The HSP90-MYC-CDK9 network drives therapeutic resistance in mantle cell lymphoma.

Brexucabtagene autoleucel CAR-T therapy is highly efficacious in overcoming resistance to Bruton's tyrosine kinase inhibitors (BTKi) in mantle cell lymphoma. However, many patients relapse post CAR-T therapy with dismal outcomes. To dissect the underlying mechanisms of sequential resistance to BTKi and CAR-T therapy, we performed single-cell RNA sequencing analysis for 66 samples from 25 patients treated with BTKi and/or CAR-T therapy and conducted in-depth bioinformatics™ analysis. Our analysis revealed that MYC activity progressively increased with sequential resistance. HSP90AB1 (Heat shock protein 90 alpha family class B member 1), a MYC target, was identified as early driver of CAR-T resistance. CDK9 (Cyclin-dependent kinase 9), another MYC target, was significantly upregulated in Dual-R samples. Both HSP90AB1 and CDK9 expression were correlated with MYC activity levels. Pharmaceutical co-targeting of HSP90 and CDK9 synergistically diminished MYC activity, leading to potent anti-MCL activity. Collectively, our study revealed that HSP90-MYC-CDK9 network is the primary driving force of therapeutic resistance.

Potentiation of apoptosis in drug-resistant mantle cell lymphoma cells by MCL-1 inhibitor involves downregulation of inhibitor of apoptosis proteins.

Bruton's tyrosine kinase inhibitors (BTKi) and CAR T-cell therapy have demonstrated tremendous clinical benefits in mantle cell lymphoma (MCL) patients, but intrinsic or acquired resistance inevitably develops. In this study, we assessed the efficacy of the highly potent and selective MCL-1 inhibitor AZD5991 in various therapy-resistant MCL cell models. AZD5991 markedly induced apoptosis in these cells. In addition to liberating BAK from the antiapoptotic MCL-1/BAK complex for the subsequent apoptosis cascade, AZD5991 downregulated inhibitor of apoptosis proteins (IAPs) through a BAK-dependent mechanism to amplify the apoptotic signal. The combination of AZD5991 with venetoclax enhanced apoptosis and reduced mitochondrial oxygen consumption capacity in MCL cell lines irrespective of their BTKi or venetoclax sensitivity. This combination also dramatically inhibited tumor growth and prolonged mouse survival in two aggressive MCL patient-derived xenograft models. Mechanistically, the augmented cell lethality was accompanied by the synergistic suppression of IAPs. Supporting this notion, the IAP antagonist BV6 induced dramatic apoptosis in resistant MCL cells and sensitized the resistant MCL cells to venetoclax. Our study uncovered another unique route for MCL-1 inhibitor to trigger apoptosis, implying that the pro-apoptotic combination of IAP antagonists and apoptosis inducers could be further exploited for MCL patients with multiple therapeutic resistance.

Recent advances in CAR T-cell therapy for lymphoma in China

Lymphoma is a hematologic malignancy which mainly consists of Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Although systemic chemotherapy, radiotherapy, and other advanced therapeutics, including rituximab or immune checkpoint inhibitors, have improved the prognosis in recent decades, there are still a number of patients with relapsed or refractory (R/R) lymphoma with a poor prognosis. Chimeric antigen receptor (CAR) T-cell therapy has provided a curative option for patients with relapsed or refractory lymphoma. Numerous clinical trials have been conducted worldwide and presented inspiring results that give insight into this breakthrough therapy. The development of cancer cell therapy in China has been rapid in the past years and dominates the field with the USA. This review aims to summarize the published results of CAR T-cell therapy alone or in combination with other therapies in mainland China, both in R/R NHL and R/R HL (AU)

Design of Furan-Based Acceptors for Organic Photovoltaics.

We explore a series of furan-based non-fullerene acceptors and report their optoelectronic properties, solid-state packing, photodegradation mechanism and application in photovoltaic devices. Incorporating furan building blocks leads to the expected enhanced backbone planarity, reduced band gap and red-shifted absorption of these acceptors. Still, their position in the molecule is critical for stability and device performance. We found that the photodegradation of these acceptors originates from two distinct pathways: electrocyclic photoisomerization and Diels-Alder cycloaddition of singlet oxygen. These mechanisms are of general significance to most non-fullerene acceptors, and the photostability depends strongly on the molecular structure. Placement of furans next to the acceptor termini leads to better photostability, well-balanced hole/electron transport, and significantly improved device performance. Methylfuran as the linker offers the best photostability and power conversion efficiency (>14 %), outperforming all furan-based acceptors reported to date and all indacenodithiophene-based acceptors. Our findings show the possibility of photostable furan-based alternatives to the currently omnipresent thiophene-based photovoltaic materials.

Thiele's Fluorocarbons: Stable Diradicaloids with Efficient Visible-to-Near-Infrared Fluorescence from a Zwitterionic Excited State.

Thiele's hydrocarbon was the first synthesized diradicaloid in the search for stable open-shell structures, but it remains sensitive to oxygen and light. We here report the synthesis of Thiele's fluorocarbon (TFC) and its derivatives exhibiting exceptional thermal, oxidative, and photostability. TFCs have remarkable luminescent properties with yellow to NIR fluorescence and up to 100% quantum yields. X-ray crystallography and ESR spectroscopy confirm their closed-shell quinoidal ground state. As expected from their symmetric nonpolar structure, the TFCs' absorption spectra show no solvent effect, but their emission reveals an extraordinarily large Stokes shift which increases with solvent polarity (from 0.9 eV in cyclohexane to 1.5 eV in acetonitrile). We show that this behavior is a result of sudden polarization, leading to a zwitterionic excited state.

Unifying temporal phase unwrapping framework using deep learning.

Temporal phase unwrapping (TPU) is significant for recovering an unambiguous phase of discontinuous surfaces or spatially isolated objects in fringe projection profilometry. Generally, temporal phase unwrapping algorithms can be classified into three groups: the multi-frequency (hierarchical) approach, the multi-wavelength (heterodyne) approach, and the number-theoretic approach. For all of them, extra fringe patterns of different spatial frequencies are required for retrieving the absolute phase. Due to the influence of image noise, people have to use many auxiliary patterns for high-accuracy phase unwrapping. Consequently, image noise limits the efficiency and the measurement speed greatly. Further, these three groups of TPU algorithms have their own theories and are usually applied in different ways. In this work, for the first time to our knowledge, we show that a generalized framework using deep learning can be developed to perform the TPU task for different groups of TPU algorithms. Experimental results show that benefiting from the assistance of deep learning the proposed framework can mitigate the impact of noise effectively and enhance the phase unwrapping reliability significantly without increasing the number of auxiliary patterns for different TPU approaches. We believe that the proposed method demonstrates great potential for developing powerful and reliable phase retrieval techniques.

Treatment patterns and clinical outcomes of mantle cell lymphoma: A retrospective cohort study by CHOICE.

Regimens based on Bruton's tyrosine kinase inhibitors (BTKi) have been increasingly used to treat mantle cell lymphoma (MCL). A real-world multicenter study was conducted to characterize treatment patterns and outcomes in patients with newly diagnosed MCL by Chinese Hematologist and Oncologist Innovation Cooperation of the Excellent (CHOICE). The final analysis included 1261 patients. Immunochemotherapy was the most common first-line treatment, including R-CHOP in 34%, cytarabine-containing regimens in 21% and BR in 3% of the patients. Eleven percent (n = 145) of the patients received BTKi-based frontline therapy. Seventeen percent of the patients received maintenance rituximab. Autologous hematopoietic stem cell transplantation (AHCT) was conducted in 12% of the younger (<65 years) patients. In younger patients, propensity score matching analysis did not show significant difference in 2-year progression-free survival and 5-year overall survival rate in patients receiving standard high-dose immunochemotherapy followed by AHCT than induction therapy with BTKi-based regimens without subsequent AHCT (72% vs 70%, P = .476 and 91% vs 84%, P = .255). In older patients, BTKi combined with bendamustine plus rituximab (BR) was associated with the lowest POD24 rate (17%) compared with BR and other BTKi-containing regimens. In patients with resolved hepatitis B at the baseline, HBV reactivation rate was 2.3% vs 5.3% in those receiving anti-HBV prophylaxis vs not; BTKi treatment was not associated with higher risk of HBV reactivation. In conclusion, non-HD-AraC chemotherapy combined with BTKi may be a viable therapeutic strategy for younger patients. Anti-HBV prophylaxis should be implemented in patients with resolved hepatitis B.

Advances in the treatment of Hodgkin's lymphoma (Review).

Hodgkin's lymphoma (HL) is a unique B­cell lymphoproliferative malignancy that has a critical pathogenesis characterized by a sparse population of Hodgkin and Reed­Sternberg cells surrounded by numerous dysfunctional immune cells. Although systemic chemotherapy with or without radiotherapy, has significantly improved the prognosis of the majority of patients with HL, a subset of patients remains refractory to first­line therapy or relapse after achieving an initial response. With the increased understanding of the biology and microenvironment of HL, novel strategies with notable efficacy and manageable toxicity, including targeted therapies, immunotherapy and cell therapy have emerged. The present review summarizes the progress made in developing novel therapies for HL and discusses future research directions in HL therapy.

Recent advances in CAR T-cell therapy for lymphoma in China.

Lymphoma is a hematologic malignancy which mainly consists of Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Although systemic chemotherapy, radiotherapy, and other advanced therapeutics, including rituximab or immune checkpoint inhibitors, have improved the prognosis in recent decades, there are still a number of patients with relapsed or refractory (R/R) lymphoma with a poor prognosis. Chimeric antigen receptor (CAR) T-cell therapy has provided a curative option for patients with relapsed or refractory lymphoma. Numerous clinical trials have been conducted worldwide and presented inspiring results that give insight into this breakthrough therapy. The development of cancer cell therapy in China has been rapid in the past years and dominates the field with the USA. This review aims to summarize the published results of CAR T-cell therapy alone or in combination with other therapies in mainland China, both in R/R NHL and R/R HL.

Exploiting PRMT5 as a target for combination therapy in mantle cell lymphoma characterized by frequent ATM and TP53 mutations.

Constant challenges for the treatment of mantle cell lymphoma (MCL) remain to be recurrent relapses and therapy resistance, especially in patients harboring somatic mutations in the tumor suppressors ATM and TP53, which are accumulated as therapy resistance emerges and the disease progresses, consistent with our OncoPrint results that ATM and TP53 alterations were most frequent in relapsed/refractory (R/R) MCL. We demonstrated that protein arginine methyltransferase-5 (PRMT5) was upregulated in R/R MCL, which predicted a poor prognosis. PRMT5 inhibitors displayed profound antitumor effects in the mouse models of MCL with mutated ATM and/or TP53, or refractory to CD19-targeted CAR T-cell therapy. Genetic knockout of PRMT5 robustly inhibited tumor growth in vivo. Co-targeting PRMT5, and ATR or CDK4 by using their inhibitors showed synergistic antitumor effects both in vitro and in vivo. Our results have provided a rational combination therapeutic strategy targeting multiple PRMT5-coordinated tumor-promoting processes for the treatment of R/R MCL with high mutation burdens.

Immunohistochemical HER2 Recognition and Analysis of Breast Cancer Based on Deep Learning.

Breast cancer is one of the common malignant tumors in women. It seriously endangers women's life and health. The human epidermal growth factor receptor 2 (HER2) protein is responsible for the division and growth of healthy breast cells. The overexpression of the HER2 protein is generally evaluated by immunohistochemistry (IHC). The IHC evaluation criteria mainly includes three indexes: staining intensity, circumferential membrane staining pattern, and proportion of positive cells. Manually scoring HER2 IHC images is an error-prone, variable, and time-consuming work. To solve these problems, this study proposes an automated predictive method for scoring whole-slide images (WSI) of HER2 slides based on a deep learning network. A total of 95 HER2 pathological slides from September 2021 to December 2021 were included. The average patch level precision and f1 score were 95.77% and 83.09%, respectively. The overall accuracy of automated scoring for slide-level classification was 97.9%. The proposed method showed excellent specificity for all IHC 0 and 3+ slides and most 1+ and 2+ slides. The evaluation effect of the integrated method is better than the effect of using the staining result only.

Cotargeting of BTK and MALT1 overcomes resistance to BTK inhibitors in mantle cell lymphoma.

Bruton's tyrosine kinase (BTK) is a proven target in mantle cell lymphoma (MCL), an aggressive subtype of non-Hodgkin lymphoma. However, resistance to BTK inhibitors is a major clinical challenge. We here report that MALT1 is one of the top overexpressed genes in ibrutinib-resistant MCL cells, while expression of CARD11, which is upstream of MALT1, is decreased. MALT1 genetic knockout or inhibition produced dramatic defects in MCL cell growth regardless of ibrutinib sensitivity. Conversely, CARD11-knockout cells showed antitumor effects only in ibrutinib-sensitive cells, suggesting that MALT1 overexpression could drive ibrutinib resistance via bypassing BTK/CARD11 signaling. Additionally, BTK knockdown and MALT1 knockout markedly impaired MCL tumor migration and dissemination, and MALT1 pharmacological inhibition decreased MCL cell viability, adhesion, and migration by suppressing NF-κB, PI3K/AKT/mTOR, and integrin signaling. Importantly, cotargeting MALT1 with safimaltib and BTK with pirtobrutinib induced potent anti-MCL activity in ibrutinib-resistant MCL cell lines and patient-derived xenografts. Therefore, we conclude that MALT1 overexpression associates with resistance to BTK inhibitors in MCL, targeting abnormal MALT1 activity could be a promising therapeutic strategy to overcome BTK inhibitor resistance, and cotargeting of MALT1 and BTK should improve MCL treatment efficacy and durability as well as patient outcomes.

Targeting glutaminase is therapeutically effective in ibrutinib-resistant mantle cell lymphoma.

Mantle cell lymphoma (MCL) is an incurable B-cell non-Hodgkin lymphoma characterized by frequent relapses. The development of resistance to ibrutinib therapy remains a major challenge in MCL. We previously showed that glutaminolysis is associated with resistance to ibrutinib. In this study, we confirmed that glutaminase (GLS), the first enzyme in glutaminolysis, is overexpressed in ibrutinib-resistant MCL cells, and that its expression correlates well with elevated glutamine dependency and glutaminolysis. Furthermore, we discovered that GLS expression correlates with MYC expression and the functioning of the glutamine transporter ASCT2. Depletion of glutamine or GLS significantly reduced cell growth, while GLS overexpression enhanced glutamine dependency and ibrutinib resistance. Consistent with this, GLS inhibition by its specific inhibitor telaglenastat suppressed MCL cell growth both in vitro and in vivo. Moreover, telaglenastat showed anti-MCL synergy when combined with ibrutinib or venetoclax in vitro, which was confirmed using an MCL patient-derived xenograft model. Our study provides the first evidence that targeting GLS with telaglenastat, alone or in combination with ibrutinib or venetoclax, is a promising strategy to overcome ibrutinib resistance in MCL.

Secondary hemophagocytic lymphohistiocytosis triggered by peripheral T-cell lymphoma: An unusual case report.

Hemophagocytic lymphohistiocytosis (HLH) is a severe syndrome of pathological immune activation caused by activated macrophages and cytotoxic T cells. We report a 65-year-old male Chinese patient with typical HLH features caused by peripheral T-cell lymphoma and then received chemotherapy. However, though the patient's symptoms and signs improved much, his liver function, especially bilirubin, worsened which could be caused by overwhelming cytokines production. Therefore, plasmapheresis was conducted two times and then his liver function significantly recovered. The patient got temporary remission and good quality of life for nearly 2 months but died because of disease progression. In conclusion, as HLH is associated with multiorgan failure, high rates of morbidity and mortality, there are three points to be mentioned. First, it is critical that HLH should be screened as early as possible and initiate effective therapies. Second, plasmapheresis could be a useful method to eliminate excess cytokines production and improve liver function. Third, organs support and nutrient supply are also necessary and important.

TIGIT is the central player in T-cell suppression associated with CAR T-cell relapse in mantle cell lymphoma.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy using brexucabtagene autoleucel (BA) induces remission in many patients with mantle cell lymphoma (MCL), and BA is the only CAR T-cell therapy approved by the FDA for MCL. However, development of relapses to BA is recognized with poor patient outcomes. Multiple CAR T-cell therapies have been approved for other lymphomas and the resistance mechanisms have been investigated. However, the mechanisms underlying BA relapse in MCL have not been investigated and whether any previously reported resistance mechanisms apply to BA-relapsed patients with MCL is unknown. METHODS: To interrogate BA resistance mechanisms in MCL, we performed single-cell RNA sequencing on 39 longitudinally collected samples from 15 BA-treated patients, and multiplex cytokine profiling on 80 serial samples from 20 patients. RESULTS: We demonstrate that after BA relapse, the proportion of T cells, especially cytotoxic T cells (CTLs), decreased among non-tumor cells, while the proportion of myeloid cells correspondingly increased. TIGIT, LAG3, and CD96 were the predominant checkpoint molecules expressed on exhausted T cells and CTLs; only TIGIT was significantly increased after relapse. CTLs expanded during remission, and then contracted during relapse with upregulated TIGIT expression. Tumor cells also acquired TIGIT expression after relapse, leading to the enhanced interaction of tumor cell TIGIT with monocyte CD155/PVR. In myeloid cells, post-relapse HLA-II expression was reduced relative to pretreatment and during remission. Myeloid-derived suppressor cells (MDSCs) were enriched after relapse with elevated expression of activation markers, including CLU (clusterin) and VCAN (versican). Extracellular chemokines (CCL4, CXCL9, CXCL13), soluble checkpoint inhibitors (sPD-L1, sTIM3, s4-1BB), and soluble receptors (sIL-2R, sTNFRII) were decreased during remission but elevated after relapse. CONCLUSIONS: Our data demonstrate that multiple tumor-intrinsic and -extrinsic factors are associated with T-cell suppression and BA relapse. Among these, TIGIT appears to be the central player given its elevated expression after BA relapse in not only CTLs but also MCL cells. The acquisition of TIGIT expression on tumor cells is MCL-specific and has not been reported in other CAR T-treated diseases. Together, our data suggest that co-targeting TIGIT may prevent CAR T relapses and thus promote long-term progression-free survival in MCL patients.

Deep Learning-Based 3D Measurements with Near-Infrared Fringe Projection.

Fringe projection profilometry (FPP) is widely applied to 3D measurements, owing to its advantages of high accuracy, non-contact, and full-field scanning. Compared with most FPP systems that project visible patterns, invisible fringe patterns in the spectra of near-infrared demonstrate fewer impacts on human eyes or on scenes where bright illumination may be avoided. However, the invisible patterns, which are generated by a near-infrared laser, are usually captured with severe speckle noise, resulting in 3D reconstructions of limited quality. To cope with this issue, we propose a deep learning-based framework that can remove the effect of the speckle noise and improve the precision of the 3D reconstruction. The framework consists of two deep neural networks where one learns to produce a clean fringe pattern and the other to obtain an accurate phase from the pattern. Compared with traditional denoising methods that depend on complex physical models, the proposed learning-based method is much faster. The experimental results show that the measurement accuracy can be increased effectively by the presented method.

Targeting FcγRIIB by antagonistic antibody BI-1206 improves the efficacy of rituximab-based therapies in aggressive mantle cell lymphoma.

Inevitable relapses remain as the major therapeutic challenge in patients with mantle cell lymphoma (MCL) despite FDA approval of multiple targeted therapies and immunotherapies. Fc gamma receptors (FcγRs) play important roles in regulating antibody-mediated immunity. FcγRIIB, the unique immune-checkpoint inhibitory member of the FcγR family, has been implicated in immune cell desensitization and tumor cell resistance to the anti-CD20 antibody rituximab and other antibody-mediated immunotherapies; however, little is known about its expression and its immune-modulatory function in patients with aggressive MCL, especially those with multi-resistance. In this study, we found that FcγRIIB was ubiquitously expressed in both MCL cell lines and primary patient samples. FcγRIIB expression is significantly higher in CAR T-relapsed patient samples (p < 0.0001) compared to ibrutinib/rituximab-naïve, sensitive or resistant samples. Rituximab-induced CD20 internalization in JeKo-1 cells was completely blocked by concurrent treatment with BI-1206, a recombinant human monoclonal antibody targeting FcγRIIB. Combinational therapies with rituximab-ibrutinib, rituximab-venetoclax and rituximab-CHOP also induced CD20 internalization which was again effectively blocked by BI-1206. BI-1206 significantly enhanced the in vivo anti-MCL efficacy of rituximab-ibrutinib (p = 0.05) and rituximab-venetoclax (p = 0.02), but not the rituximab-CHOP combination in JeKo-1 cell line-derived xenograft models. In patient-derived xenograft (PDX) models, BI-1206, as a single agent, showed high potency (p < 0.0001, compared to vehicle control) in one aggressive PDX model that is resistant to both ibrutinib and venetoclax but sensitive to the combination of rituximab and lenalidomide (the preclinical mimetic of R2 therapy). BI-1206 sensitized the efficacy of rituximab monotherapy in a PDX model with triple resistance to rituximab, ibrutinib and CAR T-therapies (p = 0.030). Moreover, BI-1206 significantly enhanced the efficacy of the rituximab-venetoclax combination (p < 0.05), which led to long-term tumor remission in 25% of mice. Altogether, these data support that targeting this new immune-checkpoint blockade enhances the therapeutic activity of rituximab-based regimens in aggressive MCL models with multi-resistance.

Mechanism of the Photodegradation of A-D-A Acceptors for Organic Photovoltaics*.

Herein, we elucidate the photodegradation pathway of A-D-A-type non-fullerene acceptors for organic photovoltaics. Using IT-4F as a benchmark example, we isolated the photoproducts and proved them isomers of IT-4F formed by a 6-e electrocyclic reaction between the dicyanomethylene unit and the thiophene ring, followed by a 1,5-sigmatropic hydride shift. This photoisomerization was accelerated under inert conditions, as explained by DFT calculations predicting a triplet-mediated reaction path (quenchable by oxygen). Adding controlled amounts of the photoproduct P1 to PM6:IT-4F bulk heterojunction cells led to a progressive decrease in photocurrent and fill factor attributed to its poor absorption and charge transport properties. The reaction is a general photodegradation pathway for a series of A-D-A molecules with 1,1-dicyanomethylene-3-indanone termini, and its rate varies with the structure of the donor and acceptor moiety.