CTLA-4 Research Articles

Systematic decoding of cis gene regulation defines context-dependent control of the multi-gene costimulatory receptor locus in human T cells

Cis-regulatory elements (CREs) interact with trans regulators to orchestrate gene expression, but how transcriptional regulation is coordinated in multi-gene loci has not been experimentally defined. We sought to characterize the CREs controlling dynamic expression of the adjacent costimulatory genes CD28, CTLA4 and ICOS, encoding regulators of T cell-mediated immunity. Tiling CRISPR interference (CRISPRi) screens in primary human T cells, both conventional and regulatory subsets, uncovered gene-, cell subset- and stimulation-specific CREs. Integration with CRISPR knockout screens and assay for transposase-accessible chromatin with sequencing (ATAC-seq) profiling identified trans regulators influencing chromatin states at specific CRISPRi-responsive elements to control costimulatory gene expression. We then discovered a critical CCCTC-binding factor (CTCF) boundary that reinforces CRE interaction with CTLA4 while also preventing promiscuous activation of CD28. By systematically mapping CREs and associated trans regulators directly in primary human T cell subsets, this work overcomes longstanding experimental limitations to decode context-dependent gene regulatory programs in a complex, multi-gene locus critical to immune homeostasis.

Antitumor activity of Z15-0-2, a bispecific nanobody targeting PD-1 and CTLA-4

The combination of programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies has potential for enhancing clinical efficacy. We described the development and antitumor activity of Z15-0, a bispecific nanobody targeting both the PD-1 and CTLA-4 pathways simultaneously. We designed and optimized the mRNA sequence encoding Z15-0, referred to as Z15-0-2 and through a series of in vitro and in vivo experiments, we established that the optimized Z15-0-2 mRNA sequence significantly increased the expression of the bispecific nanobody. Administration of Z15-0-2 mRNA to tumor-bearing mice led to greater inhibition of tumor growth compared to controls. In aggregate, we introduced a novel bispecific nanobody and have re-engineered it to boost expression of mRNA, representing a new drug development paradigm.

Recent advances in immunotherapy in cancer treatment.

Immunotherapy has emerged as a transformative approach in cancer treatment, leveraging the body's own immune system to recognize and eradicate cancer cells. This review provides an overview of the recent advances and aspects in immunotherapy in cancer biology, from established therapies like checkpoint inhibitors and CAR-T cells to emerging innovative approaches and the challenges associated with their clinical translation. The exploration includes an examination of checkpoint inhibitors, elucidating the mechanisms behind programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors. Recent clinical successes and ongoing trials demonstrate the efficacy of checkpoint inhibitors across diverse malignancies, underscoring the potential for durable responses and improved patient outcomes. CAR-T cell therapy represents a groundbreaking avenue in immunotherapy, involving the genetic modification of a patient's T cells to express chimeric antigen receptors (CARs) for targeted cancer cell recognition. Furthermore, the review touches on the challenges associated with immunotherapy, including resistance mechanisms and adverse effects. Insightful discussions on overcoming resistance through combination therapies, adaptive treatment strategies, and emerging technologies underscore the ongoing efforts to enhance the long-term efficacy of immunotherapeutic interventions. In summary, this extensive review provides a comprehensive overview of recent advances in immunotherapy in cancer biology, highlighting the transformative impact of these therapies on patient outcomes, the challenges faced, and the promising directions for future research and clinical applications.

Checkpoint Inhibitors in Dogs: Are We There Yet?

Immune checkpoint inhibitors (ICI) have revolutionised cancer treatment in people. Immune checkpoints are important regulators of the body's reaction to immunological stimuli. The most studied immune checkpoint molecules are programmed death (PD-1) with its ligand (PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) with its ligands CD80 (B7-1) and CD86 (B7-2). Certain tumours can evade immunosurveillance by activating these immunological checkpoint targets. These proteins are often upregulated in cancer cells and tumour-infiltrating lymphocytes, allowing cancer cells to evade immune surveillance and promote tumour growth. By blocking inhibitory checkpoints, ICI can help restore the immune system to effectively fight cancer. Several studies have investigated the expression of these and other immune checkpoints in human cancers and have shown their potential as therapeutic targets. In recent years, there has been growing interest in studying the expression of immune checkpoints in dogs with cancer, and a few small clinical trials with ICI have already been performed on these species. Emerging studies in veterinary oncology are centred around developing and validating canine-targeted antibodies. Among ICIs, anti-PD-1 and anti-PD-L1 treatments stand out as the most promising, mirroring the success in human medicine over the past decade. Nevertheless, the efficacy of caninized antibodies remains suboptimal, especially for canine oral melanoma. To enhance the utilisation of ICIs, the identification of predictive biomarkers for treatment response and the thorough screening of individual tumours are crucial. Such endeavours hold promise for advancing personalised medicine within veterinary practice, thereby improving treatment outcomes. This article aims to review the current research literature about the expression of immune checkpoints in canine cancer and the current results of ICI treatment in dogs.

ARHGAP4 promotes colon cancer metastasis through the TGF-β signaling pathway and may be associated with T cell exhaustion

BackgroundColon cancer is a prevalent invasive neoplasm in the gastrointestinal system with a high degree of malignancy. Despite extensive research, the underlying mechanisms of its recurrence and metastasis remain elusive.Rho GTPase activating protein 4 (ARHGAP4), a member of the small GTPases protein family, may be closely related to tumor metastasis, and its expression is increased in colon cancer. However, the role of ARHGAP4 in colon cancer metastasis is uncertain. This study investigates the impact of ARHGAP4 on the metastasis of colon cancer cells. Our objective is to determine the role of ARHGAP4 in regulating the invasive behavior of colon cancer cells. MethodsWe downloaded colon adenocarcinoma (COAD) data from the Cancer Genome Atlas (TCGA), and performed differential analysis and survival analysis. By using the CIBERSORT algorithm, we evaluated the proportion of infiltrating immune cells in colon cancer. We further analyzed whether ARHGAP4 is associated with T cell exhaustion. Finally, we investigated the impact of ARHGAP4 knockdown on the migration and invasion of colon cancer cells through in vitro cell experiments. Additionally, we utilized western blotting to assess the expression of protein related to the TGF-β signaling pathway and epithelial-mesenchymal transition (EMT). ResultsWe found that ARHGAP4 is upregulated in colon cancer. Subsequent survival analysis revealed that the high-expression group had significantly lower survival rates compared to the low-expression group. Immune infiltration analysis showed that ARHGAP4 was not only positively correlated with CD8+ T cells, but also positively correlated with T cell exhaustion markers programmed cell death 1 (PDCD-1), cytotoxic T-lymphocyte associated protein 4 (CTLA-4), and lymphocyte activating 3 (LAG-3). In vitro cell experiments, the knockdown of ARHGAP4 inhibited the migration and invasion of colon cancer cells. Among EMT-related proteins, when ARHGAP4 was knocked down, the expression of E-cadherin was increased, while the expression of N-cadherin and Vimentin was decreased. Meanwhile, the expression of TGF-β1, p-Smad2, and p-Smad3, which are associated with the TGF-β/Smad pathway, all decreased. ConclusionARHGAP4 promotes colon cancer metastasis through the TGF-β/Smad signaling pathway and may be associated with T cell exhaustion. It plays an important role in the progression of colon cancer and may serve as a potential target for diagnosis and treatment of colon cancer.

Cadonilimab with chemotherapy in HER2-negative gastric or gastroesophageal junction adenocarcinoma: the phase 1b/2 COMPASSION-04 trial.

Treatment with anti-programmed cell death protein 1 (PD-1) therapy and chemotherapy prolongs the survival of patients with unresectable advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma. The benefit from anti-PD-1 therapy is enriched in patients with programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS)-positive or CPS-high tumors compared with patients with PD-L1 CPS-negative or CPS-low tumors. In this phase 1b/2 study, we evaluated the efficacy and safety of cadonilimab, a bispecific antibody targeting PD-1 and cytotoxic T-lymphocyte antigen-4, plus chemotherapy as first-line treatment in patients with human epidermal growth factor receptor 2-negative unresectable advanced or metastatic gastric or GEJ adenocarcinoma. The primary endpoint was the recommended phase 2 dose (RP2D) for phase 1b and the objective response rate for phase 2. Secondary endpoints included disease control rate, duration of response, time to response, progression-free survival, overall survival (OS) and safety. The primary endpoint was met. No dose-limiting toxicities were observed during dose escalation in phase 1b; the recommended phase 2 dose was determined as 6 mg kg-1 every 2 weeks. The objective response rate was 52.1% (95% confidence interval (CI) = 41.6-62.5), consisting of complete and partial responses in 4.3% and 47.9% of patients, respectively. The median duration of response, progression-free survival and OS were 13.73 months (95% CI = 7.79-19.12), 8.18 months (95% CI = 6.67-10.48) and 17.48 months (95% CI = 12.35-26.55), respectively. The median OS in patients with a PD-L1 CPS ≥ 5 was 20.32 months (95% CI = 4.67-not estimable); in patients with a PD-L1 CPS < 1, the median OS reached 17.64 months (95% CI = 11.63-31.70). The most common treatment-related grade 3 or higher adverse events were decreased neutrophil count (19.1%), decreased platelet count (16.0%), anemia (12.8%) and decreased leukocyte count (8.5%). No new safety signal was identified. The current regimen showed promising clinical activity and manageable safety in patients with gastric or GEJ adenocarcinoma regardless of PD-L1 expression. Chinadrugtrials.org.cn registration: CTR20182027.

Immunomodulatory Precision: A Narrative Review Exploring the Critical Role of Immune Checkpoint Inhibitors in Cancer Treatment

An immune checkpoint is a signaling pathway that regulates the recognition of antigens by T-cell receptors (TCRs) during an immune response. These checkpoints play a pivotal role in suppressing excessive immune responses and maintaining immune homeostasis against viral or microbial infections. There are several FDA-approved immune checkpoint inhibitors (ICIs), including ipilimumab, pembrolizumab, and avelumab. These ICIs target cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed death ligand 1 (PD-L1). Furthermore, ongoing efforts are focused on developing new ICIs with emerging potential. In comparison to conventional treatments, ICIs offer the advantages of reduced side effects and durable responses. There is growing interest in the potential of combining different ICIs with chemotherapy, radiation therapy, or targeted therapies. This article comprehensively reviews the classification, mechanism of action, application, and combination strategies of ICIs in various cancers and discusses their current limitations. Our objective is to contribute to the future development of more effective anticancer drugs targeting immune checkpoints.

Immune-related dermatological adverse events of antitumor immunotherapy with PD-1, PD-L1, CTLA-4 inhibitors

The discovery of a new group of modern anticancer drugs was a breakthrough in the treatment of cancer. Immune checkpoint inhibitors that block cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death protein-1 (PD-1), and programmed cell death receptor ligand (PD-L1) may improve prognosis for patients with malignant neoplasms with a high level of microsatellite instability. Despite the high effectiveness of these drugs, immune checkpoint inhibitors can lead to dysregulation of immune responses and the occurrence of adverse reactions associated with an increase in the activity of immunocompetent cells in the body. The aim of this review is to analyze the available data on the immune-related dermatological adverse events during treatment with immune checkpoint inhibitors.

IBI310 (anti-CTLA-4 antibody) monotherapy or in combination with sintilimab in advanced melanoma or urothelial carcinoma

IBI310 is a recombinant fully human IgG1 antibody against cytotoxic T-lymphocyte antigen 4 (CTLA-4). This study was conducted to evaluate IBI310 monotherapy or combination therapy with sintilimab in the patients with advanced melanoma or urothelial carcinoma (UC). Patients in phase Ia received IBI310 at 0.3/1/2/3 mg/kg intravenously (IV) every three weeks (Q3W) following the accelerated titration and 3 + 3 escalation design. Patients in phase Ib received IBI310 (1/2/3 mg/kg IV, Q3W) plus sintilimab (200 mg IV, Q3W) for 4 cycles, followed by sintilimab maintenance therapy. The phase Ib expansion of IBI310 plus sintilimab was performed in patients with advanced melanoma or UC. Overall, 53 patients were enrolled including 10 patients with melanoma in phase Ia, 34 with melanoma and 9 with UC in phase Ib. 94.3% (50/53) patients experienced at least one treatment-related adverse event (TRAE) with most being grade 1-2; 26.4% (14/53) patients experienced grade ≥3 TRAEs. In phase Ia, disease control rate (DCR) was 50.0% (95% CI: 18.7%-81.3%). In phase Ib, objective response rate (ORR) and DCR were 17.6% (95% CI: 6.8%-34.5%) and 44.1% (95% CI: 27.2%-62.1%) respectively for melanoma, and were 22.2% (95% CI: 2.8%-60.0%) and 66.7% (95% CI: 29.9%-92.5%) respectively for UC. IBI310 monotherapy or combination therapy with sintilimab was well-tolerated with favorable antitumor activity across patients with advanced melanoma and UC.

Safety of Janus kinase inhibitors compared to biological DMARDs in patients with rheumatoid arthritis and renal impairment: the ANSWER cohort study

Data on the safety of Janus kinase inhibitors (JAKis) in patients with renal impairment are lacking. This study aimed to investigate the safety of JAKis compared to biological (b) DMARDs in patients with rheumatoid arthritis (RA) and renal impairment. We used a multi-centre observational registry of patients with RA in Japan (the ANSWER cohort). We assessed the drug retention rates of b/targeted synthetic DMARDs with different modes of action (tumour necrosis factor inhibitors (TNFis), immunoglobulins fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), interleukin-6 receptor inhibitors (IL-6Ris), and JAKis) in patients with RA stratified by pre-treatment estimated glomerular filtration rate (eGFR) levels. The time to discontinuation of bDMARDs or JAKis was analysed using a multivariate Cox proportional hazards model This study included 3775 patients, who were classified into three groups (the normal group (eGFR ≥ 60 mL/min/1.73 m2): 2893 patients; CKDa group (eGFR 45–60 mL/min/1.73 m2): 551; and CKDb group (eGFR < 45 mL/min/1.73 m2): 331). In the CKDb group, the 12-month drug retention rate due to adverse events (AE) was the lowest in patients treated with JAKi (TNFi: 93.1%; IL-6Ri: 94.1%; CTLA-4-Ig: 92.3%; JAKi: 75.1%). In the normal and CKDa groups, drug retention rates due to AE were similar among patients treated with bDMARDs and JAKi. In contrast, drug retention rates due to inefficacy were similar between bDMARDs and JAKis in all groups. In the Cox-proportional model, in the CKDb group, TNFi, IL-6Ri, and CTLA-4-Ig showed lower incidence of drug discontinuation due to AE than JAKis (TNFi: hazard ratio = 0.23 (95% confidence interval 0.09–0.61), IL-6Ri: 0.34 (0.14–0.81), CTLA-4-Ig: 0.36 (0.15–0.89)). JAKis showed the lowest drug retention due to AE in patients with moderate-to-severe and severe renal impairment (eGFR < 45 mL/min/1.73 m2). Physicians should pay more attention to renal function when using JAKis than when using bDMARDs.

Association of tuberculosis risk with genetic polymorphisms of the immune checkpoint genes PDCD1, CTLA-4, and TIM3.

The immune checkpoint proteins were reported to involve to host resistance to Mycobacteria tuberculosis (Mtb). Here, we evaluated 11 single nucleotide polymorphisms (SNPs) in PDCD1, CTLA4, and HAVCR2 genes between participants with and without TB infection. Genomic DNA isolated from 285 patients with TB and 270 controls without TB infection were used to perform the genotyping assay. Odds ratios were used to characterize the association of 11 SNPs with TB risk. In this study, the various genotypes of the 11 SNPs did not differ significantly in frequency between the non-TB and TB groups. When patients were stratified by sex, however, men differed significantly from women in genotype frequencies at HAVCR2 rs13170556. Odds ratios indicated that rs2227982, rs13170556, rs231775, and rs231779 were sex-specifically associated with TB risk. In addition, the combinations of rs2227982/rs13170556 GA/TC in men and the A-C-C haplotype of rs231775-rs231777-rs231779 in women were significantly associated with TB risk. Our results indicate that rs2227982 in PDCD1 and rs13170556 in HAVCR2 are associated with increased TB susceptibility in men and that the CTLA4 haplotype appears protective against TB in women.

Abstract PO3-25-01: CTLA4 expression profiles and their association with clinical outcomes of breast cancer

Abstract The cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is involved in the progression of various cancers, but its biological roles in breast cancer (BRCA) remain unclear. Therefore, we performed a systematic multiomic analysis to expound on the prognostic value and underlying mechanism of CTLA4 in BRCA. First, the expression of CTLA4 in pan-cancer was evaluated using the platforms of Oncomine. Afterward, the web-based bioinformatics platforms of GEPIA and UCLAN were used to compare the expression of CTLA4 in breast cancer and normal tissues. Next, we assessed the relationship between CTLA4 mRNA expression and prognosis in breast cancer patients using the PrognoScan Database, Kaplan-Meier Plotter, and R2: Kaplan-Meier Scanner. Additionally, the correlation between CTLA4 expression and immune cell infiltration in breast cancer and functional enrichment analysis of Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways was performed to elucidate the potential biological functions of CTLA4. Finally, we used the STRINGdb and cytoHubba plugin Cytoscape to create a PPI network and identify known and predicted structural essentials for CTLA4 functions and the top five hub genes. CTLA4 was highly expressed in BRCA tumor tissue compared to normal tissue (p&amp;lt; 0.01). The CTLA4 mRNA levels in BRCA based on breast cancer subtypes of luminal, Human epidermal growth factor receptor 2 (HER-2), and Triple-negative breast cancer (TNBC) were considerably higher than in normal tissues (p&amp;lt; 0.001). However, the overexpression of CTLA4 was associated with a better prognosis in BRCA (P&amp;lt; 0.001), and was correlated with clinicopathological characteristics including age, T-stage, estrogen receptors (ER), progesterone receptors (PR), and PAM50 (P&amp;lt; 0.01). The infiltration of multiple immune cells was associated with increased CTLA4 expression in BRCA (P&amp;lt; 0.001). CTLA4 was highly enriched in antigen binding, immunoglobulin complexes, lymphocyte-mediated immunity, and cytokine-cytokine receptor interaction. This study provides suggestive evidence of the prognostic role of CTLA4 in breast cancer, which may be a therapeutic target for breast cancer. Furthermore, CTLA4 may influence breast cancer prognosis through antigen binding, immunoglobulin complexes, lymphocyte-mediated immunity, and cytokine-cytokine receptor interaction. These findings help us understand how CTLA4 plays a role in breast cancer and set the stage for more research. Citation Format: Woo Chul Noh, Young Bum Yoo, Kyoung Sik Park, Sang Eun Nam, Seung Hwan Lim. CTLA4 expression profiles and their association with clinical outcomes of breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-25-01.

Cholesterol and Immune Microenvironment: Path Towards Tumorigenesis.

Since obesity is a major risk factor for many different types of cancer, examining one of the most closely associated comorbidities, such as hypercholesterolemia, is crucial to understanding how obesity causes cancer. Hypercholesterolemia is usually associated with many cardiovascular complications such as hypertension, angina, and atherosclerosis. In addition, cholesterol may be a major factor in increasing cancer risk. Cancer patients who received statins, an anti-hypercholesteremic medicine, demonstrated improved prognosis possibly through its effect on tumor proliferation, apoptosis, and oxidative stress.Cholesterol could also aid in tumor progression through reprogramming tumor immunological architecture and mediators. This review focuses on the immunomodulatory role of cholesterol on cellular and molecular levels, which may explain its oncogenic driving activity. We look at how cholesterol modulates tumor immune cells like dendritic cells, T cells, Tregs, and neutrophils. Further, this study sheds light on the modification of the expression pattern of the common cancer-related immune mediators in the tumor immune microenvironment, such as programmed cell death 1 (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA-4), transforming growth factor-beta (TGF-β), interleukin 12 (IL-12), IL-23, and forkhead box protein P3 (FOXP3). We highlight relevant literature demonstrating cholesterol's immunosuppressive role, leading to a worse cancer prognosis. This review invites further research regarding the pathobiological role of cholesterol in many obesity-related cancers such as uterine fibroids, post-menopausal breast, colorectal, endometrial, kidney, esophageal, pancreatic, liver, and gallbladder cancers. This review suggests that targeting cholesterol synthesis may be a fruitful approach to cancer targeting, in addition to traditional chemotherapeutics.

Abstract PO1-18-06: Phase 1/2a Open-label Clinical Trial of BI-1607, an Fc Engineered Monoclonal Antibody to CD32b (FcγRIIB), in Combination with Trastuzumab in Subjects with HER2-positive Advanced Solid Tumors – CONTRAST

Abstract Background The introduction of trastuzumab has dramatically changed outcomes in patients with human epidermal growth factor receptor 2 positive (HER2+) cancer. However, primary or acquired resistance to trastuzumab has been increasingly recognized as a major obstacle in the clinical management of this disease. Combination of anti-HER2 antibodies with other immunotherapies is likely to improve the quantity and quality of responses. BI-1607 is a human monoclonal antibody (mAb) targeting FcRIIB (CD32b) with antagonistic function capable of blocking the inhibitory function of FcRIIB on immune effector cells. BI-1607 has been engineered to lack a glycan in position N297Q in the constant domain (Fc), and thus cannot interact with FcγRs through its Fc. Given its high specificity and affinity for FcγRIIB, BI-1607 blocks other antibodies’ binding to FcγRIIB. As a result, BI-1607 is expected to shift tumor cells coated antibodies (here anti-HER2) to selectively engage activating FcγRs, thus augmenting FcγR-dependent therapeutic activity (ADDC, ADCP). Tumor-associated macrophages express high levels of FcγRIIB and are a major target of BI-1607 in the tumor microenvironment. This concept was demonstrated in preclinical in vivo models showing increased efficacy of the combination therapy with the murine surrogate of BI-1607 and an anti-HER2, an anti–cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and an anti-CD20 (rituximab) as compared to monotherapy. It important to note that BI-1607 will have no single-agent activity. Instead, its clinical use will be in combination with other immunotherapies and tumor-targeting antibodies such as trastuzumab. The choice of trastuzumab as the combination agent in this trial was based on promising preclinical studies, a recognized need for additional options for those patients who fail to respond or stop responding to trastuzumab, and promising results from the newly approved Fc-engineered anti-HER2 mAb margetuximab. Ultimately, if shown to be safe and effective in combination with trastuzumab, BI-1607 can also be used in combination with other cytotoxic or immunomodulatory antibodies for cancer treatment. Methods This is a Phase 1/2a, first-in-human, open-label, multicenter, dose-escalation, consecutive-cohort study of BI-1607 in combination with trastuzumab in subjects with HER2+ advanced solid tumors. Phase 1 aims to assess safety and tolerability and to determine the RP2D of BI-1607 in combination with trastuzumab. Phase 2a will explore efficacy at RP2D of BI-1607 in combination with trastuzumab in two separate expansion cohorts, a) in subjects with locally advanced or metastatic HER2+ breast cancer and b) in subjects with HER2+ metastatic gastric or gastroesophageal junction adenocarcinoma. Eligible patents must have a HER2+ locally advanced unresectable or metastatic solid tumors and have received standard of care or be intolerant to standard of care antineoplastic therapy, with progressive disease after the last line of treatment. Accrual/Planned Accrual As of June 222d, 2023 10 patients have been treated into trial and dosed with BI-1607 and trastuzumab at doses from 75-900 mg every 3 weeks (Q3W) in Phase 1. Phase 2a will enroll 15 subjects each in two cohorts of HER2+ advanced/metastatic breast cancer or HER2+ gastric/GEJ adenocarcinoma respectively. For information regarding the study, please contact: anna.ropenga@bioinvent.com Citation Format: Javier Cortés, Araceli Priego, Elena Garralda Cabanas, Katerin Rojas Lamito, Simon Lord, Thorsten Goetze, Sherko Küemmel, Simon Crabb, Marie Borggren, Ingrid Karlsson, Linda Mårtensson, Anna Ropenga, Ingrid Teige, Johan Wallin, Björn Frendeus, Andres McAllister. Phase 1/2a Open-label Clinical Trial of BI-1607, an Fc Engineered Monoclonal Antibody to CD32b (FcγRIIB), in Combination with Trastuzumab in Subjects with HER2-positive Advanced Solid Tumors – CONTRAST [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-18-06.

Genetic biomarkers for diagnosis and treatment of spondyloarthropathies in Moroccan population

BackgroundThe spondyloarthropathies (SpA) are inflammatory rheumatologic diseases whose pathogenesis comes from interaction between genetic and environmental factors. MethodsThis is a case-control analysis that aims to explore in Moroccan population the relationship of some allelic polymorphisms of the CTLA-4 CT60, FCGR3A-158G/T SNPs and HLA-B locus with SpA disease. Eighty-four Spa patients grouped according to pain site and 95 healthy individuals from Morocco were typed by sequence-based-typing methods. ResultsThe CTLA-4 CT60 investigation showed a significantly increased frequency of rs11571319 A allele in male patients with sacroiliitis (pcorr.=0.048, OR=2.756) and a protective role of A/G genotype in SPA patients with thoracic spine (pcorr.=0.016, OR=0.055) and peripheral joints pain (pcorr.=0.036 OR=0.068), compared to controls. Furthermore, a significant increase of A/A in rs3087243 was shown in male patients with peripheral joints pain (p = 0.035 OR = 4.45). Data from FCGR3A-158 analysis evidenced a reduction of T/T (F/F) genotype in patients with thoracic spine pain (p = 0.030, OR = 0.09) and a higher frequency of G/T (F/V) (p = 0.038 OR = 5.045) towards controls. With regard to HLA-B locus, we noticed a protective role of HLA-B*45:01 (pcorr. = 0.033,OR = 0.041) and an increased frequency of HLA-B*51 alleles (51:01, 51:02, 51:08, 51:09, 51:29) and B*52:01:01 (p = 0.041,OR = 2.714), in addition to HLA-B*27 alleles (p = 0.028, OR = 2.593) commonly associated with AS pathologies. ConclusionsOur data suggest the role of some additional CTLA-4, FCGR3A and HLA-B gene polymorphisms in SPA pathogenesis of Moroccan population, useful as new diagnostic biomarkers and targets for immunotherapy.

Expressions of CD80 and CD86 in Cancer Patients and Its Prognostic Significance

Background: Strategies for modulating the tumor microenvironment (TME) have opened up new treatment paths in a variety of malignancies, with dramatic but variable intertemporal success. Consequently, studying TME's molecular players may aid in understanding how tumor cells and TME interact. Tumor cells and infiltrative tumor lymphocytes express immune checkpoint proteins including Cluster of Differentiation 80 (CD80) and CD86 on their surface. CD80 and CD86 are members of the immunoglobulin superfamily (IgSF). The costimulatory protein CD28, which is present on the outermost portion of all T cells, and the inhibitory receptor CTLA-4 (cytotoxic T-lymphocyte antigen-4, also known as CD152) are ligands for CD86 and CD80. CD28 and CTLA-4 have essential yet opposing functions in T cell activation. T cell responses are stimulated when they bind to CD28, but they are suppressed when they connect to CTLA-4. Aim of the study: The goal of the study was to determine how much the CD80 and CD86 genes were expressed genetically. In five blood malignancies and ten solid tumors. Methods: Clinical specimen were collected from patient with different cancers attending Kirkuk oncology centre. Patients were categorised into two main groups: solid tumour group and Blood derived cancer group alongside with their control counterparts. The study investigated the genetic expression of the CD80 and CD86 genes using q RT-PCR technologies. Results: Using q RT- PCR we measured the expression of a gene CD80 /CD86. The results showed different levels of elevation in patient samples of solid tumors and hematological tumors and compared with the control group for this study First, evaluation of this marker CD80/CD86 in solid tumors showed a significant increase in patients with brain cancer compared to their counterparts in the control group. Secondly, the second solid tumor appears increased gene expression as ovarian cancer. The least expressed solid tumors are breast cancer. As for cancers that occur in the blood, lymphoma has an upregulation expression. And the least expression is CD80/CD86 were in ALL. Conclusion: There is evidence that several cancer types and immune cells have expressed CD80 and CD86. This investigation demonstrated that the cell surface markers CD80/CD86 have a role in progression of carcinomas of the brain.

Role of Molecular Biomarkers in Endometriosis-Related Infertility: A Narrative Review of the Literature.

Endometriosis is a chronic benign inflammatory disease that affects womenof reproductive age. The clinical presentations of endometriosis include dysmenorrhea, dyspareunia, chronic pelvic pain, and infertility. There is awell-established association between endometriosis and infertility. Therefore, there is a need for an early diagnosis of endometriosis-related infertility. In this study, we aim to identify the role of biomarkers as predictive factors of the presence of the disease and its severity and their correlation with the pregnancy outcome. We performed an electronic database search of all published studies in PubMed and EMBASE from January 2018 to May 2023. Numerous innovative biomarkers identified in cases of endometriosis and infertility have been studied over the past years, including micro-RNAs, BCL6 endometrial expression, cytotoxic T-lymphocyte antigen 4, human leukocyte antigen G, programmed cell death protein 1, programmed cell death ligand 1 immune checkpoint molecules, plasma fibronectin-fibrin complexes, homeobox A10 gene, systemic inflammatory response markers, uterine natural killer cells, and the eutopic endometrium proteome. Considerable research has been done to identify diagnostic biomarkers for the early detection and prevention of endometriosis-associated infertility. However, none of these biomarkers displayed enough diagnostic accuracy to be used in daily clinical practice. Future research is valuable to establish them as reliable diagnostic tools.

Impact of Chemotherapeutic Agents on PD-L1, CTLA-4, and VISTA Gene Expression in Cervical Cancer Cell Lines: An In Vitro Study

Impact of Chemotherapeutic Agents on PD-L1, CTLA-4, and VISTA Gene Expression in Cervical Cancer Cell Lines: An In Vitro Study

Primary immune regulatory disorders (PIRD): expanding the mutation spectrum in Turkey and identification of sixteen novel variants

Human Inborn Errors of Immunity (IEIs) encompass a clinically and genetically heterogeneous group of disorders, ranging from mild cases to severe, life-threatening types. Among these, Primary Immune Regulatory Disorders (PIRDs) constitute a subset of IEIs characterized by diverse clinical phenotypes, prominently featuring severe atopy, autoimmunity, lymphoproliferation, hyperinflammation, autoinflammation, and susceptibility to malignancies. According to the latest report from the International Union of Immunological Societies (IUIS), PIRDs arise from mutations in various genes including LYST, RAB27A, AP3B1, AP3D1, PRF1, UNC13D, STX11, STXBP2, FAAP24, SLC7A7, RASGRP1, CD70, CTPS1, RLTPR, ITK, MAGT1, PRKCD, TNFRSF9, SH2DIA, XIAP, CD27 (TNFRSF7), FAS (TNFRSF6), FASLG (TNFSF6), CASP10, CASP8, FADD, LRBA, STAT3, AIRE, ITCH, ZAP70, TPP2, JAK1, PEPD, FOXP3, IL2RA, CTLA4, BACH2, IL2RB, DEF6, FERMT1, IL10, IL10RA, IL10RB, NFAT5, TGFB1, and RIPK1 genes. We designed a targeted next-generation sequencing (TNGS) workflow using the Ion AmpliSeq™ Primary Immune Deficiency Research Panel to sequence 264 genes associated with IEIs on the Ion S5™ Sequencer. In this study, we report the identification of 38 disease-causing variants, including 16 novel ones, detected in 40 patients across 15 distinct PIRD genes. The application of next-generation sequencing enabled rapid and precise diagnosis of patients with PIRDs.

Periparturient blood T-lymphocyte PD-1 and CTLA-4 expression as potential predictors of new intramammary infections in dairy cows during early lactation (short communication)

BackgroundThe periparturient period in dairy cows is marked by immunosuppression which increases the likelihood of infectious disorders, particularly also mastitis. An in-depth understanding of peripartum leukocyte biology is vital for the implementation of highly successful post-partum disease prevention measures. Immune checkpoint molecules, such as programmed death 1 (PD-1) and cytotoxic T-lymphocyte antigen 4 (CTLA-4), are critical inhibitory receptors expressed on immune cells, particularly T cells, that drive immunosuppressive signaling pathways. However, the potential role of immune checkpoint molecules expression in T-cells on udder health has never been explored. Thus, the association between the occurrence of new postpartum intramammary infections (IMIs) and the expression of programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) on blood T-cells during the peripartum period was investigated.ResultsIn this study, the incidence of IMIs by any pathogen in early lactation was not associated with a higher expression of PD-1 and CTLA-4 in the periparturient period. However, the incidence of IMIs by major pathogens throughout the first month of lactation was significantly associated with higher expression of PD-1 at 14 days before calving (P = 0.03) and CTLA-4 at parturition (P = 0.03) by blood T-cells. Also, the expression of CTLA-4 at D0 (P = 0.012) by T-cells was associated with the occurrence of persistent IMIs during the first month of lactation.ConclusionsTo our knowledge, this is the first report to investigate the expression of PD-1 and CTLA-4 by blood T-lymphocytes during the periparturient period in dairy cows and to explore their relationship with the incidence of new IMIs in the postpartum period. Thus, a comprehensive understanding of leukocyte biology during peripartum would appear to be a prerequisite for the identification of resilient dairy cows or targets innovative (immunological) non-antibiotic approaches in the transition period.