P1, N=71, Completed, Shanghai Junshi Bioscience Co., Ltd. | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Mar 2024 | Trial primary completion date: Sep 2024 --> Mar 2024

P3, N=756, Recruiting, Shanghai Junshi Bioscience Co., Ltd. | Not yet recruiting --> Recruiting

P3, N=185, Recruiting, Shanghai Junshi Bioscience Co., Ltd. | Not yet recruiting --> Recruiting

P3, N=185, Not yet recruiting, Shanghai Junshi Bioscience Co., Ltd.

P1, N=83, Recruiting, HiFiBiO Therapeutics | Phase classification: P1a/1b --> P1

Tifcemalimab alone or in combination with toripalimab were well tolerated in all doses evaluated. The combination regimen showed favorable safety and durable efficacy in lymphoma patients with heavily pretreatment, providing evidence for future investigation.

P3, N=756, Not yet recruiting, Shanghai Junshi Bioscience Co., Ltd.

P1, N=71, Active, not recruiting, Shanghai Junshi Bioscience Co., Ltd. | N=170 --> 71

This prompted rapid development and clinical testing of the anti-BTLA blocking antibody Tifcemalimab/icatolimab as the first BTLA-targeted therapy in various ongoing phase I clinical trials with encouraging results on preliminary efficacy and safety profile as monotherapy and combined with other anti-PD-1/PD-L1 therapies. Nevertheless, it is anticipated that the intricate signaling network constituted by BTLA/HVEM/CD160/LIGHT involved in immune response regulation, tumor development and tumor microenvironment could limit therapeutic success. Therefore, in-depth functional characterization in different cancer settings is highly recommended for adequate design and implementation of BTLA-targeted therapies to guarantee the best clinical outcomes to benefit cancer patients.

P2, N=124, Not yet recruiting, Shanghai Pulmonary Hospital, Shanghai, China

P1a/1b, N=83, Recruiting, HiFiBiO Therapeutics | Not yet recruiting --> Recruiting

P1a/1b, N=83, Not yet recruiting, HiFiBiO Therapeutics

We have designed, synthesized and characterized a target-specific, stimuli-responsive MSN platform for the controlled delivery of cisplatin (cisPt) and gemcitabine (Gem) (TAB004-Gem-cisPt-MSNs) with an optimal drug ratio. Moreover, the same MSN platform has been used in a sequential treatment where MSNs containing a Sonic Hedgehog (SHh) inhibitor, cyclopamine (CyP), and the Gem-cisPt-MSNs as the main delivery system led to reduction in the tumor stroma along with an improvement in the treatment of PDAC. Taken together, our findings support the potential of drug delivery using MSN nanoparticles for stroma modulation and to prevent pancreatic cancer progression.

Tifcemalimab alone or in combination with toripalimab were well tolerated in all doses evaluated. The combination showed encouraging preliminary clinical efficacy in patients with R/R HL refractory to anti-PD-1/L1 and/or anti-CD30.

TAB004 treatment slowed the growth of PDA xenograft compared to IgG control and enhanced survival of mice when combined with 5-FU. Since TAB004 significantly reduced colony forming potential and triggered anoikis in the PDA cells, we suggest that it could be used as a potential prophylactic agent to curb tumor relapse after surgery, prevent metastasis and help increase the efficacy of chemotherapeutic agents.

Icatolimab alone or in combination with toripalimab were well tolerated in all doses evaluated and showed preliminary clinical efficacy in patients with R/R lymphoma.

The response was still ongoing over 12 months in the melanoma patient who had progressed upon prior nivolumab and BRAF/MEK inhibitors treatments. Icatolimab monotherapy were well tolerated in all doses evaluated and showed preliminary clinical efficacy as a monotherapy. Icatolimab in combination with toripalimab (anti-PD-1) for the treatment of patients with advanced solid tumors is currently ongoing.

In addition, Ccr7 knockdown significantly attenuated the growth of KMPC44 cells. These results suggest that Fx is a promising candidate for pancreatic cancer chemoprevention that mediates the suppression of the CCL21/CCR7 axis, BTLA, tumor microenvironment, epithelial mesenchymal transition, and adhesion.

Expression of IL-1α was significantly correlated with the prognosis of RCC patients. IL-1α may participate in the development and progression of renal cancer through interactions with immune infiltrating mast cells. Our data demonstrate that IL-1α is a prognostic factor and potential therapeutic target for RCC.

However, the frequency of BTLA positive Ki67+ B cells in CLL was higher compared to corresponding cells from controls (p = 0.055) while there were no differences between the examined groups regarding frequency of BTLA negative Ki67+ B cells. Our studies suggest that miR-155-5p is involved in BTLA deficiency, affecting proliferation of CLL B cells, which may be one of the mechanisms responsible for CLL pathogenesis.

The comprehensive results showed that high IPI-IPM risk scores were correlated with immune-related signaling pathways, high KMT2D and CD79B mutation rates, and upregulation of inhibitory immune checkpoints, including PD-L1, BTLA, and SIGLEC7, indicating a greater potential response to ICB therapy. The IPI-IPM has independent prognostic significance for DLBCL patients, which provides an immunological perspective to elucidate the mechanisms of tumor progression and sheds light on the development of immunotherapy for DLBCL.

The dynamic nature of the TME, including the immune cells, nonimmune cells, and acellular components, can serve as viable targets for combination therapy in ATC. Understanding the complex interactions of these associated cells and the paradigm in which their secretions and components can serve as immunomodulators are critical points of understanding when trying to develop therapeutics specifically tailored for the anaplastic thyroid carcinoma microenvironment.

The two molecules currently approved clinically are ipilimumab and nivolumab, which target the molecules CTLA-4 and PD-1, respectively.A plethora of immunomodulatory molecules exist, many with redundant functions. New links are being uncovered between the expression of immunomodulatory molecules and the BRAFV600E genetic lesion in melanoma. Small molecule inhibitors of the MAPK pathway regulate the surface expression of this multifaceted molecule, making BTLA a promising target for immuno-oncology to be targeted in combination with small molecule inhibitors, potentially alleviating T regulatory cell activation and improving patient prognosis.

These therapeutic benefits of the CD47 blockade were further unleashed by adjuvant interferon-α, which stimulates cytotoxic cells, underscoring the importance of an inflamed microenvironment in facilitating the response to immunotherapy. Collectively, these findings support CD47 as a therapeutic target in treating mycosis fungoides and demonstrate a synergistic role of interferon-α in exploiting these clinical benefits.

Our identified and validated risk model based on six pyroptosis-related genes is an independent prognostic factor for BC patients. Through comprehensive analyses, the findings of our study uncovered the potential biomarkers and therapeutic target for the risk model based on PRGs.

Immune checkpoints including PD-1, LAG3, CTLA4, and BTLA were also differently expressed between the two groups. In patients with ccRCC, we created a 14-lncRNA-based predictor as a robust prognostic and predictive tool for OS.

This pilot study proposes hypotheses for understanding the resistance to immunotherapies in patients with Hodgkin lymphoma. Hodgkin lymphoma exposed to anti-PD-1 correlated in tumor microenvironment with an immune depletion of CD8+ T lymphocytes and overexpression of LAG-3 on CD4+ helper T lymphocytes.

Nevertheless, clinically used combination regimens such as FOLFIRINOX and gemcitabine (Gem)/nab-paclitaxel still face major challenges due to lack of the safe and ratiometric delivery of multiple drugs...The platform is also rendered with additional tumor-specificity via a novel tumor-associated mucin1 (tMUC1)-specific antibody, TAB004. Overall, the platform suppresses tumor growth and eliminates the off-target toxicities of a highly toxic chemotherapy combination.

Blinatumomab is a bispecific T-cell engager (BiTE ® ) construct approved for treatment of relapsed/refractory (r/r) B-cell precursor acute lymphoblastic leukemia (BCP-ALL)...Mimicking the clinical application in an in vitro model system, we showed previously that continuous stimulation (CONT) with AMG 562, a half-life extended CD19xCD3 BiTE ® construct, induces T-cell exhaustion, as seen in chronic infections...In future analyses we will correlate RNA expression levels to functional traits using whole genome co-expression network analysis (WGCNA). Thereby we aim to identify gene clusters critical for persistent T-cell function that might serve as targets to improve efficacy of T-cell based immunotherapies.

Compared with non-inflamed controls, levels of soluble and membrane-bound immunomodulatory molecules were systemically and locally altered in MC and UC patients, with most analytes being decreased in serum but enhanced in colonic biopsies. These findings contribute to knowledge about checkpoint molecules and their role as biomarkers in MC and may also contribute to knowledge about possible mechanisms behind the seemingly protective effects of MC against colorectal cancer.

In addition, the Kyoto Encyclopedia of Genes and Genomes (KEGG) showed that PLA2G4E-AS1, AC063976.1, and LINC01592 were primarily associated with TNF signaling pathway, NF-kappa B signaling pathway, and ECM-receptor interaction. We developed EMT-related lncRNA PLA2G4E-AS1, AC063976.1, and LINC01592 for prognostic prediction and risk stratification of Chinese ESCC patients, which might provide deep insight for personalized prognosis prediction in Chinese ESCC patients and be potential biomarkers for designing novel therapy.

In conclusion, EGFR expression was found to have different characteristics depending on breast cancer subtype. Especially, high EGFR ER-positive/HER2-negative breast cancer was significantly associated with better survival and immunity in tumor immune microenvironment.

Subgroup analysis revealed that a high miR-150 was associated with better OS in ER-positive/HER2-negative breast cancer in both cohorts ( p = 0.002 and 0.044, respectively), and in TNBC in the METABRIC cohort ( p = 0.006). In conclusion, miR-150 expression is associated with immune cell infiltration and immune response, as well as with better survival in breast cancer patients.

The ROS score was significantly associated with aggressive clinical factors, such as triple-negative breast cancer (TNBC) subtype, Nottingham histological grade, American Joint Committee on Cancer (AJCC) Stage and lymph node metastasis consistently in both GSE96058 and METABRIC (all p < 0.001). High ROS score was significantly associated with worse overall survival (OS) in the GSE96058 (hazard ratio (HR) = 3.59, 95% confidence interval (CI); 2.47-5.20, p < 0.001), as well as OS (HR = 1.55, 95%CI; 1.16-2.07, p = 0.002), disease-free survival (HR = 1.63, 95%CI; 1.10-2.43, p = 0.016), and disease-specific survival (HR = 2.57, 95%CI; 1.75-3.77, p < 0.001) in the METABRIC cohort. Subgroup analysis revealed that a high ROS score was significantly associated with worse OS in ER-positive/HER2-negative breast cancer in both cohorts.

The resident monocytes may foster a permissive microenvironment that facilitates HPV infection and persistence. Furthermore, the myeloid populations within HPV-associated tonsil cancers co-express the same immune checkpoints, providing insight into potential novel immunotherapeutic targets for HPV-associated head and neck cancers.

Among patients, the relative defect in secretory effector function of CD4 T cells was more pronounced at myeloma relapse (as seen in declined Th1/Treg and Th17/Treg cell rates). Although the contribution of PD-1 to MM clinical outcomes is suggestive, our study clearly indicated that the inappropriate expression of immune checkpoints (associated with dysfunctionality of CD4 T cells and disease clinical phase) might be responsible for the sub-optimal clinical response to therapeutic checkpoint inhibitors in MM.

Higher baseline levels of soluble ICPs in HCC patients suggest that the immune system could be already affected before antiviral treatment. Baseline sCD27, sCD40 levels can be used as HCC prognostic factors in HCV SVR patients . sCD27 may promote cancer cell proliferation and protect them from apoptosis .

This is the first preclinical investigation into the effects of combination checkpoint blockade with anti-PD-1 and anti-BTLA treatment in GBM. We also show a direct effect on activated immune cell populations such as CD4+ and CD8 + T cells and immunosuppressive regulatory T cells through this combination therapy.

The immune activity of B cells and macrophages was higher in the low-risk group, while the immune activity of natural killer cells and T cells was higher in the high-risk group. Thus, the three-gene signature closely related to immunosuppressive TME could predict the risk and prognosis in patients with EGFR-mutant LUAD.

These results indicated the potential roles of AKR1C1 in the immune reaction during the pathogenesis of breast cancer. This study firstly demonstrated that ferroptosis-related gene, AKR1C1, could be associated with immune microenvironment, thereby influencing the development and prognosis of patient with breast cancer.

No abstract available

In addition, HVEM seems to be involved in tumor immuno-evasion, especially in lung tumors lacking PD-L1 expression. Here, we propose to review the role of BTLA-HVEM in immuno-escape in order to highlight its potential for designing new immunotherapies.