Peripheral Lymph Nodes Research Articles

Evaluation of the Efficacy of Combined Sentinel Lymph Node Biopsy Using Patent Blue Dye and Peripheral Lymph Node Biopsy in Management of Nodal Negative Early Breast Cancer

Evaluation of the Efficacy of Combined Sentinel Lymph Node Biopsy Using Patent Blue Dye and Peripheral Lymph Node Biopsy in Management of Nodal Negative Early Breast Cancer

Optimal placement of a dissimilar node for chaos suppression in networks

We demonstrate that the presence of a single dissimilar chaotic system suppresses chaos in networks of chaotic oscillators, in a diverse set of network topologies, for sufficiently strong coupling. The key property is determined to be the sum of the path lengths between the dissimilar node and all the other nodes (or its maximum, if coupled to unconnected networks), and there exists a linear relation between this quantity and the critical coupling strength for the onset of a spatiotemporal fixed point. This holds true for a chain with the dissimilar node at different locations, a ring and complete network with one embedded dissimilar node, as well as star networks with a dissimilar hub or dissimilar peripheral node. Furthermore, we show that networks with high average degree and high clustering coefficient are more resilient to the influence of an external dissimilar system. These findings will potentially aid in the design of optimally placed dissimilar nodes for controlling chaos in complex networks.

LYMPHOSCORE (Lymphoscintigraphy Scoring Reliability) Reliability of a New Qualitative and Semiquantitative Lymphoscintigraphy Scoring System for Primary Lymphedema.

Primary lymphedema (PLE) is a rare chronic disorder. Extremity lymphoscintigraphy offers access for dynamic and functional information on peripheral lymphatics and lymph nodes. We aimed to assess intraobserver and interobserver reliability of a new lymphoscintigraphy quantitative and qualitative scoring system in a homogeneous population of adult patients followed for PLE of the lower limb(s). This is a monocentric retrospective study. Clinical files of patients who underwent a lymphoscintigraphy were reviewed for inclusion. Lymphoscintigraphies were interpreted twice by 2 observers with a washout period. To assess intraobserver and interobserver reliability for both lower limbs, Cohen κ and Gwet's AC1 reliability coefficients were calculated with 95% confidence interval and P value of the zero-reliability comparison test. To interpret reliability coefficients, we used the orders of magnitude reported by Landis and Koch. One hundred forty-four patients (288 limbs) with PLE were included. For intraobserver reliability, agreement range was 0.87-1 with an almost perfect agreement in all staging items of the score for both limbs with the lower limit of the 95% confidence interval ≥80%. Interobserver reliability was overall strong or almost perfect, ranging from 0.67 to 0.97. This new scoring system demonstrated excellent intraobserver reliability and a very good interobserver reliability. Lymphoscintigraphy, when performed in a referral center and interpreted by trained nuclear medicine physicians, is a reliable means of investigation in patients with PLE of the lower limbs. This reproducibility advocates for further use of lymphoscintigraphy in multicentric cohorts of PLE patients.

Abstract PO-025: Identifying tissue-specific drivers of immune evasion in Mantle Cell Lymphoma at single cell level

Abstract Background: Mantle cell lymphoma (MCL) is an aggressive subtype of B-cell non-Hodgkin lymphoma that exhibits clinical, pathological, and genetic heterogeneity. While generally thought to be incurable, recently demonstrated clinical activity of both chimeric antigen receptor T (CAR-T) cells and bispecific antibodies suggest that immune-mediated therapies offer substantial benefit in this disease and underscores the value of understanding mechanisms of immune evasion in this disease. Aim: The aim of this project is to uncover distinct cellular networks driving immune evasion in MCL across disease sites. Methods: We analyzed 10 archival samples collected from 8 clinically annotated patients with untreated MCL, including mononuclear cells from peripheral blood (PB), lymph nodes (LN) and bone marrow (BM). After generating single-cell suspensions from tumors, we performed Cellular Indexing of Transcriptomes and Epitopes sequencing (CITE-seq) and identified malignant B cells based on the co-expression of cyclin D1 (CCND1) and B cell markers (MS4A1, CD79A, CD79B). B and T cells were then subclustered using a reference mapping geneset. Molecular signatures database was utilized to perform geneset enrichment analysis (GSEA). Results: Our study first confirms the heterogeneity of mantle cell lymphoma across compartments (i.e PB, LN, BM), showing 5 different clusters of malignant cells, with different abundance in cell proportion among patients. We found that malignant B cells expressed different levels of CCND1 expression across tissue compartments. Furthermore, we identified a specific cluster of malignant cells, enriched in the PB, marked by decreased expression of the costimulatory receptor CD40 and higher levels of B-cell receptor signaling. This may explain the rapid response of circulating MCL cells to Bruton Tyrosine Kinase (BTK) inhibition. Interestingly, the higher expression of CD40 on LN-resident MCL cells suggests that MCL cells may co-opt LN-resident T-cells to support their growth, as has been previously described. Consistent with this, T-cells from LN were phenotypically exhausted, suggesting that MCL cells within the LN leverage local interactions with T-cells to promote survival while avoiding T-cell-driven cytotoxicity. Finally, we also found that high level of Ki67 correlates with myeloid-cell abundance in the TME suggesting that monocytes may support tumor cell proliferation. Conclusion: These results provide a deeper understanding of tissue-specific heterogeneity in MCL, including distinct tumor-immune interactions at different tissue sites. In ongoing analyses, we will correlate these findings with patient outcomes and response to BTK inhibition and are currently analyzing samples from patients with relapsed disease to identify microenvironmental features associated with disease progression. Citation Format: Amira Marouf, Jahan Rahman, Ashlee Joseph, Irem Isgor, Ya-Hui Lin, Ronan Chaligne, Shenon Sethi, Ahmet Dogan, Gilles Salles, Anita Kumar, Santosha A Vardhana. Identifying tissue-specific drivers of immune evasion in Mantle Cell Lymphoma at single cell level [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-025.

Ectopic pleural thymoma with T-cell lymphocytosis and bone metastasis: a case report

BackgroundThe diagnostic complexities that arise in radiographic distinction between ectopic pleural thymoma and other thoracic neoplasms are substantial, with instances of co-occurring T-cell lymphocytosis and osseous metastasis being exceedingly rare.Case presentationA 51-year-old woman was admitted to our hospital with dyspnea and chest pain. Upon imaging examination, she was found to have diffuse and nodular pleural thickening on the left side, collapse of the left lung and a compression in the second thoracic vertebrae. All lesions showed significant 18F-FDG uptake on 18F-FDG PET/CT examination. Furthermore, she exhibited T-cell lymphocytosis in her peripheral blood, lymph nodes, and bone marrow. After ruling out malignant pleural mesothelioma (MPM), lung cancer with pleural metastasis, and T-cell lymphoma, the definitive diagnosis asserted was ectopic pleural thymoma with T-cell lymphocytosis and bone metastasis.ConclusionPhysicians need to expand their knowledge of the imaging features of ectopic pleural thymoma. Cases with T-cell lymphocytosis may exhibit increased aggressiveness and prone to bone metastasis.

Group 3 innate lymphoid cells promotes Th17 cells differentiation in rheumatoid arthritis.

To investigate the correlation between innate lymphoid cell (ILC) subsets with T-helper (Th) cells and to explore the effect of ILCs on T cells in rheumatoid arthritis (RA). We analysed the frequencies of ILC subsets in RA patients with varying disease activity and their correlation with Th cell subsets. We further investigated this correlation in various organs of collagen-induced arthritis (CIA) mice. The effects of ILCs on CD4+ T cells were determined by in vitro cell co-culture experiments. ILCs were less frequent in RA patients than in healthy controls, with higher levels of group 3 ILCs (ILC3s) in RA (p<0.05). ILC3s correlated positively with Th1 and Th17 cells in RA peripheral blood (p<0.05). In the peripheral blood, spleen, and lymph nodes of CIA, ILC3s decreased and then increased during arthritis progression. ILC3s correlated positively with Th1 and Th17 cells in the spleen and lymph nodes of CIA (p<0.05). NKp46+ ILC3s in the spleen positively correlated with Th1 and Th17 cells (p<0.05). Under Th17 cell differentiation conditions, co-culturing CIA-derived ILC3s directly with naive CD4+ T cells promoted Th17 differentiation and increased IL-17 secretion. However, co-culturing through a transwell insert impeded Th17 differentiation without affecting IL-17 secretion. ILC3s positively correlated with Th1 and Th17 cells in RA. In CIA, the frequencies of ILC3s changed with disease development and showed a positive correlation with Th1 and Th17 cells. ILC3s may facilitate the differentiation of Th17 cells through direct cell-cell contact.

Scrutinizing prognostic scores’ effectiveness in non-Hodgkin’s lymphomas with primary lymph node involvement

Introduction. Non-Hodgkin lymphoma (NHL) encompasses a diverse group of malignancies arising from malignant proliferation of lymphocytes, each subtype characterized by unique epidemiological, etiological, and clinical features. Prognostication is essential for guiding treatment decisions and improving patient outcomes. Prognostic scores, including traditional and molecular systems, offer insights into survival prediction. The aim of the present study was to evaluate the applicability of traditional prognostic scores based on clinical markers and laboratory biomarkers in predicting the outcomes of patients with primary nodal NHL. Materials and methods. This study included 78 NHL patients treated at the Chisinau Oncological Institute from 2017 to 2021. Clinical and biological data were collected, and the following prognostic scores were calculated: International Prognostic Index (IPI), The combined index of hemoglobin, albumin, lymphocyte, and platelet (HALP score), Platelet to Lymphocyte Ratio (PLR), Neutrophil to Lymphocyte Ratio (NLR), Albumin/Globulin ratio (AG), and Charlson comorbidity index (CCI). Statistical analyses, including descriptive statistics, ROC curve analysis, and Kaplan-Meier survival curves, were conducted. Results. Of the patients, 40 (51.2%) were female, with a mean age of 57.1 ± 10.2 years. Peripheral lymph nodes were predominantly affected (84.6%), with diffuse large B-cell lymphoma being the most prevalent subtype (59.0%). Prognostic scores, including the International Prognostic Index (IPI), Hemoglobin, Albumin, Lymphocyte, and Platelet (HALP) score, and Charlson Comorbidity Index (CCI), demonstrated varying levels of discriminatory ability in predicting overall survival (OS). Notably, the HALP score (AUC = 0.650; p = 0.026), IPI (AUC = 0.745; p = 0.0002), and CCI (AUC = 0.636; p = 0.043) were statistically significant predictors of OS. Conclusions. Traditional prognostic scores (IPI. HALP score, CCI) offer valuable prognostic information for NHL patients. Further research is needed to validate these findings and explore cost-effective prognostic strategies.

Diagnostic approach of tuberculous lymphadenitis in a multicenter study.

Tuberculous lymphadenitis (TBLN) is the most common infectious etiology of peripheral lymphadenopathy in adults, in Turkiye. This study aimed to identify the demographic, clinical, and laboratory variables that differentiate TBLN from non-tuberculous lymphadenitis (NTBLN), as well as the etiology of lymphadenopathy in adults. Patients who were over 18 years old and were referred to the infectious disease outpatient clinics with complaints of swollen peripheral lymph nodes, and who underwent lymph node biopsy between 1 January 2010 and 1 March 2021, were included in this multicenter, nested case-control study. A total of 812 patients at 17 tertiary teaching and research hospitals in Turkiye were included in the study. TBLN was the most frequent diagnosis (53.69%). The proportion of patients diagnosed with TBLN was higher among females; and among those who had a higher erythrocyte sedimentation rate, positive purified protein derivative test, and positive interferon-gamma release test result (p < 0.05). However, TBLN was less frequent among patients with generalized lymphadenopathy, bilateral lymphadenopathy, axillary lymphadenopathy, inguinal lymphadenopathy, hepatomegaly, splenomegaly, leukocytosis, and moderately increased C reactive protein levels (p < 0.05). Identifying the variables that predict TBLN or discriminate TBLN from NTBLN will help clinicians establish optimal clinical strategies for the diagnosis of adult lymphadenopathy.

Biomarkers and Signaling Pathways Implicated in the Pathogenesis of Idiopathic Multicentric Castleman Disease/Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis, Renal Insufficiency, and Organomegaly (TAFRO) Syndrome.

Idiopathic multicentric Castleman disease (iMCD) and TAFRO syndrome present a variety of symptoms thought to be caused by excessive inflammatory cytokines and chemokines, but the underlying mechanisms are unknown. iMCD is broadly classified into two types: iMCD-NOS and iMCD-TAFRO, which have distinct laboratory findings, pathological features, and responses to treatments. It is thought that iMCD-NOS, particularly the IPL type, responds favorably to IL-6 inhibitors due to its IL-6-centric profile. iMCD-TAFRO frequently progresses acutely and seriously, similar to TAFRO syndrome. Elevated levels of cytokines, including IL-1β, TNF-α, IL-10, and IL-23, as well as chemokines like CXCL13 and CXCL-10 (especially in iMCD-TAFRO), SAA, and VEGF, have been linked to the disease's pathology. Recent research has identified key signaling pathways including PI3K/Akt/mTOR and JAK-STAT3, as well as those regulated by type I IFN, as crucial in iMCD-TAFRO. These results suggest that dominant pathways may vary between subtypes. Further research into the peripheral blood and lymph nodes is required to determine the disease spectrum of iMCD-NOS/iMCD-TAFRO/TAFRO syndrome.

Plasma, intracellular and lymph node antiretroviral concentrations and HIV DNA change during primary HIV infection: Results from the INACTION P25 study

Despite its effectiveness, combination antiretroviral treatment (cART) has a limited effect on HIV DNA reservoir, which establishes early during primary HIV infection (PHI) and is maintained by latency, homeostatic T-cells proliferation, and residual replication. This limited effect can be associated with low drug exposure in lymphoid tissues and/or suboptimal adherence to antiretroviral drugs (ARVs). The aim of this study was to assess ARV concentrations in plasma, peripheral blood mononuclear cells (PBMCs) and lymph nodes (LNs), and their association to HIV RNA and HIV DNA decay during PHI. Participants were randomised to receive standard doses of darunavir/cobicistat (Arm I), dolutegravir (Arm II) or both (Arm III), with a backbone of tenofovir alafenamide and emtricitabine. Total HIV DNA was measured using digital-droplet PCR in PBMCs at baseline, 12 and 48 weeks. Drug concentrations in plasma and PBMCs were determined at 2, 12 and 48 weeks (LNs at 12 weeks) by UHPLC-MS/MS. Seventy-two participants were enrolled, mostly male (n=68), with a median age of 34 years and variable Fiebig stages (V–VI 57.7%, I–II 23.9%, and III–IV 18.3%). Twenty-six patients were assigned to Arm I, 27 to Arm II and 19 to Arm III. After 48 weeks, most patients had undetectable viremia, with minor differences in HIV RNA decay between arms. Patients with Fiebig I–II showed faster HIV RNA and HIV DNA decay. Intracellular tissue penetration was high for nucleoside analogues and low-moderate for darunavir and dolutegravir. Only tenofovir diphosphate concentrations in PBMCs showed correlation with HIV DNA decay. Overall, these results indicate that the timing of treatment initiation and intracellular tenofovir penetration are primary and secondary factors, respectively, affecting HIV reservoir.

Detecting the core of a network by the centralities of the nodes

Abstract Many networks exhibit the core/periphery structure. Core/periphery structure is a type of meso-scale structure that consists of densely connected core nodes and sparsely connected peripheral nodes. Core nodes tend to be well-connected, both among themselves and to peripheral nodes, which tend not to be well-connected to other nodes. In this brief report, we propose a new method to detect the core of a network by the centrality of each node. It is discovered that such nodes with non-negative centralities often consist in the core of the networks. The simulation is carried out on different real networks. The results are checked by the objective function. The checked results may show the effectiveness of the simulation results by the centralities of the nodes on the real networks. Furthermore, we discuss the characters of networks with the single core/periphery structure and point out the scope of the application of our method at the end of this paper.

Enhancing core–periphery robustness of networks against link-based attacks with imprecise information

Core-Periphery structure, as a critical mesoscale structure, is commonly found in diverse real-world networks, in which nodes are endogenously categorized as core or peripheral nodes by the underlying interconnection patterns. It plays an important role in sustaining the intrinsic order and functional behavior of networked systems. However, despite the study on inherent core–periphery vulnerabilities to node removals, little is known on the core–periphery robustness when networks are suffering from the attacks that happen on links between nodes, especially for the more practical situations where attackers have limited ability to obtain precise network information. In this paper, a novel index is proposed for measuring the capacity of the core–periphery structure to resist link-based attacks. By introducing an attack precision parameter, we establish a unified evaluation framework for link-based attacks with imprecise information, which divides attack behaviors into localized attacks and non-localized attacks, and treats the usual random attacks and targeted attacks as the two special situations of our non-localized case. Several enhancing algorithms guided by our index with local search strategy are exquisitely devised, and experimental results are provided to demonstrate the efficacy of our framework and algorithms that remarkably improve the core–periphery robustness against link-based attacks with imprecise information.

Clinical Spectrum and Frequency of Bone Marrow Infiltration in Hodgkin Lymphoma Patients Presenting to a Tertiary Care Hospital

Background and Objectives: Hodgkin lymphoma (HL) is a lymphoid malignancy that affects peripheral lymph nodes as well as organs like lungs, liver and bone marrow. It has 05 types. The clinical features of HL include lymphadenopathy and constitutional 'B' symptoms (fever, night sweats &amp; weight loss). This study was conducted to describe the clinical spectrum and frequency of bone marrow infiltration in Hodgkin lymphoma patients presenting to Hematology department of AIMC Lahore.Methods: This descriptive study has utilized data of known cases of HL, referred by Oncology department for bone marrow biopsy from January 2019 to December 2022, retrieved from medical records. Information was noted regarding demographic profile of the patient along with the clinical features, type of HL and infiltration of bone marrow. Data were analyzed using SPSS version 24.0.Results: The study consisted of 24 HL patients between 10 to 60 years of age. The median age was 41 years. There were 21 male (87.5%) and 03 female (12.5%) patients (male-to-female ratio: 7:1). Lympha-denopathy was the predominant clinical feature present in all 24(100%) patients followed by 'B” symptoms in 09(37.5%) cases while bone marrow infiltration was present in 7 (29.1%) patients.Conclusion: Lymphadenopathy serves as a distinctive clinical feature of Hodgkin lymphoma and presence of bone marrow infiltration may be reasonable factor for accurate disease staging.Keywords: Hodgkin lymphoma, lymphoid malignancy, bone marrow infiltration, staging

The compensatory role of T cells from lymph nodes in mice with splenectomy.

The spleen is a vital organ for the immune system, while splenectomy may be necessary for various reasons. However, there is limited research on the impact of splenectomy on T cell function in peripheral lymph nodes as a compensatory mechanism in preventing infections. This study aimed to investigate the characteristics and function of CD8+ and CD4+ T cells in different peripheral lymph nodes during viral infection using a well-established splenectomy model. The results revealed that splenectomy caused an increase in CD8+GP33+ T cells in the mesenteric lymph nodes (MLN). Moreover, we demonstrated that splenectomy resulted in an increase of effector KLRG1+ T cells in the MLN. Additionally, the number of CD4+ cytotoxic T cells (CD4 CTLs) was also elevated in the peripheral lymph nodes of mice with splenectomy. Surprisingly, aged mice exhibited a stronger compensatory ability than adult mice, as evidenced by an increase in effector CD8+ T cells in all peripheral lymph nodes. These findings provide compelling evidence that T cells in MLN play a crucial role in protecting individuals with splenectomy against viral infections. The study offers new insights into understanding the changes in the immune system of individuals with splenectomy and highlights the potential compensatory mechanisms involved by T cells in peripheral lymph nodes.

Energy-Recognition Clustering Technique Based on Reinforcement Learning In WSN

WSN (Wireless Sensor Network) technology has recently gained a lot of attention. This began with the deployment of small WSNs and moved to the deployment of big and IoT WSNs, all with an emphasis on energy conservation. Wireless sensor networks can benefit from network clustering to increase their energy efficiency. The practise of dividing nodes into clusters before picking multiple cluster heads is known as network clustering (CHs). Clustering in wireless sensor networks is known to save energy and extend the network's lifetime (WSNs). Energy efficiency is a hot topic in existing wireless sensor networks, although it's not generally discussed. In this research, we offer a reinforcement learning (RL) based energy-aware clustering approach, whereby peripheral cluster nodes monitor environmental factors like energy use and choose an optimal cluster leader (CH). Connect the CH (BS) to the base station. In the simulation (PDR), performance factors such as network lifetime, energy tax, network stability period, and packet delivery rate are all taken into account. The simulation results show that the proposed QL-ReLeC performs around 11% better than the reference protocol in terms of PDR and 11% better in terms of energy tax.

Financialized Labor and the Fissured Workplace: An Institutionalist Understanding of Distribution Under Money Manager Capitalism

This article examines how changing economic structures and the development of the financialized business enterprise has affected labor relations and distribution under the stage of money manager capitalism as described by Hyman Minsky and Charles Whalen. Key to this transformation, I argue, is the development of what David Weil refers to as the fissured workplace and what David Peetz calls “not there capitalism.” In this context, the business enterprise operates as a network, with commands emanating from the center to be carried out by the periphery. Labor, then, contracts with these peripheral nodes, separating them from key economic decision-making processes. This reduction in power has significant implications for distribution. Using Christopher Brown’s power-based approach to the institutional theory of distribution, I then examine these impacts, especially as it pertains to workers in the gig economy before concluding with an overview of potential policy recommendations to correct these issues.

Investigation of Risk Factors for Lumpy Skin Disease and Prevention Practices in Dak Lak, Vietnam, 2021–2022

Lumpy skin disease is a transboundary animal disease primarily affecting cattle, and causing fever, anorexia, skin nodules, mastitis, swelling of peripheral lymph nodes, nasal discharge, watery eyes, and sometimes mortality. The disease was first detected in Vietnam in October 2020 and has spread to 55 out of 63 provinces with around 210,000 cattle and buffaloes infected. Dak Lak was one of the provinces seriously affected by the disease. A retrospective case-control study in three districts of the province was conducted to assess awareness of the disease among local livestock holders and to determine potential risk factors for disease transmission. A total of 276 holdings known to keep cattle or buffalo, including 138 cases (holdings that had at least one animal with clinical signs of the disease) and 138 controls (holdings with no clinically apparent infected animal), were investigated. The study revealed gaps in knowledge and practices among livestock holders on disease control with median scores of 8/20 for knowledge and 5/9 for practices. Vaccination against lumpy skin disease was the only risk factor significantly associated with disease transmission (adjusted odds ratio 0.39, 95% confidence interval 0.21–0.72). We recommend raising the awareness of livestock owners about the risk factors of lumpy skin disease and the importance of vaccination for better prevention and control of outbreaks.

Sexual Dimorphism in the Physiopathology and Immune Response during Acute Toxocara canis Infection.

Toxocara canis (T. canis) is a helminth parasite of zoonotic and veterinary health significance that causes the disease known as Toxocariasis. This disease has been associated with conditions of poverty, especially in tropical climate zones throughout the world. Although it rarely causes important clinical manifestations, T. canis can lead to blindness, meningoencephalitis, or other nervous manifestations in humans. Moreover, some studies show its importance in the development of tumor growth, which have been associated with the parasite's ability to modulate the host's immune response. While different studies have evaluated the immune response during this disease, currently, there are no studies where the infection is analyzed from the perspective of sexual dimorphism. To evaluate sex differences in susceptibility, we analyzed lesions and parasite loads in lung and liver at 7 days post-infection. In addition, immune cell subpopulations were analyzed in spleen, mesenteric and peripheral lymph nodes. Finally, the production of cytokines and specific antibodies were determined in the serum. Statical analyses were performed using a Two-way ANOVA and a post-hoc Bonferroni multiple comparison test. Female rats had a higher number of larvae in the liver, while male rats had them in the lungs. The percentages of immune cells were evaluated, and in most cases, no significant differences were observed. Regarding the cytokines production, infection can generate a decrease in Th1 such as IL-1β in both sexes and IL-6 only in females. In the case of Th2, IL-4 increases only in infected males and IL-5 increases in males while decreasing in females due to the effect of infection. IL-10 also decreases in both sexes as a consequence of the infection, and TGF-β only in females. Finally, the infection generates the production of antibodies against the parasite, however, their quantity is lower in females. This study demonstrates that T. canis infection is dimorphic and affects females more than males. This is due to a polarization of the inadequate immune response, which is reflected as a higher parasite load in this sex.

Abstract 2369: EVOLVE-105, a differentiated CD20-targeted CD2 co-stimulatory T cell engager engineered for the treatment of B cell malignancies

Abstract Despite the recent approvals of CD20-targeted CD3 bispecific molecules in follicular lymphoma (Lunsumio™, mosunetuzumab) and diffuse large B cell lymphoma (Columvi™, glofitamab; and Epkinly™, epcoritamab), significant opportunities to improve patient outcomes in these indications remain. Targeted induction of T cell costimulatory receptors (signal 2) as a complement to T cell activation mediated by T cell receptor signal 1 is an attractive strategy to sustain and optimize the redirected T cell effector response to these tumors. Drug combinations of CD3-bispecifics and tumor-targeted costimulatory biologics such as CD19-41BBL and CD19-CD28 costimulatory agonists are promising approaches that have shown preclinical efficacy and are being investigated in the clinic. EVOLVE-105 is a CD20-targeted trispecific T cell engager biotherapeutic with an integrated, affinity-tuned CD3 and a CD2 co-stimulatory agonist. The advantages of physical integration include an increased probability of simultaneous T cell receptor and CD2 receptor engagement on each T cell and a simplified patient management strategy, compared to drug combinations of molecules individually targeting each receptor. EVOLVE-105 displays improved human T cell activation, increased T cell expansion, and tumor cell killing activity without a substantial increase in cytokine release compared to CD20xCD3 bispecifics with matching CD3 affinity which does not supply CD2 costimulation. EVOLVE-105 also displays superior potency compared to the CD20xCD3 clinical benchmarks mosunetuzumab, epcoritamab, and odronextamab. Importantly, the tumor-killing potency of EVOLVE-105 was within two-fold of the activity of glofitamab, while inducing less cytokine release, suggesting its potential to establish an improved therapeutic index. In cynomolgus monkeys, EVOLVE-105 demonstrated favorable tolerability and pharmacokinetics consistent with an attractive clinical developability profile. Sustained, dose-dependent B cell depletion in peripheral blood, lymph nodes, and spleen was observed. Circulating cytokine excursions, including IL-6, IFNγ, and TNFα at efficacious doses were markedly reduced by EVOLVE-105 treatment, in contrast to the circulating levels of cytokines reported for epcoritamab and glofitamab at their efficacious doses. EVOLVE-105 demonstrates favorable biophysical properties conducive to its development as intravenous and subcutaneous formulations. The emerging profile of EVOLVE-105 suggests its potential as a differentiated CD20-targeted immunotherapy capable of providing superior, more durable tumor control with a preferred cytokine release profile, compared to current CD20-targeted T cell engager therapies. Citation Format: Xingyue An, Mohosin Sarkar, Stella Martomo, Maria Hackett, Guixian Jin, Tiffany Liang, Danielle Klaskin, Tracy Lichter, Nana Adjoa Pels, Abudukadier Abulizi, Evelyn Teran, Afsana Sabrin, Oksana A. Sergeeva, Amber Fearnley, Hayden Karp, Julio Rodriguez, Eric M. Tam, Louis Matis, Jay S. Fine, Jeremy S. Myers. EVOLVE-105, a differentiated CD20-targeted CD2 co-stimulatory T cell engager engineered for the treatment of B cell malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2369.

Abstract 3962: A CCR6+Th1-like CD4+T-cell cluster involved in HEV formation predicted lung cancer patients requiring anti-CTLA-4 therapy

Abstract Background: CD4+ T cells are known to help in cytotoxic T-cell priming, clonal proliferation, migratory and infiltrative capacity, and target cell killing function by licensing dendritic cells. Although CXCR3+ CCR6- classical Th1 CD4+ T cells are thought to be essential for acute cellular immunity, such as antiviral responses, the details of Th1-type CD4+ T cells required for anti-tumor immunity as a long-term chronic T cell immune responses over years remain unclear. We reported the Th7R, a CCR6 expressing Th1-like CD4+ T cell cluster predicted anti-PD-1 antibody therapy efficacy and postoperative recurrence-free survival. Objective: In this study, we focus on two Th1-like CD4+ T cell clusters, Th1 and Th7R, to determine their functions and roles in long-lasting anti-tumor immune phenomena. Methods: We studied patients with advanced stage lung cancer treated with immune checkpoint inhibitors (Pembrolizumab monotherapy n=63, Ipilimumab + Nivolumab n=148) and stage I-II lung cancer patients undergoing surgery (n=54). Mass cytometry, single cell RNA sequencing, and immunohistochemical staining were performed using peripheral blood, tumor-infiltrating lymphocytes and lymph node T cells. These studies were approved by the IRB of Saitama Medical University International Medical Center, and all patients gave written consent. Results: Unlike classical Th1, which highly expresses PRF1, GZMB, GNLY, and NKG7, Th7R expressed LTβ, CXCR6, CTLA-4, CD28, and CXCL13. Analysis of HEV index (MECA79+/CD31+ vessels) by MECA79 and CD31 staining of tumor tissues showed that Th7R in peripheral blood correlated with tumor tissue HEV index, suggesting that LTβ and CXCL13 expressed by Th7R are involved in HEV formation.Th1 mainly expressed PD-1 and did not express CTLA-4, whereas Th7R expressed both PD-1 and CTLA-4. When pre-treatment peripheral Th7R quartile was used to analyze OS after Ipilimumab + Nivolumab treatment, both the top 25% and intermediate 50% patients showed favorable prognosis, but the lower 25% had significantly poor OS. In contrast, only the top 25% Th7R patients but not the intermediate 50% and lower 25% patients who were treated with Pembrolizumab had favorable OS. Thus, it is likely that the Th7R intermediate 50% patients required anti-CTLA-4 therapy to achieve antitumor immune responses. These results may be useful for stratification of patients requiring anti-CTLA-4 antibody therapy as well as for predicting the therapeutic response of Ipilimumab + Nivolumab. Conclusion: Th7R exhibits LTβ and CXCL13 expression, which is absent in classical Th1, and may help maintain sustained T-cell immunity through HEV/TLS formation. Th7R may be a biomarker to select the patients who benefit from anti-CTLA-4 treatment. Citation Format: Hiroshi Kagamu, Satoshi Yamasaki, Atsuhito Mouri, Ou Yamaguchi, Ayako Shiono, Fuyumi Nishihara, Yu Miura, Kosuke Hashimoto, Hisao Imai, Kyoichi Kaira, Kunihiko Koabayashi, Katsuhisa Horimoto. A CCR6+Th1-like CD4+T-cell cluster involved in HEV formation predicted lung cancer patients requiring anti-CTLA-4 therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3962.