T-cell Cell Research Articles

Anaplastic large cell T-cell lymphoma: insights from cytological and immunological profiles across ten diverse cases.

While the latest WHO classification of hematological neoplasms helps refine the diagnostic criteria for anaplastic large cell lymphomas (ALCL), their diagnosis can still be challenging. This retrospective series of 10 ALCL cases illustrates the cytological appearance and immunological profile obtained through flow cytometry (FCM) from various sample types, including lymph node biopsies (LN), peripheral blood (PB), cerebrospinal fluid (CSF), and pleural fluid (PF). ALCL exhibits a polymorphic cytological appearance, ranging from "doughnut" cells to Hodgkin-like cells, very large cells, and small cells, with this polymorphism being particularly pronounced in ALK (-) forms. The detection of cytotoxic CD4+ T-cells by FCM aids in confirming the diagnosis, especially in small cell forms, which typically correspond to circulating phases. Cytological orientation, particularly for LNB, helps optimize the FCM panel to be used and ensures that ALCL, which frequently shows a loss of pan-T markers, is not overlooked. In conclusion, while the final diagnosis is histological, cytological analysis combined with FCM provides an initial diagnostic orientation for ALCL and guides complementary genetic analyses.

Ag85B-Induced M1 Macrophage Polarization via the TLR4/TRAF6/NF-κB Axis Leading to Bronchial Epithelial Cell Damage and TH17/Treg Imbalance.

Antigen 85B (Ag85B) is a signature antigen of Mycobacterium tuberculosis (MTB). In this study, we aimed to investigate the impact of macrophages stimulated with Ag85B on bronchial epithelial cells and T cells, as well as the underlying mechanisms involved. We used Ag85B to stimulate macrophage and investigated the impact of Ag85B on macrophage polarization. We assessed the impact of TLR4 on Ag85Bmediated macrophage polarization by silencing TLR4. Additionally, the regulatory role of TLR4 on the TRAF6/NF-κB pathway was evaluated through immunoblotting. Activated macrophages with Ag85B were co-cultured with bronchial epithelial cells and T cells, respectively. Through immunoblotting quantification, biochemical methods, and flow cytometry, we explored the effects and molecular mechanisms of Ag85B-induced macrophage activation on bronchial epithelial cell damage and T-cell transformation. In macrophages stimulated with Ag85B, levels of M1 polarization-related genes (CXCL9, CXCL10, and iNOS) and cytokines (IL-6, TNF-α, IL-1β, and IL-12) were increased, and the M1/M2 ratio was elevated. TLR4 silence inhibited the effects of Ag85B on macrophages and decreased TRAF6 and p-NF-κB/NF-κB levels. TRAF6 overexpression reversed the inhibitory effect of TLR4 on macrophage stimulation with Ag85B. After co-culturing with macrophages induced by Ag85B, MBEC cell proliferation was inhibited, apoptosis was promoted, and the TH17/Treg ratio of T cells was increased. Silencing TLR4 reversed the impact of Ag85B-induced macrophage polarization on bronchial epithelial cells and T cells, which was further reversed by TRAF6 overexpression. Ag85B promoted M1 polarization in macrophages through the TLR4/TRAF6/NF-κB axis, resulting in bronchial epithelial cell damage and an imbalance in TH17/Treg cells.

Two cellular models for analyzing mitochondrial heteroplasmy

Aim: Mitochondria are essential for brain development, and the presence of different mitochondrial types is called mitochondrial heteroplasmy. Mitochondrial dysfunction is a central aspect of many people’s neurological diseases. Heteroplasmy is commonly observed in eukaryotes due to mitochondrial genome (mtDNA) mutation, paternal leakage, mitochondria transplantation/mitotherapy, and somatic cell nuclear transfer (SCNT). In this study, we developed two novel approaches to construct mitochondrial heteroplasmy cellular models. Methods: Model 1: the yak cell line (Bos grunniens) was transfected with p-eGFP-neo plasmid while mammary alveolar cell-T (MAC-T) cell line from cattle cells (Bos taurus) was stained with MitoTracker Deep Red FM. The yak cell line was used as recipient cells which fused with enucleated cattle cells. Model 2: The cattle cell line was stained with MitoTracker Green FM while yak cells were stained with MitoTracker Deep Red FM. Cattle cells were used as recipient cells which fused with enucleated yak cells. Following fusions, the single cells exhibiting dual positive fluorescence signals were sorted into 96-well plate by fluorescence-activated cell sorting. Confocal fluorescence examination confirmed that the cells with mitochondrial heteroplasmy were sorted. Results: The two methods can generate a variety of mitochondrial heteroplasmy cells of interest which can aid in understanding the patterns and influencing factors underlying heteroplasmy changes. Conclusions: The mitochondrial heteroplasmy cellular model contributes to managing heteroplasmy mitochondrial changes and preventing the development of mitochondrial declines.

Pharmacological Properties of Platycarpha glomerata Extracts-A Plant Used to Treat and Manage Elephantiasis.

Platycarpha glomerata (Thunb.) Less. has recently become a plant species of interest to researchers due to its biological activities and less toxic effects. Therefore, the aim of the study is to evaluate the in vitro anticancer potential and phytochemical constituents of P. glomerata plant extracts. Phytochemical screening and FTIR were carried out using standard methods. The antioxidant activity was accessed by determining its ability to scavenge the DPPH radical and nitric oxide radical, whereas the anticancer activity against prostate (DU-145 and PC-3), human T-lymphocyte (SKU-T), gastric adenocarcinoma (AGS), and human prostatic epithelial (PNTA1) cell line was evaluated using the MTT assay. The phytochemical analysis revealed the presence of tannins, flavonoids, saponins, steroids, terpenoids, and cardiac glycosides. The FTIR spectrum for the aqueous extract displayed characteristic peaks for O-H, C=O, C=C, and =C-H stretch. The aqueous ethanol and methanol extracts showed significant dose-dependent DPPH radical scavenging capacity. The aqueous, ethanol, and methanol extracts showed minimum NO scavenging activity of 4.3%, 9.6%, and 11.7% at 2500 µg/mL. The water extract demonstrated good activity against S. aureus, E. coli, and B. pumilus with an MIC of 0.195 mg/mL. The ethanol and methanol extracts significantly reduced the percentage proliferation of DU-145, PC-3, and SKU-T cells at 100 μg/mL. These extracts demonstrated strong dose-dependent DPPH and NO scavenging and antibacterial and cell proliferation inhibition activities. The strong bioactivity of P. glomerata makes it a good candidate for the isolation and identification of active compounds for anticancer and related illnesses.

Senescent cell-derived extracellular vesicles inhibit cancer recurrence by coordinating immune surveillance.

Senescence is a non-proliferative, survival state that cancer cells can enter to escape therapy. In addition to soluble factors, senescence cells secrete extracellular vesicles (EVs), which are important mediators of intercellular communication. To explore the role of senescent cell-derived EVs (senEVs) in inflammatory responses to senescence, we developed an engraftment-based senescence model in wild-type mice and genetically blocked senEV release in vivo, without significantly affecting soluble mediators. SenEVs were both necessary and sufficient to trigger immune-mediated clearance of senescent cells, thereby suppressing tumor growth. In the absence of senEVs, the recruitment of MHC-II+ antigen-presenting cells to the senescence microenvironment was markedly impaired. Blocking senEV release redirected the primary target of senescent cell signaling from antigen-presenting cells to neutrophils. Comprehensive transcriptional and proteomic analyses identified six ligands specific to senEVs, highlighting their role in promoting antigen-presenting cell-T cell adhesion and synapse formation. Antigen-presenting cells activated CCR2+CD4+ TH17 cells, which appeared to inhibit B cell activation, and CD4+ T cells were essential for preventing tumor recurrence. These findings suggest that senEVs complement the activity of secreted inflammatory mediators by recruiting and activating distinct immune cell subsets, thereby enhancing the efficient clearance of senescent cells. These conclusions may have implications not only for tumor recurrence but also for understanding senescence during de novo carcinogenesis. Consequently, this work could inform the development of early detection strategies for cancer based on the biology of cellular senescence.

Navigating a complex dance: the interplay between RNA-binding proteins and T cells in oral epithelial plasticity.

The oral epithelium, a dynamic interface constantly facing environmental challenges, relies on intricate molecular pathways to maintain its homeostasis. This comprehensive review delves into the nuanced interplay between T-lymphocytic cells (T cells) and RNA-binding proteins (RBPs) within the oral epithelium, elucidating their roles in orchestrating immune responses and influencing tissue plasticity. By synthesizing current knowledge, we aim to unravel the molecular intricacies that govern this interplay, with a focus on potential therapeutic implications for oral health and diseases. Understanding the regulatory networks shaped by T cells and RBPs in the oral epithelial microenvironment holds promise for innovative strategies in managing conditions associated with epithelial dysfunction.

Identification of antigen-presenting cell-T cell interactions driving immune responses to food.

The intestinal immune system must concomitantly tolerate food and commensals and protect against pathogens. Antigen-presenting cells (APCs) orchestrate these immune responses by presenting luminal antigens to CD4+ T cells and inducing their differentiation into regulatory (pTreg) or inflammatory (Th) subsets. We used a proximity labeling method (LIPSTIC) to identify APCs that presented dietary antigens under tolerizing and inflammatory conditions and understand cellular mechanisms by which tolerance to food is induced and can be disrupted by infection. Helminth infections disrupted tolerance induction proportionally to the reduction in the ratio between tolerogenic APCs, including migratory dendritic cells (cDC1s) and Rorγt+ APCs, and inflammatory APCs, that were primarily cDC2s. These inflammatory cDC2s expanded by helminth infection did not present dietary antigens, thus avoiding diet-specific Th2 responses.

Cutaneous T-Cell Lymphoma Masquerading as Leishmaniasis Via 18F-FDG PET/CT.

Cutaneous T-cell lymphomas (CTCLs) characterized by infiltration of the skin of T-cell lymphocytes represent an uncommon and rare subset of extranodal non-Hodgkin lymphomas. Primary CTCL, not otherwise specified, is among the most important subtypes of CTCLs characterized by rapid cutaneous dissemination and systemic involvement. Herein, we present a case of primary CTCL, not otherwise specified, diagnosed via 18F-FDG PET/CT after initial misdiagnosis of cutaneous leishmaniasis.

Pathogen spectrum and clinical characteristics of lung cancer patients: A 10-year retrospective study.

Infection is the most common non-cancer cause of death in patients with lung cancer (LC). However, original research reports with large sample sizes on the epidemiology, pathogen spectrum, immune status changes, and prognosis of these patients are lacking. A retrospective study of LC patients with infection was performed at Guangxi Medical University Cancer Hospital from 2014 to 2023. In total, 699 LC patients with disease complicated by infection were included in the study. The incidence of infection increased from 4.61% in 2014 to 9.77% in 2023 among patients with LC. A total of 109 types of pathogens were detected. The most prevalent pathogenic organisms in each category were bacteria (Klebsiella pneumoniae and Escherichia coli), fungi (Candida spp. and Aspergillus spp.), viruses (COVID-19 and Epstein-Barr virus), and special pathogens (Mycobacterium tuberculosis and Mycoplasma pneumoniae). Upon diagnosis of infection, the total T lymphocyte, helper T cell, Th/Ts ratio, and B lymphocyte counts decreased, while the natural killer cell and suppressor T-cell counts increased. Infection is a crucial risk factor affecting the prognosis and mortality of patients with LC. The susceptibility of patients with LC to infection may be related to immunodeficiency resulting from antitumor treatment and disease progression.

Neoadjuvant chemotherapy by liposomal doxorubicin boosts immune protection of tumor membrane antigens-based nanovaccine.

Autologous tumor cell membrane antigen-based vaccines (TMVs) have garnered extensive attention as personalized immunotherapy. However, patients who take TMVs therapy usually undergo various treatments prior to surgery, and these processes modulate the immunogenicity of the tumor membrane and the tumor immune microenvironment. Herein, we investigate the impact of preoperative chemotherapy on the efficacy of TMVs. Liposomal doxorubicin ameliorates the immunosuppressive tumor microenvironment and enhances immunological molecule expression on the tumor membrane. This has driven TMVs to elicit a more robust immune response than doxorubicin, resulting in more effective immune protection. The TMVs formulated from liposomal doxorubicin-treated tumors induce superior dendritic cell maturation and Tcell activation compared to doxorubicin, thus demonstrating better efficacy in preventing recurrence and metastasis in the postoperative murine model. Collectively, our study suggests that chemotherapy can induce immunomodulatory changes that augment the therapeutic potential of immunotherapy and provides valuable insights into the clinical utilization of TMVs.

FC02 Immune cell signatures and T-cell receptor profiling reveal pathogenetic mechanisms in psoriasis

Abstract Psoriasis is a chronic inflammatory disease with systemic effects and currently has no cure due to an incomplete understanding of its underlying mechanisms. To gain better insights into the immune response associated with psoriasis, we conducted single-cell RNA sequencing and parallel single-cell T-cell receptor (TCR) profiling on peripheral blood mononuclear cells obtained from 11 psoriasis patients and 8 healthy controls. Additionally, we analysed two pairs of skin samples from the psoriasis cohort and performed spatial transcriptomics on two other pairs of skin samples. Our study identified specific immune signatures in myeloid and lymphocyte subsets both in blood and skin and highlighted characteristics of the immune repertoire in psoriasis. Notably, we found an increased proportion of circulating CD14+ monocytes. Furthermore, circulating plasmacytoid dendritic cells in psoriasis patients exhibited heightened expression of genes associated with skin-homing and pro-inflammatory responses. Circulating T cells in these patients showed decreased expression of activation markers. In psoriatic lesions, we observed that resting CD8+ tissue-resident memory T (TRM) cells displayed a gene expression profile similar to that of activated CD8+ TRM cells, though they had lower expression levels of cytotoxicity-related genes. Both resting and activated CD8+ TRM cells in psoriatic lesions showed enhanced interaction strength in terms of signal transmission and reception compared with non-lesions. Activated CD8+ TRM cells were densely infiltrated in the dermis of skin lesions, while resting CD8+ TRM cells were located deeper in the dermis of non-lesion areas. TCR clones that were highly expanded in skin lesions were predominantly CD8+ TRM cells. Distinct TCR clusters showed different gene expression signatures, with one CD8+ TRM cluster expressing IFNγ and another expressing IL-17. These findings provide a valuable resource for further investigation into the pathogenesis of psoriasis by offering insights into the immune cell dynamics within both circulation and local skin environments.

Plasma arginine as a predictive biomarker for outcomes with immune checkpoint inhibition in metastatic colorectal cancer: a correlative analysis of the CCTG CO.26 trial

BackgroundNutritional stress is a mechanism that allows tumor cells to evade the immune system. Arginine (ARG), an amino acid involved in immunomodulation, aids in regulating T-lymphocyte cell activity and the...

An exploration of the natural and acquired immunological mechanisms to high-risk human papillomavirus infection and unmasking immune escape in cervical cancer: A concise synopsis.

The most common STD that triggers cervical cancer is the human papillomavirus. More than 20 types of human papillomavirus (HPV) can induce uterine cervical cancer. Almost all women acquire genital HPV infection soon after their first intercourse, with most of them clearing the virus within 3 years. An immune response is necessary to clear. The first responders to HPV infection are the innate immune system elements composed of macrophages, keratinocytes, natural killer cells, and natural killer T-lymphocytic (NKT) cells. Cytotoxic T lymphocytes (CTLs) comprise the second line of defense and kill HPV16-infected cells expressing various peptides derived from their transforming early viral oncoproteins, mainly E2•E6. Even though HPV can manage to trick away our immune systems, first of all, it is important to emphasize that HPV replication does not kill the host cells. It does not replicate viral antigens or cause inflammation. The HPV16 E6 and E7 genes suppress host cell type 1 interferons (IFNs), which are detectable after infection. The patient may have immunological tolerance; hence, there are no costimulatory signals from inflammatory cytokines like IFNs during antigen recognition. Evidence shows that HlA class I generations have been inhibited by HPV16 E5, which could protect this tumor cell from CTL attack. HPV16 E7 is responsible for initiating immunotolerance and increasing regulatory T cells (Treg) to repress immunological regression. Evasion from immune system protection plays a critical role in the outcome of persistent HPV infection and the development of cervical cancer. Vaccination against HPV16 and 18 during adolescence is the most effective method for preventing cervical cancer in women, considering the immunological processes involved.

Polyphenol-mediated assembly of toll-like receptor 7/8 agonist nanoparticles for effective tumor immunotherapy.

Toll-like receptor (TLR) 7/8 agonists have shown significant potential in tumor immunotherapy. However, the limited pharmacokinetic properties and systemic toxicity resulting from off-target effects limits their biomedical applications. We here report the polyphenol-mediated assembly of resiquimod (R848, a TLR7/8 agonist) nanoparticles (RTP NPs) to achieve tumor-selective immunotherapy while avoiding systemic adverse effects. Upon intravenous administration, the prepared RTP NPs are effectively accumulated at tumor sites, which increase their bioavailability and reduce systemic inflammation. RTP NPs can trigger a potent antitumor immune response in a mouse tumor model to inhibit tumor growth. Additionally, after subcutaneous injection at the tail base, RTP NPs efficiently migrate to the lymph nodes, where they elicit immune memory to prevent tumorigenesis. This study underscores the potential application of polyphenol-mediated assembly in developing nanomedicines with reduced toxicity for tumor-specific immunotherapy. STATEMENT OF SIGNIFICANCE: Toll-like receptor agonist (R848) nanoparticles for tumor-selective immunotherapy were synthesized through polyphenol-mediated assembly, a method that simplifies preparation process and minimizes potential side effects. Intravenously administered these nanoparticles effectively extended circulation time, enhanced tumor enrichment, and reduced systemic inflammation, thus augmenting the bioavailability and minimizing the side effects of R848. The nanoparticles significantly inhibited tumor growth by triggering a potent antitumor immune response, including dendritic cell maturation, macrophage polarization, T-cell infiltration, and cytokine secretion. Moreover, after subcutaneous injection at the tail base, they can elicit immune memory to prevent tumorigenesis.

A Novel Scoring System to Predict Acute Radiation Enteritis Recovery in Cervical Cancer Patients Undergoing Concurrent Chemoradiotherapy: A Southwest China Cohort Study.

To establish a pragmatic and effective predictive model for monitoring the recovery of radiation enteritis (RE) in cervical cancer patients undergoing concurrent chemoradiotherapy (CCRT). This study included 105 cervical cancer patients undergoing CCRT. We assessed baseline clinicopathologic characteristics, evaluated the effects of CCRT on circulating immune cells, tumor biomarkers, and inflammatory cytokines, and developed a predictive scoring system, the Immune-Tumor-Score (ITS), using the LASSO-Cox regression model. The model performance of LASSO-Cox and nomogram was compared via ROC curve and calibration curve. The median age of the patients was 55 years, with 53.3% having a normal BMI and 46.7% having positive lymph nodes. Post-CCRT, significant decreases were observed in lymphocyte counts, T-cell subpopulations, and tumor markers (CA125, TPA, SCCA, CYFRA21). The CD4/CD8 ratio and IL10 levels were significantly higher post-CCRT, while inflammation indexes (NLR, ELR) increased, and LMR decreased. The ITS, derived from 11 significant parameters, effectively predicted RE recovery, outperforming a traditional nomogram. Higher ITS scores correlated with shorter RE recovery times, as validated by Kaplan-Meier analyses and ROC curves (AUC = 0.822). The ITS system provides a robust and reliable tool for predicting RE recovery in cervical cancer patients undergoing CCRT, surpassing traditional models in accuracy and reliability. This tool enables better patient management by allowing for timely interventions and personalized treatment strategies. Future research should focus on validating these findings in larger cohorts and integrating additional clinical parameters to enhance the predictive power of the ITS.

Ruxolitinib and oHSV combination therapy increases CD4 Tcell activity and germinal center B cell populations in murine sarcoma.

Malignant peripheral nerve sheath tumors (MPNSTs) are a highly aggressive neoplasm of the peripheral nervous system and are resistant to most conventional cancer therapies. We previously showed that pretreatment with ruxolitinib (RUX) enhanced the efficacy of oncolytic herpes simplex virus (oHSV) virotherapy in this murine sarcoma model. A low abundance of tumor-infiltrating leukocytes and limitations in conventional flow cytometry restrict analyses to a narrow subset of immune cells, potentially introducing a confirmation bias. To address these limitations, we developed a 46-color spectral flow cytometry panel for the detailed analysis of immune cell dynamics following repeated oHSV dosing. Beyond the cytotoxic T lymphocyte (CTL) and regulatory Tcell (Treg) changes reported in our earlier studies, RUX+oHSV treatment modulates myeloid and other lymphoid compartments, including germinal center B cell populations with enhanced activation. RUX+oHSV therapy also increased cytokine-expressing CD4(+) populations, predominantly granzyme B(+) cytotoxic-like, interferon (IFN)-γ(+) T helper type 1 (Th1)-like, and interleukin (IL)-21(+) T follicular helper (Tfh)-like phenotypes, within the tumor infiltrates, suggestive of potential tertiary lymphoid structure development in the treated tumors. Here, we illustrate the utility of a high-dimensional spectral flow cytometry panel that permits simultaneous evaluation of intratumoral CD4/CD8 Tcell, Treg, γδ-T cell, natural killer T (NKT) cell, B cell, NK cell, monocyte, macrophage, granulocyte, myeloid-derived suppressor cell (MDSC), and dendritic cell functional changes from RUX+oHSV-treated MPNSTs.

Rapidly Manufactured CAR-T with Conserved Cell Stemness and Distinctive Cytokine-Secreting Profile Shows Improved Anti-Tumor Efficacy.

Background: The emergence of chimeric antigen receptor T-cell (CAR-T) immunotherapy holds great promise in treating hematologic malignancies. While advancements in CAR design have enhanced therapeutic efficacy, the time-consuming manufacturing process has not been improved in the commercial production of CAR-T cells. In this study, we developed a "DASH CAR-T" process to manufacture CAR-T cells in 72 h and found the excelling anti-tumor efficacy of DASH CAR-T cells over conventionally manufactured CAR-T cells. Methods: Four different CAR-T manufacturing processes were first proposed and examined by flow cytometry in regard to cell viability, T-cell purity and activation, CAR expression, and cell apoptosis. The selected two processes, 48H DASH CAR-T and 72H DASH CAR-T, were applied to the subsequent functional assessments, including T-cell differentiation, antigen-dependent cytotoxicity and expansion, cytokines secretion profile, and in vivo anti-tumor efficacy. Results: We demonstrated that rapidly manufactured CAR-T cells generated within 48-72 h was feasible and exhibited increased naïve and memory T-cell ratios, a distinctive secretory profile, superior expansion capacity, and enhanced in vitro and in vivo anti-tumor activity compared to conventionally manufactured CAR-T cells. Conclusions: Our findings suggest that "DASH CAR-T" process is a valuable platform in reducing CAR-T manufacturing time and producing high-efficacy CAR-T cells for future clinical application.

Expression of senescence-related CD161 promotes extranodal NK/T cell lymphoma by affecting T cell phenotype and cell cycle

PurposeThe intention of this work is to probe the role of senescence-related gene CD161 in extranodal NK/T cell lymphoma (ENKTL).MethodsThis study used H2O2 to establish three distinct in vitro oxidative stress aging models (NKL, SNT-8, and YT). Western blotting was employed to assess the levels of two iconic aging proteins, MMP1 and P53, and flow cytometry was utilized to investigate cell cycle and the expressions of CD4, CD8, and CD161. Cell viability was evaluated via the CCK-8 assay. The transcriptome analysis assessed the differential gene expression between the control and aging group of NKL. In vivo, we established a BALB/c mice aging tumor model. After 15 days, the mice were euthanized to harvest tumors. ELISA was employed to measure aging indicators in the mouse tissues. Flow cytometry was utilized to assess the levels of CD4, CD8, and CD161 in tumor samples. Hematoxylin-eosin (HE) staining was performed to evaluate the structure and cellular morphology of the tumor tissue.ResultsIn the NKL, SNT-8 and YT aging models, the levels of MMP1 and P53 proteins were significantly increased. Flow cytometry results indicated that all three cell types exhibited marked arrest in the G1 phase. Compared with the control group, the expressions of CD4 and CD161 in the aging group were significantly increased, while the expression of CD8 was decreased. Transcriptome analysis revealed 2,843 differentially expressed genes (DEGs) between the control and aging groups, with 2,060 up-regulated and 783 down-regulated genes identified. Following CD161 knockdown, cell viability of three cell types in the aging group was significantly reduced compared to the control group. The G1 phase of the cells was significantly interrupted. The expressions of CD4 and CD161 were significantly increased, and the expression of CD8 was decreased. However, in the aging + si-CD161 group, a partial alleviation of oxidative stress was observed with a reduction in CD161 expression levels. Animal experiments demonstrated that knockout of CD161 can inhibit tumor progression and partially mitigate oxidative stress.ConclusionsCD161 may inhibit ENKTL tumor development by regulating cell cycle and T-cell phenotype.

Single intravenous administration of oncolytic adenovirus TILT-123 results in systemic tumor transduction and immune response in patients with advanced solid tumors

BackgroundA limitation of approved oncolytic viruses is their requirement for intratumoral (i.t.) injection. TILT-123 (igrelimogene litadenorepvec, Ad5/3-E2F-D24-hTNFα-IRES-hIL-2) is a chimeric oncolytic adenovirus suitable for intravenous (i.v.) delivery due to its capsid modification and dual selectivity devices. It is armed with tumor necrosis alpha and interleukin-2 for promoting T-cell activation and lymphocyte trafficking to tumors, thereby enhancing the antitumor immune response. Here, we present the findings after a single i.v. administration of TILT-123 in three phase I dose escalation clinical trials.MethodsPatients with advanced solid tumors initially received a single i.v. dose of TILT-123 ranging from 3 × 109 to 4 × 1012 viral particles (VP). Blood was collected at baseline, 1, 16, and 192 h (7 days) post-treatment for bioavailability and serum analysis. Tumor biopsies were collected prior to treatment and 7 days post-treatment for analysis of viral presence and immunological effects. Patients did not receive any other cancer therapies during this period.ResultsAcross all three trials (TUNIMO, TUNINTIL, and PROTA), 52 total patients were treated with i.v. TILT-123. Overall, TILT-123 was found to be well-tolerated, with no dose-limiting toxicities observed. Post-treatment tumor biopsies showed expression of viral genes, presence of TILT-123 adenovirus proteins or DNA, and changes in immune cell infiltration from baseline. Increased virus dose did not lead to increased virus detection in tumors. Median overall survival was longer in patients with confirmed presence of TILT-123 in post-treatment biopsies (280 versus 190 days, p = 0.0405).ConclusionTILT-123 demonstrated safety and significant intratumoral immunomodulation following a single i.v. administration, warranting further investigation.Trial registrationsTUNIMO—NCT04695327. Registered 4 January 2021, https://clinicaltrials.gov/study/NCT04695327. TUNINTIL—NCT04217473. Registered 19 December 2019, https://clinicaltrials.gov/study/NCT04217473. PROTA—NCT05271318. Registered 4 February 2022, https://clinicaltrials.gov/study/NCT05271318.

Forimtamig, a novel GPRC5D-targeting T-cell bispecific antibody with a 2+1 format, for the treatment of multiple myeloma

AbstractDespite several approved therapies, multiple myeloma (MM) remains an incurable disease with high unmet medical need. “Off-the-shelf” T-cell bispecific antibodies (TCBs) targeting B-cell maturation antigen (BCMA) and G protein–coupled receptor class C group 5 member D (GPRC5D) have demonstrated high objective response rates in heavily pretreated patients with MM; however, primary resistance, short duration of response, and relapse driven by antigen shift frequently occur. Although GPRC5D represents the most selective target in MM, recent findings indicate antigen loss occurs more frequently than with BCMA. Thus, anti-GPRC5D immunotherapies must hit hard during a short period of time. Here, we characterize forimtamig, a novel GPRC5D-targeting TCB with 2+1 format. Bivalent binding of forimtamig to GPRC5D confers higher affinity than classical 1+1 TCB formats correlating with formation of more stable immunological synapses and higher potency in tumor cell killing and T-cell activation. Using an orthotopic mouse model of MM, forimtamig recruited T effector cells to the bone marrow and induced rapid tumor killing even after the introduction of step-up dosing to mitigate cytokine release. Combination of forimtamig with standard-of-care agents including anti-CD38 antibodies, immunomodulatory drugs, and proteasome inhibitors improved depth and duration of response. The combination of forimtamig with novel therapeutic agents including BCMA TCB and cereblon E3 ligase modulatory drugs was potent and prevented occurrence of GPRC5D -negative tumor relapse. Forimtamig is currently being evaluated in phase 1 clinical trials in patients with relapsed and refractory MM for monotherapy and in combination treatments. This trial was registered at www.ClinicalTrials.gov as #NCT04557150.