Biomedicine Daily · Wednesday, 2 September 2026
CBA FRONTIER INSIGHTS
Novartis and BMS Halt Autoimmune CAR-T Trials After Three Deaths from IEC-HS
Novartis and Bristol Myers Squibb have paused their CD19 CAR-T programs across autoimmune diseases after three patients died in Novartis phase 2 trials from immune effector cell-associated hemophagocytic syndrome, a severe complication of immune overactivation. The halted studies span systemic lupus erythematosus, lupus nephritis, systemic sclerosis, ANCA-associated vasculitis, idiopathic inflammatory myopathies, rheumatoid arthritis with Sjogren's syndrome, generalized myasthenia gravis and multiple sclerosis; BMS also paused new enrollment in its zola-cel autoimmune trial. The setback strikes the leading immune-resetting modality in autoimmune disease and could accelerate a shift toward lower-cost, lower-complexity B-cell-depleting alternatives. It lands the same week China approved satri-cel, the first CAR T-cell therapy cleared for a solid tumor, in claudin 18.2-positive gastric cancer.
Clinical readouts and safety
PADN plus GDMT cuts clinical worsening risk 51 percent in PH-LHD, NEJM trial shows
Pulmonary artery denervation (PADN) added to guideline-directed medical therapy (GDMT) reduced the risk of clinical worsening by 51% (HR 0.49, 95% CI 0.30-0.82; P=0.006) in patients with pulmonary hypertension due to left heart disease (PH-LHD). In the 264-patient, 25-center randomized PADN-HF-PH trial, presented at ESC 2026 and published in the New England Journal of Medicine, the combination also cut the annualized recurrence of clinical worsening events by 35.5% and lowered the risk of exercise-capacity decline by 63%, with a net 24.8-meter gain in six-minute walk distance. It is the first device randomized trial to show a positive primary endpoint in PH-LHD.
Repatha Cuts All-Cause Death Risk 20 Percent in High-Risk Primary Prevention, VESALIUS-CV Shows
A prespecified secondary analysis of the phase 3 VESALIUS-CV trial found that Repatha (evolocumab) added to standard statins or other LDL-C-lowering therapy reduced the risk of all-cause death by a significant 20% in more than 12,000 high-risk adults with no history of myocardial infarction or stroke. Amgen reports this makes Repatha the first and only PCSK9 inhibitor shown in a phase 3 trial to reduce all-cause death, including cardiovascular death, in high-risk primary prevention patients.
Atezolizumab in early triple-negative breast cancer: the randomized phase 3 NSABP B-59/GeparDouze trial
Adding atezolizumab to neoadjuvant chemotherapy did not improve event-free survival in the phase 3 NSABP B-59/GeparDouze trial of patients with early-stage triple-negative breast cancer, missing its primary endpoint. Translational analyses identified tumor microenvironment-dependent determinants of response, indicating basal-like immune-activated tumors may respond to atezolizumab plus chemotherapy.
Dapagliflozin and Acute Kidney Injury Following Cardiac Surgery: A Randomized Clinical Trial.
Dapagliflozin started one day before elective cardiac surgery cut postoperative acute kidney injury nearly in half. Among 784 adults randomized at Dutch hospitals, AKI within 7 days occurred in 28% of the dapagliflozin group versus 52% on placebo (relative risk, 0.54; P < .001). Four perioperative doses of 10 mg offer a preventive strategy where none had been identified.
Novartis and BMS Pause CD19 CAR-T Autoimmune Trials After Three Deaths from IEC-HS
Novartis and Bristol Myers Squibb have paused their CD19 CAR-T trials across multiple autoimmune diseases after observing immune-related adverse events. Three deaths occurred in Novartis trials, all attributed to immune effector cell-associated hemophagocytic syndrome (IEC-HS), a severe complication of immune overactivation. The halted studies include Phase 2 trials in systemic lupus erythematosus/lupus nephritis, systemic sclerosis, ANCA-associated vasculitis and idiopathic inflammatory myopathies, plus Phase 1/2 trials in rheumatoid arthritis with Sjögren's syndrome, generalized myasthenia gravis and multiple sclerosis indications.
What CAR T’s new safety concern could mean for immune reset competition
Novartis has paused all immunology and neurology studies of its CAR T cell therapy rapcabtagene autoleucel after three autoimmune disease patients died of immune effector cell-associated hemophagocytic syndrome in Phase II testing. The deaths hit the leading immune-resetting modality in autoimmune disease and could accelerate a shift toward lower-cost, lower-complexity B-cell-depleting alternatives.
Hengrui's SHR-1918 Cuts LDL-C 64.2% Versus Placebo in HoFH Phase 3 Trial at ESC 2026
The anti-ANGPTL3 fully human monoclonal antibody SHR-1918 (ruisiruiximab) from Hengrui Medicine cut LDL-C by 64.2% relative to placebo in a nationwide multicenter phase 3 trial in patients with homozygous familial hypercholesterolemia. Led by Professor Daoquan Peng of the Second Xiangya Hospital of Central South University, the study was selected for the LBA session and presented orally at the ESC congress in Munich, held August 28 to 31, 2026.
Novartis and Bristol-Myers Squibb Halt Autoimmune CAR-T Trials After Three Deaths
Three patient deaths and multiple serious adverse events in clinical trials have led Novartis and Bristol-Myers Squibb to halt their CAR-T therapy trials in autoimmune diseases in late August 2026. Bristol-Myers Squibb also voluntarily paused enrollment of new patients in its autoimmune trial of zola-cel, citing an abundance of caution.
Cellular Neighborhoods Govern Antitumor T-cell Infiltration Following Anti–CTLA-4 in Melanoma with Primary Resistance to Anti–PD-1
Spatial proteomics of biopsies from the SWOG S1616 trial shows that melanoma patients responding to ipilimumab plus nivolumab after primary resistance to anti-PD-1 have activated CD8 T-cell networks near melanoma cells, while progressing biopsies show impaired T-cell infiltration adjacent to plasma cells. Responding baseline biopsies also showed complement expression in myeloid cells, interferon pathways in endothelial cells, and oxidative phosphorylation and lipid metabolism in melanoma cells. The work defines tumor microenvironment features that accompany reversal of anti-PD-1 resistance.
Intramyocardial injection of allogeneic human induced pluripotent stem cell-derived cardiomyocytes in advanced ischemic heart failure: an early-stage randomized trial.
Allogeneic human induced pluripotent stem cell-derived cardiomyocytes injected into the myocardium during CABG met the safety primary endpoint in the HEAL-CHF trial (n = 20): no sustained ventricular tachycardia in the 1- to 6-month window and no tumorigenicity at 12 months. All 10 cell-treated patients developed accelerated idioventricular rhythm within 4 weeks, and 2 had ventricular tachycardia over 140 bpm that resolved after cardioversion. Cell therapy improved 6-min walk distance, myocardial perfusion and relative wall thickening beyond CABG alone, but not ejection fraction, ventricular volumes, scar size, NYHA class or quality-of-life scores.
STAT+: Pharmalittle: We’re reading about Novartis and Bristol pausing cell therapy trials, a $480K cancer drug, and more
Novartis and Bristol Myers Squibb have paused multiple trials of their CAR-T cell therapies, rap-cel and zola-cel, in autoimmune conditions after inflammatory side effects, with three patient deaths in Novartis trials from an immune system reaction. Bristol Myers voluntarily paused enrollment in its autoimmune trials. Both therapies use technology meant to speed up production compared with earlier CAR-T products.
Novartis claims MS win as Rhapsido clears phase 3 with ‘no liver safety signal’
Novartis reported that two phase 3 trials of Rhapsido in relapsing multiple sclerosis met their goals, with no liver safety signal in either. The BTK inhibitor class has been dogged by liver safety concerns, and Rhapsido's clean readout suggests that barrier may not apply here. The company positions the result as a class first.
Regulatory and policy
MHRA concludes review of Avacopan Vifor following reassessment of benefit-risk balance
The MHRA will suspend the use, supply and sale of Avacopan Vifor (previously Tavneos) to new patients from 1 September 2026, after concluding that data integrity problems in the pivotal trial mean the study can no longer demonstrate efficacy. The drug, authorised on 6 May 2022 with rituximab or cyclophosphamide for severe, active GPA or MPA in adults, will be supplied only to existing patients during a six-month managed withdrawal, with the UK marketing authorisation to be revoked on 1 March 2027. Clinicians should not start new patients on the medicine and should review current patients for alternative treatments.
Trump Adds Nine Drugmakers Including BeOne Medicines to MFN Pricing Deals, Covering 89% of US Brand-Drug Market
The White House said on August 31 that President Trump signed new most-favored-nation drug pricing agreements with nine manufacturers: Alcon, Astellas Pharma, BeOne Medicines, BridgeBio, CSL, Kyowa Kirin, Sun Pharma, Teva Pharmaceuticals and UCB. The deals push US prescription drug prices down to the lowest level among other developed countries. With this round, 26 companies have signed MFN agreements, covering 89% of the US brand-drug market.
White House Signs MFN Drug Pricing Deals With Nine More Companies Including BeiGene and Teva
The White House announced on August 31 most-favored-nation drug pricing agreements with nine pharmaceutical companies: Alcon, Astellas, BeiGene, BridgeBio, CSL, Kyowa Kirin, Sun Pharma, Teva and UCB. The move extends the negotiation effort beyond large multinationals to mid-sized drugmakers. Companies with MFN arrangements now total 26, covering about 89% of the US branded drug market.
First CAR T-Cell Therapy Approved for Solid Tumors
China has approved satricabtagene autoleucel (satri-cel), the first CAR T-cell therapy for solid tumors, for patients with claudin 18.2-positive, HER2-negative gastric or gastro-esophageal junction cancer. The approval is based on a phase II trial showing improved progression-free and overall survival. Scientists welcome the decision but say more research is needed to improve CAR T-cell effectiveness against solid tumors.
STAT+: House votes to temporarily block Trump plan to politicize federal grants
The House voted 370-48 to pass a stopgap government-funding bill that temporarily blocks a White House proposal to give political appointees more control over federal research grants. The Senate passed the same bill a month ago, and it now goes to the president for signature. The measure funds the government until Dec. 11, and the ban on the research-funding policy expires at the same time.
Voluntary data submission pilot to advance innovative alternatives to animal testing
EMA has launched a voluntary data submission pilot that lets companies, method developers, contract research organisations and academic laboratories share data on New Approach Methodologies outside of a marketing authorisation application. Participants receive non-binding, non-decisional feedback from a group of non-clinical experts across the European medicines regulatory network, supporting regulatory acceptance of alternatives to animal testing under the 3Rs principles. Submissions run until the third quarter of 2027, after which EMA will publish a lessons-learned report.
Industry and deals
Dizhe Medicine-AstraZeneca License for Sunvozertinib Takes Effect, $600 Million Upfront Due
Dizhe Pharmaceutical (Dizhe Medicine) said its July 14, 2026 license agreement with AstraZeneca has taken effect, granting AstraZeneca exclusive worldwide rights to develop and commercialize Sunvozertinib (Shuwozhe). AstraZeneca plans to launch the drug in the US in the fourth quarter of this year. Dizhe receives a $600 million upfront payment, up to $400 million in clinical development milestones, up to $500 million in sales milestones, and tiered royalties on global sales from high single to low double digits.
Dizhe Files for Hong Kong Listing After AstraZeneca Sunvozertinib Deal With $600 Million Upfront
Dizhe Pharmaceutical (Dizhe Pharmaceutical) has filed an H-share listing application with the Hong Kong Stock Exchange in August 2026, four years after raising about 2.1 billion yuan on the STAR Market. Concurrently, a global exclusive license with AstraZeneca for sunvozertinib (sunvozertinib, DZD9008), effective August 31, gives Dizhe a $600 million upfront payment, up to $400 million in development milestones and up to $500 million in sales milestones, plus tiered royalties; AstraZeneca will commercialize the EGFR exon20ins NSCLC drug in the US in Q4 2026. Dizhe posted 522 million yuan in revenue in H1 2026 and will channel proceeds into clinical development of golidocitinib, DZD6008 and birutinib (DZD8586).
Research papers
Structure-function analysis of the FCRL5-IgG1 Fc complex reveals an unappreciated pathway for B cell modulation by Fc-attenuated IgG.
Common Fc function-silencing mutations in therapeutic IgG1 fail to eliminate FCRL5 binding, so Fc effector function is attenuated rather than silenced. The FCRL5-IgG1 Fc crystal structure, solved at 3.4 Å, shows a 1:1 complex with a binding mode distinct from classical Fcγ receptors. Fc-engineered antibodies selectively engaging FCRL5 inhibited B cell receptor-induced Ca2+ flux in FCRL5-expressing B cells, revealing a pathway for B cell modulation relevant to multiple myeloma targeting.
TNG961 Is a Selective Oral HBS1L Molecular Glue Degrader for the Treatment of FOCAD- Deleted Cancers
TNG961, an oral molecular glue degrader of HBS1L, exploits the synthetic lethal dependency that FOCAD deletion creates on the HBS1L-PELO ribosome rescue complex. FOCAD is deleted in about 1 in 3 MTAP-deleted cancers. TNG961 disrupts the HBS1L-PELO complex, causing translational arrest, and oral dosing regressed FOCAD-negative xenografts, including PRMT5 inhibitor-refractory models.
Expansion and CAR engineering of granulocyte-monocyte progenitors for cellular immunotherapy.
Defined culture conditions allow long-term ex vivo expansion of mouse and human granulocyte-monocyte progenitors (GMPs) while preserving progenitor identity, with myeloperoxidase identified as a regulator of GMP proliferation. After transfer, engineered GMPs seed hematopoietic niches, restore antibacterial defense in chronic granulomatous disease mice, and generate tumor-infiltrating macrophages. CAR-engineered GMPs suppress CD19-positive leukemia and HER2-positive solid tumors, including in immunocompetent allogeneic models using a CAR with an IgG Fc domain.
Correcting Mitochondrial Complex I Defect in Tumor-Associated Natural Killer Cells Potentiates Immunotherapy for Glioblastoma
Mitochondrial complex I deficiency, driven by loss of the subunit NDUFA9, undermines natural killer (NK) cell function in glioblastoma. NDUFA9 abundance in NK cells informed patient outcomes, and Ndufa9 knockout shifted NK cells toward glutamine dependence and repressive H3K27me3 epigenetic marking. Resveratrol-mediated NDUFA9 activation or its overexpression restored complex I activity and enhanced NK cell anti-GBM function, marking complex I as a pharmacologically targetable node for NK cell-based immunotherapy.
Intestinal fructose catabolism promotes obesity and insulin resistance via ileal lacteal remodeling.
Blocking fructose catabolism specifically in the murine small intestine mitigates fructose-induced obesity and insulin resistance, an unexpected finding since intestinal fructose clearance was thought to protect the liver. The effect traces to decreased dietary fat absorption caused by shortening of ileal lacteals. Fecal transplantation showed the altered microbiome reduces ileal macrophages required for lacteal growth.
Spatial Integration of Protein and Chromosomal States Reveals Early Copy-Number Changes and Genotype-Associated Immune Neighborhoods in Serous Ovarian Cancer Evolution
ORION-FISH combines high-plex tissue imaging with morphology-preserving DNA-FISH and single-cell registration to measure copy-number alterations alongside protein-defined cell states in intact tissue, with results concordant with clinical FISH. In high-grade serous ovarian carcinoma it recapitulated known chromosomal changes and revealed subclonal heterogeneity missed by targeted sequencing. In serous tubal intraepithelial carcinomas it found intermixed cells with MYC or CCNE1 gains linked to distinct immune microenvironments, and detected MYC and CCNE1 gains in morphologically normal fallopian tube epithelium, plus rare MDM4 increases.
Ratiometric transcriptional activation by protein degradation
Tethering a protein of interest to anti-CRISPR converts protein degradation into amplified, programmable transcriptional outputs through Cas-based transcription factors, with sensitivity to protein loss set by the anti-CRISPR-Cas ratio. The circuits can be multiplexed for high-throughput discovery of protein-degrading and -destabilizing molecules. The work appeared in Cell.
Structure and operating principles of a monkeypox virus replisome.
Cryo-electron microscopy structures of DNA-bound monkeypox virus replisomes, comprising the polymerase holoenzyme (F8, A22 and E4) and the E5 helicase hexamer, reveal how the pieces assemble. During assembly, E5 undergoes large-scale conformational changes in which two primase domains contact the F8 thumb and A22 subunit. Biochemical assays and single-molecule experiments show this change activates the otherwise autoinhibited helicase and enhances primase activity, defining how helicase and polymerase activities are coordinated during MPXV DNA replication.
Automated prototyping of genetic codes.
The tRNA 3' CCA end, long required for ribosomal recognition, tolerates mutation far more than expected: most non-CCA-3' tRNAs (otRNAs) are aminoacylated by all E. coli aminoacyl tRNA synthetases. The authors built AGENTEX, an automated robotic prototyping platform, and used it to run cell-free translation systems with compressed genetic codes of 34 aaRSs for 34 codons, evaluating two genetic codes with non-standard amino acid incorporation and reassignment of up to three codons. The work opens a route to designing translation systems and biopolymers with multiple non-standard monomers.
Development of mitochondrial mutator pigs exhibiting increased mitochondrial DNA mutations and premature aging via prime editing.
Prime editing combined with somatic cell nuclear transfer produced pigs expressing proofreading-deficient POLG, the catalytic subunit of DNA polymerase gamma. The pigs accumulated elevated somatic mitochondrial DNA mutation loads and showed premature aging phenotypes, including weight loss, anemia, increased apoptosis, up-regulation of senescence-associated markers, and shortened life span. The model offers a large-animal platform for studying mtDNA mutations in aging and testing therapies.
IL1RAP Antibody–Drug Conjugates Potently Target Primary and Metastatic Diseases in Multiple Oncofusion-Driven Cancers
IL1RAP, a surface protein induced by oncofusions such as EWSR1-ETS in Ewing sarcoma, NPM-ALK in anaplastic large cell lymphoma, and ETV6-NTRK3 in multiple tumor types, can be targeted with engineered antibody-drug conjugates. The ADCs induced durable regression of Ewing sarcoma xenografts, reduced metastatic dissemination, and blocked growth of ALCL xenografts and syngeneic ETV6-NTRK3+ sarcomas in vivo. No detectable normal tissue toxicity, including in nonhuman primates, supports clinical translation.
PHGDH-High Dormant Tumor Cells Evade Immunity and Drive Metastasis
Rare disseminated tumor cells enter a transient PHGDH-high state that allows them to evade immunity and drive metastatic outgrowth. The work frames a progression from immune clearance to dormancy to outgrowth, with the cells coevolving with their microenvironment. Targeting PHGDH or CX3CR1-high macrophages may stop dormant tumor cells from progressing to metastases.
Arachidonic Acid Metabolism in PMN-MDSCs Suppresses Antitumor Capacity of T Cells in KRAS -Mutant Cholangiocarcinoma
KRAS-mutant intrahepatic cholangiocarcinoma carries the worst prognosis among metabolic subtypes, marked by enriched COX/arachidonic acid metabolism. KRAS mutation activates NF-κB to upregulate CXCL5, recruiting CXCR2+ PMN-MDSCs, while tumor-derived PGE2 boosts AA uptake and COX-2 in those cells, forming a feedback loop that suppresses CD8+ T cells via EP4. Targeting the COX-2-PGE2-EP4 axis combined with anti-PD-1 showed synergistic efficacy in KRAS-mutant mouse models and patient-derived tumor fragments.
Spatial Mapping of the Precancer-to-Cancer Transition in Breast and Prostate
Lightsheet microscopy on intact tumors pinpointed junctions between precancerous and invasive regions, and a multimodal serial-section workflow combining volumetric reconstruction with spatial transcriptomics analyzed 319 spatial assays from 51 cases. In breast cancer, loss of MGP and PLAT marked and promoted invasive transition; in prostate cancer, GDF15, ALDH1A3, ANPEP and FASN rose with invasion and their knockdown suppressed PC-3 proliferation and migration. The approach exposes spatially defined drivers of invasion and candidate targets in the two most prevalent cancers.
Generation of a highly versatile TCR bispecific scaffold optimized for targeting tumor-specific peptide-HLA antigens
A TCR-based T-cell-engaging bispecific scaffold, TCER (T-Cell-Engaging Receptor), was developed to target tumor-specific peptide-HLA antigens, where lineage antigens such as CD19, CD20 and BCMA have largely limited progress to hematological cancers. The scaffold is optimized for in vivo efficacy, tolerability, plasma half-life and stability, and is designed for broad use against these low-copy, highly promiscuous antigens in oncology.
Methods and resources
A pervasive RT–qPCR artifact inflates RNA knockdown by RNA-targeting CRISPR
RT-qPCR amplicons spanning the guide RNA binding site falsely report RNA knockdown by RNA-targeting CRISPR systems. For RNase-dead Csm targeting XIST, a spanning amplicon showed 90% apparent knockdown while a downstream amplicon showed 14%, and WT Csm knockdown was inflated (90% spanning versus 35% downstream). The artifact, driven by copurifying gRNAs inhibiting RT-qPCR, affects Csm, Psp Cas13b and CasRx, meaning published knockdown efficiencies measured this way may be overestimated.
AI-enhanced adaptive virtual screening of large libraries for ligand discovery
The open-source platform AdaptiveFlow performs ultralarge virtual screening using Adaptive Target-Guided Virtual Screens, an 18-dimensional grid of molecular properties that focuses docking on promising regions of chemical space, plus an optional active learning layer. It supports over 1,500 docking protocols and runs on CPU and GPU architectures. Applied to FSP1 and PARP1, it identified nanomolar inhibitors confirmed by high-resolution co-crystal structures.
Ultrafast and reference-free sequence discovery in single-cell data.
Malva is a computational platform that lets researchers search raw sequence space across single-cell and spatial transcriptomics data without a reference genome, at species-agnostic scale. Its expanding index already covers about 74 million cells from thousands of experiments in health and disease, supporting searches for any sequence, mutation, splice junction or pathogen, and reference-free cell type identification. It turns single-cell atlases from static gene count tables into dynamic, sequence-resolved resources.
MAXTIA: A high-throughput platform for rapid functional epitope mapping by kinetic screening of mutant libraries
MAXTIA, a high-throughput kinetic screening platform combining cell-free protein synthesis with high-throughput surface plasmon resonance, maps functional epitopes by alanine scanning up to 384 protein variants within 3 days while providing KD, kon and koff. Applied to the VHH N1 antibody against the neuronal pentraxin-2 pentraxin domain, affinity-disrupting alanine substitutions clustered on the AlphaFold3-predicted structure and matched the crystallographic interface, validating residue-level accuracy.
A multiplex tissue resource for high-resolution spatial protein profiling in the Human Protein Atlas
The Human Protein Atlas now includes a multiplex tissue resource built on large-scale multiplex immunohistochemistry, combining optimized marker panels with candidate proteins to place expression in cellular and subcellular context. Version 25 covers 1106 proteins across eight antibody panels and nine tissue settings, including testis, kidney, endocrine pancreas and salivary gland. The resource refines spatial protein annotation where single-marker staining falls short.
Rapid and robust diagnosis of bloodstream infections by single-cell analysis.
STREAM, a platform combining sedimentation-assisted pathogen enrichment with single-cell analysis, diagnoses bloodstream infections directly from whole blood. Pathogen identification matched clinical laboratory results in 96.15% of 104 positive blood culture samples, and single-cell antimicrobial susceptibility testing showed 97.96% essential agreement across 219 drug-dose combinations. Detection reaches 0.1 to 1 CFU/ml with full results in 6.75 to 17 hours, bypassing slow blood culture.
In brief
- Endogenous Metabolite Glues Can Be Therapeutically Exploitedaacrjournals.org
- Genomic Evolution of Myeloproliferative Neoplasms and Therapy-Associated Mutagenesisaacrjournals.org
- Critical role for the TGF-β1/mTORC1 signaling axis in defining the transcriptional identity of CTHRC1+ pathologic fibroblasts.Sci Adv
- Circulating Tumor DNA Status and Adjuvant Chemotherapy in Resected Colorectal Liver Metastasesjamanetwork.com
- Insights into longevity and virus-driven adaptation from Myotis bat genomes.Nature
- Baat-Deficient Mice Recapitulate Elevated 7α-Hydroxy-3-Oxo-4-Cholestenoic Acid Observed in a Japanese Patient With BAAT Deficiencypubmed.ncbi.nlm.nih.gov