppers snapped up its low-cost goods, which are widely promoted on social media.
However, the company paid just $18m in corporation tax, almost $3m of which was a mandatory top-up tax brought in at the end of 2023 after the EU signed up to a global minimum tax rate for large companies.
The accounts filed for the group’s Ireland-based EU parent group, Whaleco Technology, also show revenues rose to $1.7bn, compared with $758m the previous year, before new controls on the super-budget retailer.
Separate documents show Temu now has more than 115 million customers across the EU – equivalent to more than a quarter of the population.
The figures emerged after separate accounts showed almost doubling profits and revenues at the online marketplace’s UK operations.
The rise in sales comes before moves by the EU to close a loophole that allows packages worth less than €150 (£130) to avoid customs duty and some border checks.
Last year, 4.6bn low-value parcels entered the EU, equivalent to 12m a day, three times more than in 2022. More than 91% of parcels valued at less than €150 came from China, where Temu and its fellow low-cost seller Shein make and dispatch most of their goods.
However, controls began to be tightened in July this year, and customs duty is expected to be applied from 2028.
The US this summer abolished its “de minimis” exemption, which allowed goods worth less than $800 to skip import duty, to limit the rise of Temu and Shein, while the UK chancellor has said she is reviewing a similar loophole.
Paul Monaghan, the chief executive of the Fair Tax Foundation, estimates that Temu’s Irish entity facilitated consumer sales of $10bn in the EU – as its revenue figure only accounts for the company’s commission and fees from independent sellers on its marketplace.
If Temu’s estimated $2bn in sales via its sellers are included in the UK, that would make the marketplace bigger than the UK retailer Next and about the same size as Primark.
“Serious questions need to be asked as to why Temu has such a negligible economic and tax footprint in the UK and across Europe despite its enormous sales,” Monaghan said.
“What we have here is a chain of companies in a series of tax havens, that have been structured so as to leave little or no tax benefit in Europe.
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“The UK and other European governments need to move much more quickly to not only protect their tax base, but allow existing retailers to compete on a level playing field with these Chinese e-commerce giants that have overseas tax avoidance hard-wired into their structures.
“Standing strong on the global minimum tax and digital services tax, reviewing customs duty exemptions and bolstering requirements for multinationals to publish a country-by-country breakdown of the taxes they pay would be a great place for politicians to start.”
A spokesperson for Temu said its operations in Ireland were “real operating companies employing real people” and the employee numbers did not reflect the full scale of its operation presence.
“Temu categorically rejects any suggestion that our structure or operations are designed to avoid taxes or minimise our economic footprint in Europe. Despite being a young and fast-growing company still in the investment phase, we have already paid billions of euros in taxes across European jurisdictions, and that figure will continue to rise as our operations mature.
“The tax figure cited refers only to the tax paid by a single legal entity and does not include customs duties, VAT, and other taxes.
“Temu entered the European market just two years ago and has invested heavily in building its platform to connect sellers and consumers more efficiently, passing those efficiencies back to consumers in the form of lower prices on quality goods. At the same time, we have been creating new growth opportunities for local sellers across Europe.
“Our focus is on the long term: building a sustainable, compliant, and trusted platform that helps consumers access quality products at affordable prices while enabling local sellers across Europe to grow their businesses and reach new markets.”
Efforts to leverage the immunomodulatory effects and synergistic combinability of CELMoDs like iberdomide (CC-220) and mezigdomide (CC-92480) to augment standard T-cell redirection therapies could lead to more durable remissions or even cures for patients with relapsed/refractory multiple myeloma, according to Joshua Richter, MD.1
Preclinical data suggest that these CELMoDs, which operate through targeted degradation of the cereblon protein, could provide benefit to patients who are resistant to older drugs like lenalidomide (Revlimid) and pomalidomide (Pomalyst), providing a well-tolerated treatment that could be administered for longer durations and in combination with immune therapies or proteasome inhibitors.
“We are using these drugs to prime the collection [of T cells], and that may lead to higher curability using the CAR T-cell modality,” Richer shared in an interview with OncLive® at the 22nd Annual International Myeloma Society Meeting and Exposition.
In the interview, Richter discussed how next-generation immunomodulatory drugs could enhance current T-cell therapies in myeloma, current avenues of investigation for CELMoDs in multiple myeloma, and the desired balance between outcomes and toxicity for future immune-based treatments in myeloma.
Richter is an associate professor of medicine in the Division of Hematology and Medical Oncology at The Tisch Cancer Institute, and director of Multiple Myeloma at Blavatnik Family Chelsea Medical Center, Mount Sinai, in New York.
OncLive: How might next-generation immunomodulatory drugs enhance current T-cell therapies in myeloma, and what is the ultimate goal of these combinations?
Richter: [There have been] 3 great epochs of treatment in myeloma. In the old days, we started with classical chemotherapy. Then we moved on to the second generation [of treatment], with novel agents like immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies. Now we are in that third phase of T-cell redirection with CAR T-cell therapies and bispecific antibodies, and we are heading towards trispecific antibodies.
These therapies are amazing, and they provide some of the most incredible and durable responses we have ever seen, but we have not exactly perfected them. What can we do to help the T cells work even better to fight myeloma? It turns out that there are many drugs that we use already in myeloma for their anti–plasma cell [activity]; one of the ways they do that is by augmenting T-cell responses. [This approach] is the perfect [addition to] T-cell redirection therapy.
We are taking these next-generation immunomodulatory drugs that we call CELMoDs and adding them into the fray. This is not because they are directly killing plasma cells, but because they are augmenting an already robust T-cell response from bispecific antibodies and CAR T-cell therapy. [We want to see whether] there is a depth of response that we can achieve with these combinations that could lead to either unbelievably durable remissions or a cure.
What are some of the current avenues of investigation for CELMoDs in multiple myeloma?
There are a couple ongoing trials that are evaluating using CELMoDs in a variety of settings. The obvious areas [of investigation involve] using CELMoDs either after CAR T-cell therapy as a maintenance approach to maintain and prolong that activated T-cell response against the myeloma, or combining CELMoDs with bispecific antibodies and with drugs like elranatamab-bccm [Elrexfio] and teclistamab [Tecvayli] to see if you can improve overall response rates and progression-free survival.
[There’s another] cool study [of novel CELMoDs], data [from which have] been presented by my colleague Adolfo Aleman, PhD, [of Icahn School of Medicine at Mount Sinai].2 Usually, when we are getting ready to collect T cells for apheresis, we hold all treatment for at least a month and have [the patient receive no therapy] so we do not hurt the T cells en route to collecting them. However, [the data from this study] showed that if, instead of holding all treatment, we provide [patients with] iberdomide and mezigdomide during the time leading up to direct apheresis, the T-cell product we collect is more robust. Basically, we are using these drugs to prime the collection [of T cells], and that may lead to higher curability using the CAR T-cell therapy modality.
What balance between outcomes and toxicity do you hope will be achieved with future immune-based treatments in myeloma?
When it comes to immune responses, we can use the Goldilocks [analogy]. We do not want the porridge too cold, where [the drug] is not fighting things off. We also do not want the porridge too hot, where you have adverse effects [AEs]; we want it just right. In the world of myeloma, that is the way we classically think about [treatment]. It is either one and done, like with CAR T-cell therapy, or the patient receives therapy forever. [A compromise] we are going to have with some of our immunotherapies is fixed-duration, immune-based therapy. It is not necessarily one dose, but it is not treatment forever. Maybe we can figure out a treatment that is not forever, but is enough to get those deep and hopefully cure-based responses.
How does the toxicity profile of CELMoDs make them well suited for combination and long-term use?
One major AE we have noted from the immunomodulatory drug class has been cytopenias. In general, the CELMoDs, like iberdomide, have a great hematologic toxicity profile. This makes iberdomide an ideal drug to combine with other drugs because it does not lead to that grade 3/4 hematologic toxicity as much.
When we think about dose intensity, instead of thinking about it at one point in time for non-curable disease at this current moment, we want to think about longitudinal dose intensity and drugs like CELMoDs. In general, they have less myelotoxicity, so we can keep patients on them in the long term.
Are approvals for CELMoDs anticipated? How could collaboration between academic centers and community doctors support their future implementation into clinical practice?
At the moment, CELMoDs are not approved. Fingers crossed [that] we will hopefully get them FDA approved either in the fourth quarter of 2026 or first quarter of 2027. As these drugs enter the clinical space, [there will need to be] interaction between community and academic oncologists. We can have a conversation with a patient and then pass along the information to the community doctors, because these drugs are coming, and they are going to be part of our armamentarium. We need to figure out together how to optimize them.
References
van de Donk NWCJ, Bahlis NJ, Pawlyn C, et al. The role of CELMoD agents in multiple myeloma. Onco Targets Ther. 2025;18:921-933. doi:10.2147/OTT.S398118
Aleman A, Kogan-Zadjman A, Upadhyaya B, et al. Improving anti-BCMA CAR-T functionality with novel celmods in multiple myeloma. Blood. 2024;144(suppl 1):3259. doi:10.1182/blood-2024-201186
