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"Chen, Li-Juan"
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Long-term remission and survival in patients with relapsed or refractory multiple myeloma after treatment with LCAR-B38M CAR T cells: 5-year follow-up of the LEGEND-2 trial
Background
The autologous anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M has been approved for the treatment of relapsed and refractory multiple myeloma in many countries across the world under the name ciltacabtagene autoleucel. LEGEND-2 was the first-in-human trial of LCAR-B38M and yielded deep and durable therapeutic responses. Here, we reported the outcomes in LEGEND-2 after a minimal 5-year follow-up.
Methods
Participants received an average dose of 0.5 × 10
6
cells/kg LCAR-B38M in split or single unfractionated infusions after cyclophosphamide-based lymphodepletion therapy. Investigator-assessed response, survival, safety and pharmacokinetics were evaluated.
Results
Seventy-four participants enrolled and had a median follow-up of 65.4 months. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 21.0% and 49.1%, with progressive flattening of the survival curves over time. Patients with complete response (CR) had longer PFS and OS, with 5-year rates of 28.4% and 65.7%, respectively. Twelve patients (16.2%) remained relapse-free irrespective of baseline high-risk cytogenetic abnormality and all had normal humoral immunity reconstituted. An ongoing CR closely correlated with several prognostic baseline indices including favorable performance status, immunoglobulin G subtype, and absence of extramedullary disease, as well as a combination cyclophosphamide and fludarabine preconditioning strategy. Sixty-two (83.8%) suffered progressive disease (PD) and/or death; however, 61.1% of PD patients could well respond to subsequent therapies, among which, the proteasome inhibitor-based regimens benefited the most. Concerning the safety, hematologic and hepatic function recovery were not significantly different between non-PD and PD/Death groups. A low rate of second primary malignancy (5.4%) and no severe virus infection were observed. The patients who tested positive for COVID-19 merely presented self-limiting symptoms. In addition, a sustainable CAR T population of one case with persistent remission was delineated, which was enriched with indolently proliferative and lowly cytotoxic CD4/CD8 double-negative functional T lymphocytes.
Conclusions
These data, representing the longest follow-up of BCMA-redirected CAR T-cell therapy to date, demonstrate long-term remission and survival with LCAR-B38M for advanced myeloma.
Trial registration
LEGEND-2 was registered under the trial numbers NCT03090659, ChiCTRONH-17012285.
Journal Article
Four-year follow-up of LCAR-B38M in relapsed or refractory multiple myeloma: a phase 1, single-arm, open-label, multicenter study in China (LEGEND-2)
Background
LCAR-B38M is a chimeric antigen receptor T cell product with two binding domains targeting B cell maturation antigen. Our previous reports showed a remarkable efficacy of LCAR-B38M in patients with relapsed/refractory multiple myeloma (RRMM) at a median follow-up of 2 years. Here, we report long-term safety and efficacy data from a median follow-up of 4 years.
Methods
LEGEND-2 was a phase 1, single-arm, open-label study conducted in four registered sites in China. Seventy-four participants with RRMM received LCAR-B38M treatment. Lymphodepletion was performed using cyclophosphamide or cyclophosphamide plus fludarabine. LCAR-B38M, at a median dose of 0.513 × 10
6
cells/kg, was intravenously administered either in three split infusions or in a single infusion. The primary objective was the safety of LCAR-B38M, and the secondary objective was efficacy.
Results
As of May 25, 2021, the median follow-up was 47.8 months. All patients experienced ≥ 1 adverse events (AEs). Grade ≥ 3 AEs were observed in 45/74 (60.8%) patients. Cytokine release syndrome (CRS) occurred in 68/74 (91.9%) cases; 7 (9.5%) had grade ≥ 3 CRS. One patient experienced grade 1 central nervous system toxicity. The overall response rate was 87.8%. Fifty-four out of 74 (73.0%) patients achieved complete response. The median progression-free survival was 18.0 months, and the median overall survival for all patients was not reached. The median duration of response was 23.3 months. Four patients experienced viral infection more than 6 months post-infusion, and four patients developed second primary non-hematological malignancies at a median time of 11.5 months post-CAR-T cell transfer.
Conclusions
The 4-year follow-up data of LCAR-B38M therapy demonstrated a favorable long-term safety profile and a durable response in patients with RRMM.
Trial registration
Clinicaltrials.gov NCT03090659 (retrospectively registered on March 27, 2017); ChiCTR-ONH-17012285.
Journal Article
An unprecedented dumbbell-shaped pentadeca-nuclear W-Er heterometal cluster stabilizing nanoscale hexameric arsenotungstate aggregate and electrochemical sensing properties of its conductive hybrid film-modified electrode
Cluster-based functional materials have made remarkable progress owing to their wonderful structures and distinctive physicochemical performances, one of on-going advancements of which is basically driven by synthetic chemistry of exploring and constructing novel nanosized gigantic polyoxometalate (POM) aggregates. In this article, an unprecedented nanoscale hexameric arsenotungstate aggregate Na
9
K
16
H
4
[Er
0.5
K
0.5
(H
2
O)
7
][Er
5
W
10
O
26
(H
2
O)
14
][B-
α
-AsW
9
O
33
]
6
·102H
2
O (
1
) has been synthesized by the combined synthetic strategy of simultaneously using the arsenotungstate precursor and simple tungstate material in a highly acidic aqueous solution. The {[Er
5
W
10
O
26
(H
2
O)
14
][B-α-AsW
9
O
33
]
6
}
31−
polyanion in
1
consists of an intriguing dumbbell-shaped pentadeca-nuclear W-Er heterometal {Er
5
W
10
O
26
(H
2
O)
14
}
23+
cluster connecting six trilacunary [B-α-AsW
9
O
33
]
9−
moieties, which has never been seen previously. Furthermore, through electropolymerization of
1
and pyrrole on the conductive substrate, a thickness-controllable and robust
1
-PPY (PPY = polypyrrole) hybrid film was successfully prepared, which represents the first POM-PPY film assembled from high-nuclear lanthanide (Ln) encapsulated POM and PPY hitherto. The
1
-PPY film-based electrochemical biosensor exhibits a favorable recognition performance for ochratoxin A in multiple media. This work not only provides a feasible combined synthetic strategy of the POM precursor and simple tungstate material for constructing complicated multi-Ln-inserted POM aggregates, but also offers a promising electrochemical platform constructed from POM-based conductive films for identifying trace biomolecules in complex environments.
Journal Article
Case Report: Experience in the diagnosis and treatment of a male patient with plasma cell mastitis in the lump stage and review of the literature
Plasma cell mastitis (PCM) is a rare chronic inflammatory disorder primarily affecting non-lactating women, with fewer than 100 male cases reported globally. Male PCM is characterized by nonspecific clinical and radiological features that frequently mimic breast cancer, leading to diagnostic delays and mismanagement. Herein, we present a 55-year-old male patient with a 6-month history of a left subareolar mass initially misdiagnosed as malignancy due to spiculated margins on ultrasound (BI-RADS 4C) and mammography (BI-RADS 5). Despite negative percutaneous biopsy and normal tumor markers, surgical excision was performed following multidisciplinary evaluation. Pathological analysis confirmed PCM with dense plasma cell infiltration, multinucleated giant cells, and ductal ectasia. The patient achieved complete remission after margin-negative resection and remained recurrence-free at 12-month follow-up. Male PCM pathogenesis differs from female cases, with obesity (BMI 31 kg/m 2 ) and nipple inversion identified as key risk factors in this case. Obesity likely contributes via adipose tissue-mediated estrogen dysregulation and hypoxia-induced inflammation, while nipple inversion promotes ductal obstruction and antigenic debris accumulation. This case highlights the diagnostic challenges of male breast masses, emphasizing the necessity of histopathological confirmation to differentiate PCM from carcinoma. Surgical excision remains the gold standard for localized disease, as nonsurgical approaches (e.g., antibiotics, glucocorticoids) often fail to prevent recurrence. Our findings underscore the importance of early surgical intervention in male PCM to optimize outcomes and reduce malignancy-associated morbidity. Further studies are needed to establish evidence-based guidelines for this understudied condition.
Journal Article
Hepatocellular carcinoma with indocyanine green excretory defect: a case report and review of the literature
Constitutional indocyanine green (ICG) excretory defect is rare. However, ICG excretory defect concomitant with hepatocellular carcinoma (HCC) is extremely rare, and only six reports of hepatectomy in patients with constitutional ICG excretory defect have been published in the English language literature through 2020. In this study, we report a case of combined HCC and ICG excretory defect and discuss its clinicopathological features and outcomes. The case featured a 68-year-old man who was admitted to the hospital with a diagnosis of resectable HCC. The preoperative ICG retention rate at 15 minutes was 82.9%. Despite this finding, the Child–Pugh assessment and hepatobiliary-specific magnetic resonance imaging (MRI) did not reveal any abnormal findings. Therefore, we diagnosed the patient with constitutional ICG excretory defect and performed partial hepatectomy. For patients requiring hepatectomy, the indications and procedure for surgery should be considered. These should be based on liver function tests such as gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced MRI.
Journal Article
Tobacco alpha-expansin EXPA4 plays a role in Nicotiana benthamiana defence against Tobacco mosaic virus
Expansins are cell wall-loosening proteins known for their endogenous functions in cell wall extensibility during plant growth. The effects of expansins on plant growth, developmental processes and environment stress responses have been well studied. However, the exploration of expansins in plant virus resistance is rarely reported. In the present study, virus-induced gene silencing (VIGS) and Agrobacterium-mediated transient overexpression were conducted to investigate the role of Nicotiana tabacum alpha-expansin 4 (EXPA4) in modulating Tobacco mosaic virus (TMV-GFP) resistance in Nicotiana benthamiana. The results indicated that silencing of EXPA4 reduced the sensitivity of N. benthamiana to TMV-GFP, and EXPA4 overexpression accelerated virus reproduction on tobacco. In addition, our data suggested that the changes of virus accumulation in response to EXPA4 expression levels could further affect the antioxidative metabolism and phytohormone-related pathways in tobacco induced by virus inoculation. EXPA4-silenced plants with TMV-GFP have enhanced antioxidant enzymes activities, which were down-regulated in virus-inoculated 35S:EXPA4 plants. Salicylic acid accumulation and SA-mediated defence genes induced by TMV-GFP were up-regulated in EXPA4-silenced plants, but depressed in 35S:EXPA4 plants. Furthermore, a VIGS approach was used in combination with exogenous phytohormone treatments, suggesting that EXPA4 has different responses to different phytohormones. Taken together, these results suggested that EXPA4 plays a role in tobacco defence against viral pathogens.
Journal Article
Two types of lung cancer with situs inversus totalis: a case report and review of the literature
Situs inversus totalis (SIT) is a rare congenital anatomical variation. However, patients with SIT combined with cancer are rare and these patients with two types of lung cancer have not been reported. We report here a case of combined lung adenocarcinoma and solitary fibrous tumor of the pleura with SIT and discuss its clinicopathological features and outcomes. A 68-year-old asymptomatic woman was referred to the Affiliated Hospital of Qingdao University because of an abnormal shadow on chest radiography. Computed tomography showed SIT and an irregularly shaped nodule (measuring 38 × 27 mm in diameter) in the pleural area of the left lower lobe and a 5-mm nodule in the dorsal segment of the lower lobe of the left lung. Surgery was then performed. For such patients, we should eliminate anxiety in patients, perform regular reexaminations, focus on the individual features of these patients, and avoid misdiagnosis because of habitual thinking. At the same time, the lymph nodes should be completely removed and different parts of the tumor with different properties should be treated differently according to the situation.
Journal Article
Ethylene Receptor ETR2 Delays Floral Transition and Affects Starch Accumulation in Rice
Ethylene regulates multiple aspects of plant growth and development in dicotyledonous plants; however, its roles in monocotyledonous plants are poorly known. Here, we characterized a subfamily II ethylene receptor, ETHYLENE RESPONSE2 (ETR2), in rice (Oryza sativa). The ETR2 receptor with a diverged His kinase domain is a Ser/Thr kinase, but not a His kinase, and can phosphorylate its receiver domain. Mutation of the N box of the kinase domain abolished the kinase activity of ETR2. Overexpression of ETR2 in transgenic rice plants reduced ethylene sensitivity and delayed floral transition. Conversely, RNA interference (RNAi) plants exhibited early flowering and the ETR2 T-DNA insertion mutant etr2 showed enhanced ethylene sensitivity and early flowering. The effective panicles and seed-setting rate were reduced in the ETR2-overexpressing plants, while thousand-seed weight was substantially enhanced in both the ETR2-RNAi plants and the etr2 mutant compared with controls. Starch granules accumulated in the internodes of the ETR2-overexpressing plants, but not in the etr2 mutant. The GIGANTEA and TERMINAL FLOWER1/CENTRORADIALIS homolog (RCN1) that cause delayed flowering were upregulated in ETR2-overexpressing plants but downregulated in the etr2 mutant. Conversely, the α-amylase gene RAmy3D was suppressed in ETR2-overexpressing plants but enhanced in the etr2 mutant. Thus, ETR2 may delay flowering and cause starch accumulation in stems by regulating downstream genes.
Journal Article
Three-Dimensional Modeling of the Xichang Crust in Sichuan, China by Machine Learning
Seismicity and distribution of earthquakes can provide active fault structural information on the crust at a regional scale. The morphology of faults can be derived from the epicentral distribution of micro-earthquakes. In this study, we combined both the relocated earthquake catalogue and related preliminary geophysical information for 3D modeling of the crust in the Xichang area, Sichuan province, China. The fault morphology and deep crustal structure were automatically extracted by the machine learning approach, such as the supervised classification and cluster analysis methods. This new 3D crustal model includes the seismic velocity distribution, fault planes in 3D and 3D seismicity. There are many earthquake clusters located in the folded basement and low-velocity zone. Our model revealed the topological relation between the folded basement and faults. Our work show the crustal model derived is supported by the earthquake clusters which in turn controls the morphological characteristics of the crystalline basement in this area. Our use of machine learning techniques can not only be used to predict the refined fault geometry, but also to combine the seismic velocity structure with the known geological information. This 3D crustal model can also be used for geodynamic analysis and simulation of strong motionseismic waves.
Journal Article