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Background: This study aims to identify symptom clusters in patients with intermediate and advanced liver cancer receiving targeted immunotherapy, focusing on core and bridge symptoms to establish a foundation for precise symptom management. Methods: This study used a cross-sectional survey and utilized convenience sampling from May 2023 to January 2024 at a third-class hospital in Shanghai, China. The severity of symptoms in liver cancer patients during treatment was evaluated using the Memorial Symptom Assessment Scale. Network analysis was employed to depict the interrelation of symptom clusters and identify core and bridge symptoms. Results: The symptoms were classified by severity into five clusters: oral, gastrointestinal, fatigue-related, body image, and pain-sleep. Within the symptom network, the core symptoms were pain, “I don’t look like myself,” and nausea, while the critical bridge symptoms included pain, itching, and feeling bloated. The strongest connections were observed between nausea and vomiting, followed by taste changes and dry mouth, as well as weight loss and “I don’t look like myself.” Conclusion: In patients receiving targeted immunotherapy for intermediate and advanced liver cancer, multiple symptoms can emerge simultaneously, forming interconnected clusters. By identifying and intervening in core and bridge symptoms, personalized management strategies can be developed to relieve other symptoms and disrupt connections between symptom clusters, thereby enhancing symptom management efficacy. This study has significant clinical and research implications, offering new insights to improve patients’ quality of life and treatment outcomes. [ABSTRACT FROM AUTHOR]

Abstract Breast cancer (BC) is the second-leading factor of mortality for women globally and is brought on by a variety of genetic and environmental causes. The conventional treatments for this disease have limitations, making it difficult to improve the lifespan of breast cancer patients. As a result, extensive research has been conducted over the past decade to find innovative solutions to these challenges. Targeting of the antitumor immune response through the immunomodulatory checkpoint protein B7 family has revolutionized cancer treatment and led to intermittent patient responses. B7-H3 has recently received attention because of its significant demodulation and its immunomodulatory effects in many cancers. Uncontrolled B7-H3 expression and a bad outlook are strongly associated, according to a substantial body of cancer research. Numerous studies have shown that BC has significant B7-H3 expression, and B7-H3 induces an immune evasion phenotype, consequently enhancing the survival, proliferation, metastasis, and drug resistance of BC cells. Thus, an innovative target for immunotherapy against BC may be the B7-H3 checkpoint. In this review, we discuss the structure and regulation of B7-H3 and its double costimulatory/coinhibitory function within the framework of cancer and normal physiology. Then we expound the malignant behavior of B7-H3 in BC and its role in the tumor microenvironment (TME) and finally focus on targeted drugs against B7-H3 that have opened new therapeutic opportunities in BC.

Breast cancer (BC) is the second-leading factor of mortality for women globally and is brought on by a variety of genetic and environmental causes. The conventional treatments for this disease have limitations, making it difficult to improve the lifespan of breast cancer patients. As a result, extensive research has been conducted over the past decade to find innovative solutions to these challenges. Targeting of the antitumor immune response through the immunomodulatory checkpoint protein B7 family has revolutionized cancer treatment and led to intermittent patient responses. B7-H3 has recently received attention because of its significant demodulation and its immunomodulatory effects in many cancers. Uncontrolled B7-H3 expression and a bad outlook are strongly associated, according to a substantial body of cancer research. Numerous studies have shown that BC has significant B7-H3 expression, and B7-H3 induces an immune evasion phenotype, consequently enhancing the survival, proliferation, metastasis, and drug resistance of BC cells. Thus, an innovative target for immunotherapy against BC may be the B7-H3 checkpoint. In this review, we discuss the structure and regulation of B7-H3 and its double costimulatory/coinhibitory function within the framework of cancer and normal physiology. Then we expound the malignant behavior of B7-H3 in BC and its role in the tumor microenvironment (TME) and finally focus on targeted drugs against B7-H3 that have opened new therapeutic opportunities in BC. [ABSTRACT FROM AUTHOR]

Aim: The present study aims to generate chimeric mouse single-chain variable fragment (scFv) and immunoglobulin G1 (IgG1) crystallizable fragment (Fc) antibody against disialoganglioside (GD2) for the treatment of neuroblastoma (NB). The generated scFv-IgG Fc antibody, lacking first constant domain of heavy chain (CH1), is of a smaller size than the natural antibody and has anti-tumor activity. Methods: Vector for scFv-IgG Fc antibody was constructed and scFv-IgG Fc antibody was expressed in human embryonic kidney 293T (HEK293T) cell line. Purification of scFv-IgG Fc antibody from the culture supernatant of transfected HEK293T cells was performed by Protein G affinity chromatography. The structure and binding activity of scFv-IgG Fc antibody were verified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), western blotting (WB), and immunofluorescence techniques. Anti-tumor activities by antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) were determined. Results: Using plasmid fusion-human IgG1-Fc2 tag vector (pFUSE-hIgG1-Fc2), a plasmid vector encoding chimeric mouse scFv and hIgG1 Fc antibody against GD2 was successfully constructed. This vector was transfected into human HEK293T cells to produce scFv-IgG Fc antibody. The transfected HEK293T cells could produce chimeric scFv-IgG Fc antibody against GD2, which lacks the IgG heavy chain CH1 domain but carries CH2 and CH3 domains. The chimeric antibodies could be purified from the culture supernatant of the transfected HEK293T culture in the presence of zeocin drug. The produced GD2 scFv-IgG Fc antibodies, which are smaller in size than the intact antibody, could trigger the killing of GD2 expressed NB cell line SH-SY5Y by ADCC and ADCP mechanisms. Conclusions: The results indicate that chimeric scFv-hIgG Fc antibody, lacking heavy chain CH1 domain, could mediate antibody induced anti-tumor activities. The small size of this type of chimeric antibody may be employed as anti-GD2 antibody for NB therapy.

Gangliosides are glycosphingolipids with prevalence in nervous tissue and their involvement in certain neuronal diseases have been widely known. Interestingly, many recent studies highlighted their importance in the development and progression of various cancers through orchestration of multiple attributes of tumorigenesis, i.e., promoting migration, invasion, escaping the host immune system, and influencing other cancer hallmarks. Therefore, the multidimensional role of gangliosides in different cancers has established them as potential cancer targets. However, the tremendous structural complexity and functional heterogeneity are the major challenges in ganglioside research. Moreover, despite numerous immunotherapeutic attempts to target different gangliosides, it has failed to yield consistent results in clinical trials owing to their poor immunogenicity, a broad range of cross-reactivity, severe side effects, lack of uniform expression as well as heterogeneity. The recent identification of selective O-acetylated ganglioside expression in cancer tissues, but not in normal tissues, has strengthened their potential as a better and specific target for treating cancer patients. It was further supported by reduced cross-reactivity and side effects in clinical trials, although poor immunogenicity remains a major concern. Therefore, in addition to characterization and identification of the biological importance of O-acetylated gangliosides, their specific and efficient targeting in cancer through engineered antibodies is an emerging area of glycobiology research. This review highlights the modulatory effect of select gangliosides on different hallmarks of cancer and presents the overall development of ganglioside targeted immunotherapies along with recent progress. Here, we have also discussed its potential for future modifications aimed towards improvement in ganglioside-based cancer therapies. [ABSTRACT FROM AUTHOR]

Gangliosides are glycosphingolipids with prevalence in nervous tissue and their involvement in certain neuronal diseases have been widely known. Interestingly, many recent studies highlighted their importance in the development and progression of various cancers through orchestration of multiple attributes of tumorigenesis, i.e., promoting migration, invasion, escaping the host immune system, and influencing other cancer hallmarks. Therefore, the multidimensional role of gangliosides in different cancers has established them as potential cancer targets. However, the tremendous structural complexity and functional heterogeneity are the major challenges in ganglioside research. Moreover, despite numerous immunotherapeutic attempts to target different gangliosides, it has failed to yield consistent results in clinical trials owing to their poor immunogenicity, a broad range of cross-reactivity, severe side effects, lack of uniform expression as well as heterogeneity. The recent identification of selective O-acetylated ganglioside expression in cancer tissues, but not in normal tissues, has strengthened their potential as a better and specific target for treating cancer patients. It was further supported by reduced cross-reactivity and side effects in clinical trials, although poor immunogenicity remains a major concern. Therefore, in addition to characterization and identification of the biological importance of O-acetylated gangliosides, their specific and efficient targeting in cancer through engineered antibodies is an emerging area of glycobiology research. This review highlights the modulatory effect of select gangliosides on different hallmarks of cancer and presents the overall development of ganglioside targeted immunotherapies along with recent progress. Here, we have also discussed its potential for future modifications aimed towards improvement in ganglioside-based cancer therapies.

Harnessing innate immunity is an appealing strategy for cancer treatment. Herein, we report a new strategy called molecularly imprinted nanobeacons (MINBs) for redirecting innate immune killing towards triple‐negative breast cancer (TNBC). The MINBs were molecularly imprinted nanoparticles with the N‐epitope of glycoprotein nonmetastatic B (GPNMB) as the template and grafted with plentiful fluorescein moieties as the hapten. The MINBs could tag the TNBC cells via binding with GPNMB and thereby provide navigation for recruiting hapten‐specific antibodies. The gathered antibodies could further trigger effective Fc‐domain‐mediated immune killing towards the tagged cancer cells. In vivo experiments showed that the TNBC growth was significantly inhibited after MINBs treatment by intravenous injection as compared with control groups. This study not only opens a new access for redirecting innate immunity towards TNBC but also paves the way for innate immunity‐based therapy of other diseases. [ABSTRACT FROM AUTHOR]

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Lung cancer is one of the most prevalent cancer types and the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80-85% of all cancer incidences. Lung cancer therapy and prognosis largely depend on the disease’s degree at the diagnosis time. Cytokines are soluble polypeptides that contribute to cell-to-cell communication, acting paracrine or autocrine on neighboring or distant cells. Cytokines are essential for developing neoplastic growth, but they are also known to operate as biological inducers following cancer therapy. Early indications are that inflammatory cytokines such as IL-6 and IL-8 play a predictive role in lung cancer. Nevertheless, the biological significance of cytokine levels in lung cancer has not yet been investigated. This review aimed to assess the existing literature on serum cytokine levels and additional factors as potential immunotherapeutic targets and lung cancer prognostic indicators. Changes in serum cytokine levels have been identified as immunological biomarkers for lung cancer and predict the effectiveness of targeted immunotherapy.

Background: The treatment of myasthenia gravis (MG) has advanced from steroids and traditional immunosuppressants to targeted immunotherapy. Targeted immunotherapy has been successfully employed in clinical practice in recent years. This study aimed to explore the emerging trend of targeted immunotherapy in MG and summarize the knowledge structure through bibliometric methods. Methods: The Web of Science Core Collection database (WoSCC) was chosen to retrieve the literature on targeted immunotherapy for MG. Two bibliometric analysis software, VOSviewer and CiteSpace, and bibliometric online platform were mainly used to evaluate the contributions from countries/regions, institutions, journals, and authors through the construction and visualization of bibliometric networks. By systematically reviewing a knowledge domain, future research developments were determined. The R version 4.1.2 and Microsoft Excel 365 were used for statistical analysis. Results: A total of 562 original articles and 262 reviews relevant to MG targeted immunotherapy were included. The number of publications on targeted immunotherapy for MG exhibited a two-phase advancement. The first stage showed a steady growth trend from 1998 to 2016, with an annual number of no more than 35 publications. The second stage revealed an explosive growth trend from 2017, reaching a peak number of publications in 2020. The United States ranked first in the number of publications, citations, and h-index. The author with the highest citation and h-index was Vincent A. And 28.03% of the articles were published in the top 10 journals. In addition to “myasthenia gravis”, the keyword with the highest consideration was “rituximab”, followed by “double-blind”, which indicate research hotspots gradually from basic research to clinical research over time, especially in the field of targeted immunotherapy. The MG treatment has entered a personalized precision treatment phase. Exploration into new target molecules and conducting high-quality randomized controlled trials on existing biological agents are the further research direction. Conclusion: The current study summarized the global research trends concerning targeted immunotherapy for MG. Research interests gradually advanced from basic research to clinical research. MG treatment has entered a personalized precision treatment phase. Further investigations into new target molecules and high-quality randomized controlled trials on existing biological agents are required urgently to direct future immunotherapy research. [ABSTRACT FROM AUTHOR]

In addition to identifying the major B- and T-cell subpopulations involved in autoimmune rheumatic diseases (ARDs), in recent years special attention has been paid to studying the expression of their activation markers and immune checkpoints (ICPs). The activation markers on B and T cells are a consequence of the immune response, and these molecules are considered as sensitive specific markers of ARD activity and as promising targets for immunotherapy. ICPs regulate the activation of the immune response by preventing the initiation of autoimmune processes, and they modulate it by reducing immune cell-induced organ and tissue damage. The article considers the possible correlation of ICPs with the activity of ARDs, the efficacy of specific ARD treatments, and the prospects for the use of activation molecules and activation/blocking ICPs for the treatment of ARDs. [ABSTRACT FROM AUTHOR]

Targeted therapy has revolutionized the management of ANCA-associated vasculitis (AAV) over the last fifteen years. Rituximab, an approved induction and maintenance agent for severe AAV, is no less effective than cyclophosphamide as induction therapy and particularly useful in relapsing or refractory disease, or in women. In patients with relapsing AAV, granulomatosis with polyangiitis or PR3-ANCA, it is more effective than cyclophosphamide. Rituximab maintenance is superior to the conventional immunosuppressive drugs that it replaces. Low-dose preemptive rituximab infusions are recommended every 6months for 18months, followed by re-evaluation to decide whether 4 additional biannual infusions should be administered, balancing the probability of relapse and the risk of serious infections on rituximab. A growing body of experimental and clinical data shows that C5a pathway inhibition is a promising therapeutic option for AAV, which could reduce glucocorticoids needs. Avacopan is a first approved oral C5A receptor antagonist, used when there is a high risk that glucocorticoids will cause serious adverse events. In eosinophilic granulomatosis with polyangiitis, the importance of IL-5 for eosinophil activation and survival led to evaluation and approval of mepolizumab, a humanized monoclonal antibody directed against IL-5. Mepolizumab showed a steroid-sparing effect. Its effectiveness in active vasculitis remains uncertain and is currently being evaluated. Benralizumab targeting the IL-5 receptor was recently shown to be noninferior to mepolizumab. Rituximab has had disappointing results in non-severe active vasculitis and is being evaluated as maintenance therapy. Plasma exchange is not indicated as first-line treatment but remains recommended when creatinine levels exceed 300μmol/L., (Copyright © 2024 The Author. Published by Elsevier Masson SAS.. All rights reserved.)

Bladder cancer (BC) is one of the most important tumors of the genitourinary system, associated with high morbidity and mortality rates. Over the years, various antitumor treatments have been developed, and immunotherapy is one of the most effective methods. Immunotherapy aims to activate the body's immune system to kill cancer cells. It has been established that immunotherapy drugs can be classified into "non-targeted" and "targeted" drugs depending on their site of action. Immunotherapy is reportedly effective for BC. Even though it can attack cancer cells, it can also cause the immune system to attack healthy cells, which can occur at any time during treatment and sometimes even after immunotherapy is stopped. Importantly, different types of immunotherapies can cause different side effects. Side effects may manifest themselves as signs or as symptoms. The prevention and treatment of side effects caused by immunotherapy is an important part of cancer patient management. [ABSTRACT FROM AUTHOR]

Bladder cancer (BC) is one of the most important tumors of the genitourinary system, associated with high morbidity and mortality rates. Over the years, various antitumor treatments have been developed, and immunotherapy is one of the most effective methods. Immunotherapy aims to activate the body’s immune system to kill cancer cells. It has been established that immunotherapy drugs can be classified into “non-targeted” and “targeted” drugs depending on their site of action. Immunotherapy is reportedly effective for BC. Even though it can attack cancer cells, it can also cause the immune system to attack healthy cells, which can occur at any time during treatment and sometimes even after immunotherapy is stopped. Importantly, different types of immunotherapies can cause different side effects. Side effects may manifest themselves as signs or as symptoms. The prevention and treatment of side effects caused by immunotherapy is an important part of cancer patient management.

The prognosis for children with recurrent and/or refractory neuroblastoma (NB) is dismal. The receptor tyrosine kinase-like orphan receptor 1 (ROR1), which is highly expressed on the surface of NB cells, provides a potential target for novel immunotherapeutics. Anti-ROR1 chimeric antigen receptor engineered ex vivo expanded peripheral blood natural killer (anti-ROR1 CAR exPBNK) cells represent this approach. N-803 is an IL-15 superagonist with enhanced biological activity. In this study, we investigated the in vitro and in vivo anti-tumor effects of anti-ROR1 CAR exPBNK cells with or without N-803 against ROR1 + NB models. Compared to mock exPBNK cells, anti-ROR1 CAR exPBNK cells had significantly enhanced cytotoxicity against ROR1 + NB cells, and N-803 further increased cytotoxicity. High-dimensional analysis revealed that N-803 enhanced Stat5 phosphorylation and Ki67 levels in both exPBNK and anti-ROR1 CAR exPBNK cells with or without NB cells. In vivo, anti-ROR1 CAR exPBNK plus N-803 significantly ( p  < 0.05) enhanced survival in human ROR1 + NB xenografted NSG mice compared to anti-ROR1 CAR exPBNK alone. Our results provide the rationale for further development of anti-ROR1 CAR exPBNK cells plus N-803 as a novel combination immunotherapeutic for patients with recurrent and/or refractory ROR1 + NB., Competing Interests: This was presented in part at Transplantation & Cellular Therapy Meetings of the American Society for Transplantation and Cellular Therapy (2019). M.S.C. has served as a consultant for Jazz Pharmaceuticals, Omeros Pharmaceuticals, Servier Pharmaceuticals, Abbvie, and Novartis Pharmaceuticals; Speakers Bureau for Jazz Pharmaceuticals, Servier Pharmaceuticals, Amgen, Inc., Sanofi, and Sobi; Advisory Board for Astra Zeneca; and research funding from Celularity, Merck, Miltenyi Biotec, Servier, Omeros, Jazz, and Janssen. D.A.L. reports personal fees and other from Kiadis Pharma, CytoSen Therapeutics, Courier Therapeutics, and Caribou Biosciences outside the submitted work. In addition, D.A.L. has a patent broadly related to NK cell therapy of cancer with royalties paid to Kiadis Pharma. T.P.C. recently served as a one-time consultant to Blueprint, Incyte, Oncopeptides, DSMB chair for SpringWorks, and is a cofounder of Vironexis Biotherapeutics, Inc., (© 2024 The Authors.)

Background: This study aimed to investigate the safety and efficacy of preoperative targeted immunotherapy followed by surgical resection for hepatocellular carcinoma (HCC) patients with macrovascular invasion. Method: Clinical information of HCC patients with macrovascular invasion was collected from four medical centers. These patients were divided into two cohorts: the upfront surgery group (n=40) and the neoadjuvant group (n=22). Comparisons between the two groups were made with appropriate statistical methods. Results: HCC Patients with macrovascular invasion in the neoadjuvant group were associated with increased incidence of postoperative ascites (72.73% vs. 37.5%, P=0.008), but shorter postoperative hospital stay (10 days vs. 14 days, P=0.032). Furthermore, targeted immunotherapy followed by surgical resection significantly reduced the postoperative recurrence rate at both 3 months and 1 year (9% versus 28.9%, 32.1% versus 67.9%, respectively; P=0.018), but increased the postoperative nononcologic mortality rate within 1 year (20.1% vs. 2.8%; P= 0.036). Conclusion: For HCC patients with macrovascular invasion, preoperative targeted immunotherapy significantly decreased the postoperative tumor recurrence rate while maintaining relative safety, but such a treatment may also result in chronic liver damage and increased risk of nononcologic mortality., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

In addition to identifying the major B- and T-cell subpopulations involved in autoimmune rheumatic diseases (ARDs), in recent years special attention has been paid to studying the expression of their activation markers and immune checkpoints (ICPs). The activation markers on B and T cells are a consequence of the immune response, and these molecules are considered as sensitive specific markers of ARD activity and as promising targets for immunotherapy. ICPs regulate the activation of the immune response by preventing the initiation of autoimmune processes, and they modulate it by reducing immune cell-induced organ and tissue damage. The article considers the possible correlation of ICPs with the activity of ARDs, the efficacy of specific ARD treatments, and the prospects for the use of activation molecules and activation/blocking ICPs for the treatment of ARDs.

Malignant ascites occurs as a symptom of the terminal stage of cancer, affecting the quality of life through abdominal distension, pain, nausea, anorexia, dyspnea and other symptoms. We describe the current main drug treatments in addition to surgery according to the traditional and new strategies. Traditional treatments were based on anti-tumor chemotherapy and traditional Chinese medicine treatments, as well as diuretics to relieve the patient's symptoms. New treatments mainly involve photothermal therapy, intestinal therapy and targeted immunity. This study emphasizes that both traditional and new therapies have certain advantages and disadvantages, and medication should be adjusted according to different periods of use and different patients. In conclusion, this article reviews the literature to systematically describe the primary treatment modalities for malignant ascites. [Display omitted] ● Malignant ascites as a symptom of the terminal stage of cancer. ● Pharmacological treatment options other than surgery for malignant ascites are essential to relieve patients' suffering. ● The main therapeutic drugs and treatments are summarized. [ABSTRACT FROM AUTHOR]

Pyroptosis, a newly discovered form of programmed cell death, has emerged as a promising antitumor approach by releasing pro-inflammatory cytokines and immunogenic substances upon cell rupture. However, non-specific pyroptosis potentially causes systemic damage to healthy tissues, and the heterogeneity of tumors limits the anti-tumor effect of pyroptosis. To address these challenges, we propose a simple yet powerful method for creating multifunctional hybrid oncolytic virus-mimicking nanovesicles (HVMNVs) that possess tumor-targeting capabilities, adjuvant activity, and the ability to evade immune clearance induced by virus modification. Based on this multifunctional nanovesicle, we developed a functional nanoparticle (HVMNVs@Fe-C) that significantly enhances the tumor targetability and cell uptake efficiency of the extremely small iron oxide nanoparticles (ESIONPs) and carbonyl cyanide m-chlorophenyl hydrazone (CCCP), leading to rapid tumor pyroptosis. More importantly, HVMNVs@Fe-C ingeniously achieves a synergistic effect by incorporating the adjuvantic and tumor-targeting properties of oncolytic viruses with the cell lytic and pro-inflammatory functions of pyroptosis in a single nanoparticle. This leads to a cascade of specific anti-tumor immune responses and reprogramming of the immunosuppressive tumor microenvironment, resulting in excellent tumor inhibition efficacy against primary melanoma growth and pulmonary metastasis. Overall, our novel strategy offers considerable promise for precisive targeted delivery and cancer immunotherapy. [Display omitted] • HVMNVs@Fe-C combines oncolytic virus adjuvanticity with pyroptosis for potent synergy. • Mimicking oncolytic virus envelopes, HVMNVs@Fe-C enhances tumor targeting and uptake. • HVMNVs@Fe-C evades immune clearance linked to virus modification. • HVMNVs@Fe-C achieves outstanding efficacy against melanoma growth and metastasis. [ABSTRACT FROM AUTHOR]

Generalized pustular psoriasis (GPP) is a rare, inflammatory skin disease characterized by recurrent flares of pustulation accompanied by systemic symptoms. Due to its acuteness, sufficient diagnosis and treatment are essential, but often face challenges. We recently overviewed various treatment options of GPP utilizing established therapies in psoriasis vulgaris (PsO). Although there is a pathogenic relation to PsO, more and more evidence suggests a predominant involvement of the innate immune system in GPP. Recent discoveries on the genetic background of GPP with underlying mutations in IL36RN, CARD14, AP1S3 and SERPINA3 contributed to a better understanding of the pathogenesis and provide major opportunities in the development of innovative, targeted therapies. The proposed umbrella term "autoinflammatory keratinization diseases" (AIKD) helps to categorize this heterogeneous disease. Finally, we address the problem of insufficient standardized assessment tools and propose a reproducible scoring system also capturing the systemic features of GPP. In summary, GPP is a prototype disease to demonstrate both obstacles and progress in dermatology—currently insufficient definition and diagnostic tools on the one hand side, yet major advances in dissecting disease heterogeneity, opportunities for novel diagnostic techniques and therapeutic decision‐making based on molecular events on the other side. [ABSTRACT FROM AUTHOR]

In this investigation, a DNA sequence was designed and synthesized by joining coding regions of soluble programmed cell death-1 and T-cell immunoglobulin and mucin-3 domains and cloned into the lentiviral expression vector pLVX-IRES-ZsGreen1. After infection of the recombinant lentivirus into HEK 293T cells, the recombinant fusion protein, designated as sP1T3, was successfully expressed as detected by Western blotting. Binding assay was performed by incubating the cell lysate with cancer cells, which have high expressional levels of PD-L1/2 and galectin 9 and subsequent fluorescent staining showed strong membranous signals compared to negative controls using cell lysate without sP1T3, suggesting specific binding of sP1T3 to these ligand-expressing cancer cells. The recombinant fusion protein sP1T3 provided a useful tool for studying the effect of dual-blockade of immune checkpoint and its potential in targeted immunotherapy of cancer, which needs further investigation. [ABSTRACT FROM AUTHOR]

An effective therapy regimen for relapsed/refractory high-risk neuroblastoma (NB) includes the anti-GD2 monoclonal antibody, dinutuximab, in combination with temozolomide and irinotecan, supporting a role for chemo-immunotherapy in NB. γδ T cells are an attractive anti-tumor immunotherapy because of their direct cytotoxic activity mediated through cell surface receptors NKG2D and CD16. NKG2D facilitates the innate recognition of stress-induced ligands whereas CD16 recognizes antibody bound to tumors and activates mechanisms of antibody-dependent cellular cytotoxicity (ADCC). This study demonstrates an efficient method for expanding and storing γδ T cells from NB patient-derived apheresis products at clinically relevant amounts. The expanded patient-derived γδ T cells were cytotoxic against the K562 cell line and multiple NB cell lines. Combining γδ T cells with dinutuximab led to a 30% increase in tumor cell lysis compared to γδ T cells alone. Furthermore, low-dose temozolomide in combination with expanded γδ T cells and dinutuximab resulted in increased IFNγ secretion and increased γδ T-cell surface expression of FasL and CD107a. IMR5 NB cell line xenografts established subcutaneously in NSG mice were treated with a regimen of dinutuximab, temozolomide, and γδ T cells. This combination caused targeted killing of NB xenografts in vivo, reducing tumor burden and prolonging survival. These data support the continued preclinical testing of dinutuximab and temozolomide in conjunction with γδ T-cell immunotherapy for patients with recurrent/refractory NB.

Multiple myeloma (MM) remains an incurable plasma cells malignancy because of its complex genetic heterogeneity and high relapse rate post immunotherapy. The encouraging results of chimeric antigen receptor T cell (CAR-T) targeting B cell maturation antigen (BCMA) immunotherapy clinical trials have shed light on curing MM in recent years. However, many therapeutic side effects limit the promotion and clinical use of this novel effective approach such as cytokine release syndrome, antigen escape, and neurotoxicity. We should make every effort to do further study about this immunotherapy to make it safer and effective. This review focusing on this topic clarifies the following contents: present status of MM treatment, effectiveness of CAR-T cells, features of BCMA, preclinical and clinical trials of BCMA CAR-T cells therapy, and existing problems and strategies. Hoping to provide a reference for the subsequent correlative clinical and research. [ABSTRACT FROM AUTHOR]

Generalized pustular psoriasis (GPP) is a rare, multisystemic skin disease characterized by recurrent episodes of pustulation. GPP can be life‐threatening and is often difficult to treat. In the era of precision medicine in dermatology, GPP stands exemplary for both challenges and chances—while new treatments offer great hope, there is urgent need for better definition and stratification of this severe and heterogeneous disease. Our objective was to systematically review the literature for evidence of efficacy of targeted immunotherapy and their mode of action in the context of clinical phenotype, classification and pathogenesis of adult GPP. Classifying GPP is challenging since clinical criteria for description and diagnosis are not consistent between expert centres. We therefore defined diagnostic feasibility of the reviewed cases by assessing four criteria: compatible clinical history, typical dermatological features and/or diagnostic histopathology, consistent clinical pictures and the DITRA status. Pathogenesis of GPP is mediated by pathways that partly overlap plaque type psoriasis, with a more pronounced activity of the innate immune system. Both IL‐1 and IL‐36 but also IL‐17 play a major role in disease formation. We ascertained a total of 101 published cases according to our predefined criteria and identified TNF‐α, IL‐12/23, IL‐17 and IL‐1β as targets for immunotherapy for the treatment of GPP. Of those cases, 61% showed complete response and 27% partial response to targeted immunotherapy. Only 12% experienced weak or no response. These data indicate that specific immunotherapy can be used to effectively treat GPP, with most evidence existing for anti‐IL‐17 agents. [ABSTRACT FROM AUTHOR]

The treatment of multiple myeloma (MM) has entered into a new era of immunotherapy. Novel immunotherapies will significantly improve patient outcome via simultaneously targeting malignant plasma cell (PC) and reversing immunocompromised bone marrow (BM) microenvironment. B-cell maturation antigen (BCMA), selectively expressed in PCs and a key receptor for A proliferation-inducing ligand (APRIL), is highly expressed in MM cells from patients at all stages. The APRIL/BCMA signal cascades promote the survival and drug resistance of MM cells and further modulate immunosuppressive BM milieu. Impressively, anti-BCMA immunotherapeutic reagents, including chimeric antigen receptor (CAR), antibody-drug conjugate (ADC) and bispecific T cell engager (BiTE) have all shown high response rates in their first clinical trials in relapse and refractory patients with very limited treatment options. These results rapidly inspired numerous development of next-generation anti-BCMA biotherapeutics, i.e., bispecific molecule, bispecific or trispecific antibodies, a novel form of CAR T/NK cells and T Cell Antigen Coupler (TAC) receptors, antibody-coupled T cell receptor (ACTR) as well as a cancer vaccine. We here highlight seminal preclinical and clinical studies on novel BCMA-based immunotherapies as effective monotherapy and discuss their potential in combination with current anti-MM and novel checkpoint drugs in earlier disease stages to further achieve durable responses in patients.

In the last 20 years there has been a huge increase in the number of novel drugs for cancer treatment. Most of them exploit their ability to target specific oncogenic mutations in the tumors (targeted therapies−TT), while others target the immune-checkpoint inhibitor molecules (ICI) or the epigenetic DNA modifications. Among them, TT are the longest established drugs exploited against a wide spectrum of both solid and hematological tumors, often with reasonable costs and good efficacy as compared to other innovative therapies (i.e., ICI). Although they have greatly improved the treatment of cancer patients and their survival, patients often relapse or develop drug-resistance, leading to the impossibility to eradicate the disease. The outcome of TT has been often correlated with their ability to affect not only tumor cells, but also the repertoire of immune cells and their ability to interact with cancer cells. Thus, the possibility to create novel synergies among drugs an immunotherapy prompted scientists and physicians to deeply characterize the effects of TT on immune cells both by in-vitro and by ex-vivo analyses. In this context, NK cells may represent a key issue, since they have been shown to exert a potent anti-tumor activity, both against hematological malignancies and solid tumors. In the present review we will discuss most recent ex-vivo analyses that clarify the effect of TT treatment on patient's NK cells comparing them with clinical outcome and previous in-vitro data.

The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the incorporation of this new class of agents with current MM therapies. However, both antigens are also expressed on other normal tissues including hematopoietic lineages and immune effector cells, which may limit their long-term clinical use. B cell maturation antigen (BCMA), a transmembrane glycoprotein in the tumor necrosis factor receptor superfamily 17 (TNFRSF17), is expressed at significantly higher levels in all patient MM cells but not on other normal tissues except normal plasma cells. Importantly, it is an antigen targeted by chimeric antigen receptor (CAR) T-cells, which have already shown significant clinical activities in patients with RRMM who have undergone at least three prior treatments, including a proteasome inhibitor and an immunomodulatory agent. Moreover, the first anti-BCMA antibody–drug conjugate also has achieved significant clinical responses in patients who failed at least three prior lines of therapy, including an anti-CD38 antibody, a proteasome inhibitor, and an immunomodulatory agent. Both BCMA targeting immunotherapies were granted breakthrough status for patients with RRMM by FDA in Nov 2017. Other promising BCMA-based immunotherapeutic macromolecules including bispecific T-cell engagers, bispecific molecules, bispecific or trispecific antibodies, as well as improved forms of next generation CAR T cells, also demonstrate high anti-MM activity in preclinical and even early clinical studies. Here, we focus on the biology of this promising MM target antigen and then highlight preclinical and clinical data of current BCMA-targeted immunotherapies with various mechanisms of action. These crucial studies will enhance selective anti-MM response, transform the treatment paradigm, and extend disease-free survival in MM.

Human gamma delta T cells have extraordinary properties including the capacity for tumor cell killing. The major gamma delta T cell subset in human beings is designated Vγ9Vδ2 and is activated by intermediates of isoprenoid biosynthesis or aminobisphosphonate inhibitors of farnesyldiphosphate synthase. Activated cells are potent for killing a broad range of tumor cells and demonstrated the capacity for tumor reduction in murine xenotransplant tumor models. Translating these findings to the clinic produced promising initial results but greater potency is needed. Here, we review the literature on gamma delta T cells in cancer therapy with emphasis on the Vγ9Vδ2 T cell subset. Our goal was to examine obstacles preventing effective Vγ9Vδ2 T cell therapy and strategies for overcoming them. We focus on the potential for local activation of Vγ9Vδ2 T cells within the tumor environment to increase potency and achieve objective responses during cancer therapy. The gamma delta T cells and especially the Vγ9Vδ2 T cell subset, have the potential to overcome many problems in cancer therapy especially for tumors with no known treatment, lacking tumor-specific antigens for targeting by antibodies and CAR-T, or unresponsive to immune checkpoint inhibitors. Translation of amazing work from many laboratories studying gamma delta T cells is needed to fulfill the promise of effective and safe cancer immunotherapy.

Targeted cancer immunotherapy with irradiated, granulocyte–macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic cancer cell lines has been an effective approach to reduce tumor burden in several patients. It is generally assumed that to be effective, these cell lines need to express immunogenic antigens coexpressed in patient tumor cells, and antigen-presenting cells need to take up such antigens then present them to patient T cells. We have previously reported that, in a phase I pilot study (ClinicalTrials.gov NCT00095862), a subject with stage IV breast cancer experienced substantial regression of breast, lung, and brain lesions following inoculation with clinical formulations of SV-BR-1-GM, a GM-CSF-secreting breast tumor cell line. To identify diagnostic features permitting the prospective identification of patients likely to benefit from SV-BR-1-GM, we conducted a molecular analysis of the SV-BR-1-GM cell line and of patient-derived blood, as well as a tumor specimen. Compared to normal human breast cells, SV-BR-1-GM cells overexpress genes encoding tumor-associated antigens (TAAs) such as PRAME, a cancer/testis antigen. Curiously, despite its presumptive breast epithelial origin, the cell line expresses major histocompatibility complex (MHC) class II genes (HLA-DRA, HLA-DRB3, HLA-DMA, HLA-DMB), in addition to several other factors known to play immunostimulatory roles. These factors include MHC class I components (B2M, HLA-A, HLA-B), ADA (encoding adenosine deaminase), ADGRE5 (CD97), CD58 (LFA3), CD74 (encoding invariant chain and CLIP), CD83, CXCL8 (IL8), CXCL16, HLA-F, IL6, IL18, and KITLG. Moreover, both SV-BR-1-GM cells and the responding study subject carried an HLA-DRB3*02:02 allele, raising the question of whether SV-BR-1-GM cells can directly present endogenous antigens to T cells, thereby inducing a tumor-directed immune response. In support of this, SV-BR-1-GM cells (which also carry the HLA-DRB3*01:01 allele) treated with yellow fever virus (YFV) envelope (Env) 43–59 peptides reactivated YFV-DRB3*01:01-specific CD4+ T cells. Thus, the partial HLA allele match between SV-BR-1-GM and the clinical responder might have enabled patient T lymphocytes to directly recognize SV-BR-1-GM TAAs as presented on SV-BR-1-GM MHCs. Taken together, our findings are consistent with a potentially unique mechanism of action by which SV-BR-1-GM cells can act as APCs for previously primed CD4+ T cells.

As is well understood that malignant tumour progression requires additional blood vessels to provide the nutrients necessary for growth. Many patients with advanced hepatocellular carcinoma (aHCC) experience disease progression after treatment with lenvatinib (Lenva) and immune checkpoint inhibitors (ICIs). Therefore, we designed a double-arm retrospective study to evaluate the antitumour activity of additional bevacizumab (Beva, an anti-vascular endothelial growth factor-targeting drug) as a means to reduce the blood vessels needed for tumour growth. Compared with the control group, the group that received Beva had prolonged progression-free survival (PFS) and a trend toward a benefit for overall survival duration. This study aimed to evaluate the anticancer effect of Beva in patients with aHCC who experienced tumour progression after treatment with Lenva+ICIs. From April 2021 to March 2023, we retrospectively included 20 patients as the experimental group and 21 patients as the control group. The patients in the experimental group experienced disease progression after receiving targeted therapy and ICIs, after which we added Beva to the treatment. The patients in the control group only received targeted therapy and ICIs. The efficacy endpoints were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and disease control rate (DCR), which were evaluated according to RECIST v1.1. Adverse events were assessed using NCI-CTCAE v5.0. Ultimately, 20 patients with aHCC in the experimental group of received Beva after disease progression, compared with 21 patients in the control group. The median OS was 12.6 mo (95% CI: 6.8-18.7) vs. 9.3 mo (95% CI: 4.3-14.4), and the median PFS was 6.9 mo (95% CI: 6.4-7.4) vs. 4.1 mo (95% CI: 2.4-5.8). The ORR for all patients was 5%, and the DCR for all patients was 70.0%. The median follow-up time for all patients was 7.5 mo (95% CI: 5.0-10.0). All patients had adverse events, but no fatal adverse events were observed. In conclusion, Bevacizumab is a drug resistant treatment option for patients with advanced hepatocellular carcinoma after Lenva+PD-1/PD-L1 treatment., Competing Interests: None., (AJCR Copyright © 2023.)

Abstract Precision medicine holds great promise to harness genetic and epigenetic cues for targeted treatment of a variety of diseases, ranging from many types of cancers, neurodegenerative diseases, to cardiovascular diseases. The proteomic profiles resulting from the unique genetic and epigenetic signatures represent a class of relatively well accessible molecular targets for both interrogation (e.g. , diagnosis, prognosis) and intervention (e.g. , targeted therapy) of these diseases. Aptamers are promising for such applications by specific binding with cognate disease biomarkers. Nucleic acid aptamers are a class of DNA or RNA with unique three-dimensional conformations that allow them to specifically bind with target molecules. Aptamers can be relatively easily screened, reproducibly manufactured, programmably designed, and chemically modified for various biomedical applications, including targeted therapy. Aptamers can be chemically modified to resist enzymatic degradation or optimize their pharmacological behaviors, which ensured their chemical integrity and bioavailability under physiological conditions. In this review, we will focus on recent progress and discuss the challenges and opportunities in the research areas of aptamer-based targeted therapy in the forms of aptamer therapeutics and aptamer-drug conjugates (ApDCs). Graphical abstract Unlabelled Image [ABSTRACT FROM AUTHOR]

The approval of the first two monoclonal antibodies targeting CD38 (daratumumab) and SLAMF7 (elotuzumab) in late 2015 for treating relapsed and refractory multiple myeloma (RRMM) was a critical advance for immunotherapies for multiple myeloma (MM). Importantly, the outcome of patients continues to improve with the incorporation of this new class of agents with current MM therapies. However, both antigens are also expressed on other normal tissues including hematopoietic lineages and immune effector cells, which may limit their long-term clinical use. B cell maturation antigen (BCMA), a transmembrane glycoprotein in the tumor necrosis factor receptor superfamily 17 (TNFRSF17), is expressed at significantly higher levels in all patient MM cells but not on other normal tissues except normal plasma cells. Importantly, it is an antigen targeted by chimeric antigen receptor (CAR) T-cells, which have already shown significant clinical activities in patients with RRMM who have undergone at least three prior treatments, including a proteasome inhibitor and an immunomodulatory agent. Moreover, the first anti-BCMA antibody–drug conjugate also has achieved significant clinical responses in patients who failed at least three prior lines of therapy, including an anti-CD38 antibody, a proteasome inhibitor, and an immunomodulatory agent. Both BCMA targeting immunotherapies were granted breakthrough status for patients with RRMM by FDA in Nov 2017. Other promising BCMA-based immunotherapeutic macromolecules including bispecific T-cell engagers, bispecific molecules, bispecific or trispecific antibodies, as well as improved forms of next generation CAR T cells, also demonstrate high anti-MM activity in preclinical and even early clinical studies. Here, we focus on the biology of this promising MM target antigen and then highlight preclinical and clinical data of current BCMA-targeted immunotherapies with various mechanisms of action. These crucial studies will enhance selective anti-MM response, transform the treatment paradigm, and extend disease-free survival in MM. [ABSTRACT FROM AUTHOR]

Abstract: Ovarian cancer stem cells (OCSCs) are highly carcinogenic and have very strong resistance to traditional chemotherapeutic drugs; therefore, they are an important factor in ovarian cancer metastasis and recurrence. It has been reported that dendritic cell (DC)‐cytokine‐induced killer (CIK) cells have significant killing effects on all cancer cells across many systems including the blood, digestive, respiratory, urinary and reproductive systems. However, whether DC‐CIK cells can selectively kill OCSCs is currently unclear. In this study, we collected ovarian cancer patient menstrual blood (OCPMB) samples to acquire mononuclear cells and isolated DC‐CIK cells in vitro. In addition, autologous CD44+/CD133+ OCSCs were isolated and used as target cells. The experimental results showed that when DC‐CIK cells and OCSCs were mixed and cultured in vitro at ratios of 5:1, 10:1 and 50:1, the DC‐CIK cells killed significant amounts of OCSCs, inhibited their invasion in vitro and promoted their apoptosis. The qPCR and Western blot results showed that DC‐CIK cells stimulated high expression levels and phosphorylation of TNFR1, ASK1, AIP1 and JNK in OCSCs through the release of TNF‐α. After the endogenous TNFR1 gene was knocked out in OCSCs using the CRISPR/Cas9 technology, the killing function of DC‐CIK cells on target OCSCs was significantly attenuated. The results of the analyses of clinical samples suggested that the TNFR1 expression level was negatively correlated with ovarian cancer stage and prognosis. Therefore, we innovatively confirmed that DC‐CIK cells derived from OCPMB could secret TNF‐α to activate the expression of the TNFR1‐ASK1‐AIP1‐JNK pathway in OCSCs and kill autologous OCSCs. [ABSTRACT FROM AUTHOR]

Human gamma delta T cells have extraordinary properties including the capacity for tumor cell killing. The major gamma delta T cell subset in human beings is designated Vγ9Vδ2 and is activated by intermediates of isoprenoid biosynthesis or aminobisphosphonate inhibitors of farnesyldiphosphate synthase. Activated cells are potent for killing a broad range of tumor cells and demonstrated the capacity for tumor reduction in murine xenotransplant tumor models. Translating these findings to the clinic produced promising initial results but greater potency is needed. Here, we review the literature on gamma delta T cells in cancer therapy with emphasis on the Vγ9Vδ2 T cell subset. Our goal was to examine obstacles preventing effective Vγ9Vδ2 T cell therapy and strategies for overcoming them. We focus on the potential for local activation of Vγ9Vδ2 T cells within the tumor environment to increase potency and achieve objective responses during cancer therapy. The gamma delta T cells and especially the Vγ9Vδ2 T cell subset, have the potential to overcome many problems in cancer therapy especially for tumors with no known treatment, lacking tumor-specific antigens for targeting by antibodies and CAR-T, or unresponsive to immune checkpoint inhibitors. Translation of amazing work from many laboratories studying gamma delta T cells is needed to fulfill the promise of effective and safe cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Targeted cancer immunotherapy with irradiated, granulocyte-macrophage colonystimulating factor (GM-CSF)-secreting, allogeneic cancer cell lines has been an effective approach to reduce tumor burden in several patients. It is generally assumed that to be effective, these cell lines need to express immunogenic antigens coexpressed in patient tumor cells, and antigen-presenting cells need to take up such antigens then present them to patient T cells. We have previously reported that, in a phase I pilot study (ClinicalTrials.gov NCT00095862), a subject with stage IV breast cancer experienced substantial regression of breast, lung, and brain lesions following inoculation with clinical formulations of SV-BR-1-GM, a GM-CSF-secreting breast tumor cell line. To identify diagnostic features permitting the prospective identification of patients likely to benefit from SV-BR-1-GM, we conducted a molecular analysis of the SV-BR-1-GM cell line and of patient-derived blood, as well as a tumor specimen. Compared to normal human breast cells, SV-BR-1-GM cells overexpress genes encoding tumor-associated antigens (TAAs) such as PRAME, a cancer/testis antigen. Curiously, despite its presumptive breast epithelial origin, the cell line expresses major histocompatibility complex (MHC) class II genes (HLA-DRA, HLA-DRB3, HLA-DMA, HLA-DMB), in addition to several other factors known to play immunostimulatory roles. These factors include MHC class I components (B2M, HLA-A, HLA-B), ADA (encoding adenosine deaminase), ADGRE5 (CD97), CD58 (LFA3), CD74 (encoding invariant chain and CLIP), CD83, CXCL8 (IL8), CXCL16, HLA-F, IL6, IL18, and KITLG. Moreover, both SV-BR-1-GM cells and the responding study subject carried an HLA-DRB3*02:02 allele, raising the question of whether SV-BR-1-GM cells can directly present endogenous antigens to T cells, thereby inducing a tumor-directed immune response. In support of this, SV-BR-1-GM cells (which also carry the HLA-DRB3*01:01 allele) treated with yellow fever virus (YFV) envelope (Env) 43-59 peptides reactivated YFV-DRB3*01:01-specific CD4+ T cells. Thus, the partial HLA allele match between SV-BR-1-GM and the clinical responder might have enabled patient T lymphocytes to directly recognize SV-BR-1-GM TAAs as presented on SV-BR-1-GM MHCs. Taken together, our findings are consistent with a potentially unique mechanism of action by which SV-BR-1-GM cells can act as APCs for previously primed CD4+ T cells. [ABSTRACT FROM AUTHOR]

Targeted immunotherapy of high-grade cervical intra-epithelial neoplasia (CIN) has been developed as an alternative to conization, to preserve future reproductive outcomes and avoid human papillomavirus (HPV) persistence. The objectives of the review are to present drugs according to their process of development and to examine their potential future use. A search for key words associated with CIN and targeted immunotherapy was carried out in the Cochrane library, Pubmed, Embase, and ClinicalTrials.gov from 1990 to 2016. Publications (randomized, prospective and retrospective studies) in any language were eligible for inclusion, as well as ongoing trials registered on the ClinicalTrials.gov website. Targeted immunotherapy includes peptide/protein-based vaccines, nucleic acid-based vaccines (DNA), and live vector-based vaccines (bacterial or viral). A total of 18 vaccines were identified for treatment of CIN at various stages of development, and the majority were well-tolerated. Adverse effects were primarily injection site reactions and flu-like symptoms under grade 2. The efficacy of vaccines defined by regression of CIN2/3 to no CIN or CIN1 ranged from 17 to 59% following a minimum of a 12-week follow-up. In the majority of studies, there was no association demonstrated between histological response and HPV clearance, or between histological or virological response and immune T cell response. Given that the spontaneous regression of CIN2/3 is 20-25% at 6 months, targeted immunotherapy occurs an additional value, which never reaches 50%, with one trial an exception to this. However, research and development on HPV eradication drugs needs to be encouraged, due to HPV-associated disease burden. [ABSTRACT FROM AUTHOR]

Facilitating the development of alternative targeted therapeutic strategies is urgently required to improve outcome or circumvent chemotherapy resistance in children, adolescents, and adults with recurrent/refractory de novo mature B-cell (CD20) non-Hodgkin lymphoma, including Burkitt lymphoma (BL). Romidepsin, a histone deacetylase inhibitor (HDACi), has been used to treat cutaneous T-cell lymphoma. We have demonstrated the significant anti-tumor effect of anti-CD20 chimeric antigen receptor (CAR) modified expanded peripheral blood natural killer (exPBNK) against rituximab-sensitive and -resistant BL. This study examined the anti-tumor activity of romidepsin alone and in combination with anti-CD20 CAR exPBNKs against rituximab-sensitive and -resistant BL in vitro and in vivo. We found that romidepsin significantly inhibited both rituximab-sensitive and -resistant BL cell proliferation in vitro (P < 0.001) and induced cell death in rituximab-sensitive Raji (P < 0.001) and cell cycle arrest in rituximab-resistant Raji-2R and Raji-4RH (P < 0.001). Consistent with in vitro observations, we also found romidepsin significantly inhibited the growth of rituximab-sensitive and -resistant BL in BL xenografted NSG mice. We also demonstrated that romidpesin significantly induced the expression of Natural Killer Group 2, Member D (NKG2D) ligands MICA/B in both rituximab-sensitive and -resistant BL cells (P < 0.001) resulting in enhancement of exPBNK in vitro cytotoxicity through NKG2D. Finally, we observed the combination of romidepsin and anti-CD20 CAR exPBNK significantly induced cell death in BL cells in vitro, reduced tumor burden and enhanced survival in humanized BL xenografted NSG mice (p < 0.05). Our data suggests that romidepsin is an active HDAC inhibitor that also potentiates expanded NK and anti-CD20 CAR exPBNK activity against rituximab-sensitive and -resistant BL.

Minimal/measurable residual disease (MRD) is the most important independent prognostic factor for patients with B-lymphoblastic leukemia (B-LL). MRD post therapy has been incorporated into risk stratification and clinical management, resulting in substantially improved outcomes in pediatric and adult patients. Currently, MRD in B-ALL is most commonly assessed by multiparametric flow cytometry and molecular (polymerase chain reaction or high-throughput sequencing based) methods. The detection of MRD by flow cytometry in B-ALL often begins with B cell antigen-based gating strategies. Over the past several years, targeted immunotherapy directed against B cell markers has been introduced in patients with relapsed or refractory B-ALL and has demonstrated encouraging results. However, targeted therapies have significant impact on the immunophenotype of leukemic blasts, in particular, downregulation or loss of targeted antigens on blasts and normal B cell precursors, posing challenges for MRD detection using standard gating strategies. Novel flow cytometric approaches, using alternative strategies for population identification, sometimes including alternative gating reagents, have been developed and implemented to monitor MRD in the setting of post targeted therapy., (© 2023 International Clinical Cytometry Society.)

Flow cytometry has been indispensable in diagnosing B cell lymphoma and plasma cell neoplasms. The advances in novel multicolor flow cytometry have also made this technology a robust tool for monitoring minimal/measurable residual disease in chronic lymphocytic leukemia and multiple myeloma. However, challenges using conventional gating strategies to isolate neoplastic B or plasma cells are emerging due to the rapidly increasing number of antibody therapeutics targeting single or multiple classic B/plasma cell-lineage markers, such as CD19, CD20, and CD22 in B cells and CD38 in plasma cells. This review is the first of a two-part series that summarizes the most current targeted therapies used in B and plasma cell neoplasms and proposes detailed alternative approaches to overcome post-targeted therapy analysis challenges by flow cytometry. The second review in this series (Chen et al.) focuses on challenges encountered in the use of targeted therapy in precursor B cell neoplasms., (© 2022 International Clinical Cytometry Society.)

An introduction is presented in which the author refers to the topic of treatment of septic shock patients, and talks of depletion of lymphocytes through apoptosis, role of IL7R messenger RNA, and benefits of immunology-based therapy.