Targeting Immune Checkpoints Research Articles

Moving toward improved immune checkpoint immunotherapy for advanced prostate cancer.

Human prostate cancer is a heterogenous malignancy that responds poorly to immunotherapy targeting immune checkpoints. The immunosuppressive tumor microenvironment that is typical of human prostate cancer has been the main obstacle to these treatments. The effectiveness of these therapies is also hindered by acquired resistance, leading to slow progress in prostate cancer immunotherapy. Results from the highly anticipated late-stage clinical trials of PD-1/PD-L1 immune checkpoint blockade in patients with advanced prostate cancer have highlighted some of the obstacles to immunotherapy. Despite the setbacks, there is much that has been learned about the mechanisms that drive resistance, and new strategies are being developed and tested. Here, we review the status of immune checkpoint blockade and the immunosuppressive tumor microenvironment and discuss factors contributing to innate and adaptive resistance to immune checkpoint blockade within the context of prostate cancer. We then examine current strategies aiming to overcome these challenges as well as prospects.

Acyl-CoA Thioesterase 8 (ACOT8) is a Poor Prognostic Biomarker in Breast Cancer.

This study aimed to investigate the expression of Acyl-CoA thioesterase 8 (ACOT8) in breast cancer (BC) and its association with clinicopathological characteristics, patient survival, and immune infiltration. We conducted a comprehensive analysis of ACOT8 mRNA differential expression across various cancer types, followed by survival analysis. We focused on BC, where ACOT8 expression was evaluated at both the mRNA and protein levels using online databases, qRT-PCR, and immunohistochemistry. Associations between ACOT8 expression and clinicopathological parameters were assessed using different databases. Additionally, we investigated the prognostic significance of ACOT8 in BC patients by analyzing various cohorts and databases. Furthermore, we predicted a potential signaling pathway and identified miR-1-3p as a possible upstream regulator of ACOT8. Finally, the relationship between ACOT8 and immune system infiltration, as well as immune checkpoint molecules, was examined. Our findings demonstrated upregulated ACOT8 mRNA and protein levels in BC. Elevated ACOT8 expression correlated positively with various clinicopathological characteristics, indicating an unfavorable prognosis for patients. Functional enrichment analysis suggested ACOT8 involvement in lipid metabolism, mitochondrial components, and ribosomal functions. Moreover, we identified connections between ACOT8 and immune system markers, immune cell infiltration, and immune checkpoints. This study provides compelling evidence for ACOT8 upregulation in BC and its association with clinicopathological features and patient outcomes. Additionally, our findings suggest that targeting ACOT8 and immune checkpoints might enhance the effectiveness of immunotherapy in BC patients.

CRP and soluble CTLA4 are determinants of anti-PD1 resistance in gastrointestinal cancer.

Targeting immune inhibitory checkpoint (IC) pathways have attracted great attention as a promising strategy for treating gastrointestinal (GI) cancer. However, the therapeutic efficacy is low in most cases, and little progress has been made in establishing biomarkers that predict the possible responses, and combination regimens that enhance the therapeutic efficacy. As a predictive biomarker, soluble forms of IC molecules have been recently highlighted. However, little is known about which IC molecules is most critically associated with the treatment resistance, and also about the biological and immunological roles of the IC molecules in GI cancer. In this study, we analyzed sera obtained from advanced gastric cancer patients before and one month after treatment with anti-PD1 nivolumab for soluble IC molecules by ELISA. We found that decrease of soluble CTLA4 (sCTLA4) at posttreatment were significantly associated with a better prognosis, and combination with low level of CRP at posttreatment more clearly defined anti-PD1 responders with long-term survival. Indeed, in the in vitro setting, CRP stimulation upregulated CTLA4 expression in tumor cells followed by generation of sCTLA4 that suppressed CTL induction, and simultaneously conferred high self-renewal and invasive abilities on the tumor cells accompanied by increase of EMT-related gene expressions. In the in vivo setting, CRP injection elevated sCTLA4 level in sera of mouse tumor metastasis models, leading to failure of anti-PD1 therapy. However, treatment with anti-CTLA4 mAb or a PPARγ agonist that can reduce in vivo CRP successfully elicited anti-tumor efficacy in the anti-PD1 resistant models. These suggest that targeting CRP and sCTLA4 may be a promising strategy for improving clinical outcomes in the treatments, including anti-PD1 therapy, of GI cancer.

Oleate alters the immune response in non-small cell lung adenocarcinoma through regulation of HMGB1 release.

Background: Cancer cell evasion of the immune response is critical to cancer development and metastases. Clinicians' ability to kickstart the immune system to target these rogue cells is an ever-growing area of research and medicine. This study delved into the relationship between lipid metabolism, High Mobility Group Box 1 protein (HMGB1)-a pro-inflammatory damage-associated molecular pattern protein-and immune regulation within non-small cell lung adenocarcinoma (NSCLC). Method: To address this question, we used a combination of proteomics, molecular biology, and bioinformatic techniques to investigate the relationship between fatty acids and immune signals within NSCLC. Results: We found that the expression of stearoyl CoA desaturase 1 (SCD1) was decreased in NSCLC tumors compared to normal tissues. This emphasized the critical role of lipid metabolism in tumor progression. Interestingly, monounsaturated fatty acid (MUFA) availability affected the expression of programmed death ligand-1 (PD-L1), a pivotal immune checkpoint target in lung cancer cells and immune cells, as well as HMGB1, suggesting a novel approach to modulating the immune response. This study uncovered a complex interplay between SCD1, PD-L1, and HMGB1, influencing the immunological sensitivity of tumors. Conclusion: Our work underscores the critical importance of understanding the intricate relationships between lipid metabolism and immune modulation to develop more effective NSCLC treatments and personalized therapies. As we continue to explore these connections, we hope to contribute significantly to the ever-evolving field of cancer research, improving patient outcomes and advancing precision medicine in NSCLC.

Antagonizing Vasoactive Intestinal Peptide (VIP) Receptors on CAR T Cells Improves Efficacy and Persistence

Vasoactive intestinal peptide (VIP) is an emerging checkpoint pathway for T cell function 1. VIP is expressed by both T cells 2,3 and tumor cells 1 and is upregulated during TCR activation 1,4,5. Augmentation of the VIP/VIPR axis during expansion of primary human T cells enhances less differentiated T cell phenotypes, anti-tumor cytotoxicity, and in vivo persistence 6. In this work, we elucidate the mechanisms by which the VIP/VIPR axis is a critical and targetable immune checkpoint pathway for chimeric antigen receptor (CAR) T cell therapy. By engineering CAR T cells to secrete novel and potent VIPR antagonistic peptides, these cells can overcome the immunosuppression of VIP-rich tumor microenvironments. First, we demonstrated that VIP suppresses CAR T cell function as evident by reduced expansion with exogenous VIP supplementation, which can be rescued by the addition of VIPRa peptides. The VIP/VIPR axis is relevant to CAR T cell signaling as these cells produce VIP after antigen stimulation and upregulate VIPR expression. In fact, polyfunctionality and cytotoxic killing is enhanced by VIPR knockout of CAR T cells. Together, these results demonstrate the critical role of the VIP/VIPR axis in CAR T cell function. To harness this axis, CAR T cells were engineered to secrete VIPRa peptides (VIPRa CAR T) to provide continuous and localized delivery of VIPRa peptides. Continuously delivered VIPR antagonism increases the viability and proportions of less-differentiated and less-exhaustive phenotypes of CAR T cells at baseline. Functionally, VIPRa CAR T cells have a proliferative advantage and enhanced activation compared to parental CAR T cells. RNA sequencing was performed on VIPRa CAR T cells before and after antigen-stimulation to illuminate in-depth phenotypic and functional differences compared parental CAR T cells. Finally, these novel CAR T cells were tested in xenograft and syngeneic mouse models. VIPRa CAR T cells show improved tumor control and persistence as evidence long-lived circulating cells in the peripheral blood. To validate the clinical relevance of this target for CAR T therapy, patient-derived xenograft (PDX) pancreatic tumors were assayed to show robust expression of VIP. VIPRa CAR T cells significantly reduced tumor burden and improved survival in PDX tumor-bearing mice. Collectively, this data demonstrates that targeting VIP is a novel and successful approach to improving CAR T cell anti-tumor efficacy. VIPR antagonism enhances initial CAR T cell phenotypes and function, which has the potential to improve CAR T cell therapy for a variety of tumor types. The mechanisms by which CAR T cell-mediated delivery of VIPRa peptides can modulate tumor microenvironments in a syngeneic model are currently being evaluated. VIPRa CAR T cells are a uniquely improved cellular therapy capable of enhanced anti-tumor function against clinically relevant tumors.

Site-Selective Functionalized PD-1 Mutant for a Modular Immunological Activity against Cancer Cells.

Targeting immune checkpoints is a well-established strategy in cancer therapy, and antibodies blocking PD-1/PD-L1 interactions to restore the immunological activity against cancer cells have been clinically validated. High-affinity mutants of the PD-1 ectodomain have recently been proposed as an alternative to antibodies to target PD-L1 on cancer cells, shedding new light on this research area. In this dynamic scenario, the PD-1 mutant, here reported, largely expands the chemical space of nonantibody and nonsmall-molecule inhibitor therapeutics that can be used to target cancer cells overexpressing PD-L1 receptors. The polyethylene glycol moieties and the immune response-stimulating carbohydrates, used as site-selective tags, represent the proof of concept for future applications.

The prognostic impact of SIGLEC5-induced impairment of CD8+ T cell activation in sepsis

Sepsis is associated with T-cell exhaustion, which significantly reduces patient outcomes. Therefore, targeting of immune checkpoints (ICs) is deemed necessary for effective sepsis management. Here, we evaluated the role of SIGLEC5 as an IC ligand and explored its potential as a biomarker for sepsis. Invitro and invivo assays were conducted to both analyse SIGLEC5's role as an IC ligand, as well as assess its impact on survival in sepsis. A multicentre prospective cohort study was conducted to evaluate the plasmatic soluble SIGLEC5 (sSIGLEC5) as a mortality predictor in the first 60 days after admission in sepsis patients. Recruitment included sepsis patients (n=346), controls with systemic inflammatory response syndrome (n=80), aneurism (n=11), stroke (n=16), and healthy volunteers (HVs, n=100). SIGLEC5 expression on monocytes was increased by HIF1α and was higher in septic patients than in healthy volunteers after exvivo LPS challenge. Furthermore, SIGLEC5-PSGL1 interaction inhibited CD8+ T-cell proliferation. Administration of sSIGLEC5r (0.8 mg/kg) had adverse effects in mouse endotoxemia models. Additionally, plasma sSIGLEC5 levels of septic patients were higher than HVs and ROC analysis revealed it as a mortality marker with an AUC of 0.713 (95% CI, 0.656-0.769; p<0.0001). Kaplan-Meier survival curve showed a significant decrease in survival above the calculated cut-off (HR of 3.418, 95% CI, 2.380-4.907, p<0.0001 by log-rank test) estimated by Youden Index (523.6ng/mL). SIGLEC5 displays the hallmarks of an IC ligand, and plasma levels of sSIGLEC5 have been linked with increased mortality in septic patients. Instituto de Salud Carlos III (ISCIII) and "Fondos FEDER" to ELC (PIE15/00065, PI18/00148, PI14/01234, PI21/00869), CDF (PI21/01178), RLR (FI19/00334) and JAO (CD21/00059).

Potential subtype-specific therapeutic approaches in small cell lung cancer.

Small cell lung cancer (SCLC) remains one of the most aggressive thoracic malignancies with an especially dismal prognosis. While the detection of various targetable driver mutations and immune checkpoints have revolutionized the treatment of non-small cell lung cancer (NSCLC), there has been only modest therapeutic innovation over the past decades in SCLC. In this review, we aim to provide a brief summary on the clinical relevance of recent research findings, which could soon pave the way towards a more personalized and targeted management of SCLC patients. Substantial research on the biological and molecular heterogeneity of SCLC has been conducted in the last years. Recent results from comprehensive profiling studies have shown that unique major SCLC subtypes can be distinguished based on the relative expression of key transcription regulators (ASCL1, NEUROD1, POU2F3) or distinct inflammatory features. Understanding the differing molecular characteristics of these distinct subtypes has resulted in the identification of specific therapeutic vulnerabilities. The recently introduced molecular SCLC subtype classification represents a substantial progress towards a personalized and more efficacious approach in SCLC. The consequences of this paradigm shift provide hope for improved patient care and clinical outcomes in this exceptionally lethal thoracic malignancy.

Characterization of Immunosuppressive Myeloid Cells in Merkel Cell Carcinoma: Correlation with Resistance to PD-1 Pathway Blockade.

Merkel cell carcinoma (MCC) is a highly immunogenic skin cancer. Although essentially all MCCs are antigenic through viral antigens or high tumor mutation burden, MCC has a response rate of only approximately 50% to PD-(L)1 blockade suggesting barriers to T-cell responses. Prior studies of MCC immunobiology have focused on CD8 T-cell infiltration and their exhaustion status, while the role of innate immunity, particularly myeloid cells, in MCC remains underexplored. We utilized single-cell transcriptomics from 9 patients with MCC and multiplex IHC staining of 54 patients' preimmunotherapy tumors, to identify myeloid cells and evaluate association with immunotherapy response. Single-cell transcriptomics identified tumor-associated macrophages (TAM) as the dominant myeloid component within MCC tumors. These TAMs express an immunosuppressive gene signature characteristic of monocytic myeloid-derived suppressor cells and importantly express several targetable immune checkpoint molecules, including PD-L1 and LILRB receptors, that are not present on tumor cells. Analysis of 54 preimmunotherapy tumor samples showed that a subset of TAMs (CD163+, CD14+, S100A8+) selectively infiltrated tumors that had significant CD8 T cells. Indeed, higher TAM prevalence was associated with resistance to PD-1 blockade. While spatial interactions between TAMs and CD8 T cells were not associated with response, myeloid transcriptomic data showed evidence for cytokine signaling and expression of LILRB receptors, suggesting potential immunosuppressive mechanisms. This study further characterizes TAMs in MCC tumors and provides insights into their possible immunosuppressive mechanism. TAMs may reduce the likelihood of treatment response in MCC by counteracting the benefit of CD8 T-cell infiltration. See related commentary by Silk and Davar, p. 1076.

B7H3 targeting gold nanocage pH-sensitive conjugates for precise and synergistic chemo-photothermal therapy against NSCLC

BackgroundThe combination of drug delivery with immune checkpoint targeting has been extensively studied in cancer therapy. However, the clinical benefit for patients from this strategy is still limited. B7 homolog 3 protein (B7-H3), also known as CD276 (B7-H3/CD276), is a promising therapeutic target for anti-cancer treatment. It is widely overexpressed on the surface of malignant cells and tumor vasculature, and its overexpression is associated with poor prognosis. Herein, we report B7H3 targeting doxorubicin (Dox)-conjugated gold nanocages (B7H3/Dox@GNCs) with pH-responsive drug release as a selective, precise, and synergistic chemotherapy-photothermal therapy agent against non-small-cell lung cancer (NSCLC).ResultsIn vitro, B7H3/Dox@GNCs exhibited a responsive release of Dox in the tumor acidic microenvironment. We also demonstrated enhanced intracellular uptake, induced cell cycle arrest, and increased apoptosis in B7H3 overexpressing NSCLC cells. In xenograft tumor models, B7H3/Dox@GNCs exhibited tumor tissue targeting and sustained drug release in response to the acidic environment. Wherein they synchronously destroyed B7H3 positive tumor cells, tumor-associated vasculature, and stromal fibroblasts.ConclusionThis study presents a dual-compartment targeted B7H3 multifunctional gold conjugate system that can precisely control Dox exposure in a spatio-temporal manner without evident toxicity and suggests a general strategy for synergistic therapy against NSCLC.

Single-cell mass cytometric analysis of peripheral immunity and multiplex plasma marker profiling of non-small cell lung cancer patients receiving PD-1 targeting immune checkpoint inhibitors in comparison with platinum-based chemotherapy.

The effect of platinum-based chemotherapy (Chem.) and second- or multiple- line immune checkpoint PD-1 blocking therapy by Nivolumab or Pembrolizumab (ICI) was assayed in the peripheral blood of non-small cell lung cancer (NSCLC) patients. Flow cytometry was used to detect NSCLC-related antigen binding IgG antibodies. The Luminex MagPix multiplex bead-based cytokine/chemokine detecting system was used to quantitatively measure 17 soluble markers in the plasma samples. Single-cell mass cytometry was applied for the immunophenotyping of peripheral leukocytes. The incubation of patient derived plasma with human NSCLC tumor cell lines, such as A549, H1975, and H1650, detected NSCLC-specific antibodies reaching a maximum of up to 32% reactive IgG-positive NSCLC cells. The following markers were detected in significantly higher concentration in the plasma of Chem. group versus healthy non-smoker and smoker controls: BTLA, CD27, CD28, CD40, CD80, CD86, GITRL, ICOS, LAG-3, PD-1, PD-L1, and TLR-2. The following markers were detected in significantly higher concentration in the plasma of ICI group versus healthy non-smoker and smoker controls: CD27, CD28, CD40, GITRL, LAG-3, PD-1, PD-L1, and TLR-2. We showed the induction of CD69 and IL-2R on CD4+ CD25+ T-cells upon chemotherapy; the exhaustion of one CD8+ T-cell population was detected by the loss of CD127 and a decrease in CD27. CD19+CD20+, CD79B+, or activated B-cell subtypes showed CD69 increase and downregulation of BTLA, CD27, and IL-2R in NSCLC patients following chemotherapy or ICI. Peripheral immunophenotype caused by chemotherapy or PD-1 blocking was shown in the context of advanced NSCLC.

Immune checkpoint targeting antibodies hold promise for combinatorial cancer therapeutics.

Through improving the immune system's ability to recognize and combat tumor cells as well as its receptivity to changes in the tumor microenvironment, immunotherapy has emerged as a highly successful addition to the treatment of cancer. However, tumor heterogeneity poses a significant challenge in cancer therapy as it can undermine the anti-tumor immune response through the manipulation of the extracellular matrix. To address these challenges and improve targeted therapies and combination treatments, the food and drug administration has approved several immunomodulatory antibodies to suppress immunological checkpoints. Combinatorial therapies necessitate the identification of multiple targets that regulate the intricate communication between immune cells, cytokines, chemokines, and cellular responses within the tumor microenvironment. The purpose of this study is to provide a comprehensive overview of the ongoing clinical trials involving immunomodulatory antibodies in various cancer types. It explores the potential of these antibodies to modulate the immune system and enhance anti-tumor responses. Additionally, it discusses the perspectives and prospects of immunomodulatory therapeutics in cancer treatment. Although immunotherapy shows great promise in cancer treatment, it is not exempt from side effects that can arise due to hyperactivity of the immune system. Therefore, understanding the intricate balance between immune activation and regulation is crucial for minimizing these adverse effects and optimizing treatment outcomes. This study aims to contribute to the growing body of knowledge surrounding immunomodulatory antibodies and their potential as effective therapeutic options in cancer treatment, ultimately paving the way for improved patient outcomes and deepening our perception of the intricate interactivity between the immune system and tumors.

1116P Long term outcome of complete responders to immune checkpoint inhibitors (ICI) or target therapy (TT) in advanced melanoma

1116P Long term outcome of complete responders to immune checkpoint inhibitors (ICI) or target therapy (TT) in advanced melanoma

3O IGSF8 is an innate immune checkpoint and cancer immunotherapy target

3O IGSF8 is an innate immune checkpoint and cancer immunotherapy target

Development of a 1:1-binding biparatopic anti-TNFR2 antagonist by reducing signaling activity through epitope selection

Conventional bivalent antibodies against cell surface receptors often initiate unwanted signal transduction by crosslinking two antigen molecules. Biparatopic antibodies (BpAbs) bind to two different epitopes on the same antigen, thus altering crosslinking ability. In this study, we develop BpAbs against tumor necrosis factor receptor 2 (TNFR2), which is an attractive immune checkpoint target. Using different pairs of antibody variable regions specific to topographically distinct TNFR2 epitopes, we successfully regulate the size of BpAb–TNFR2 immunocomplexes to result in controlled agonistic activities. Our series of results indicate that the relative positions of the two epitopes recognized by the BpAb are critical for controlling its signaling activity. One particular antagonist, Bp109-92, binds TNFR2 in a 1:1 manner without unwanted signal transduction, and its structural basis is determined using cryo-electron microscopy. This antagonist suppresses the proliferation of regulatory T cells expressing TNFR2. Therefore, the BpAb format would be useful in designing specific and distinct antibody functions.

Targeting DNA Damage Repair and Immune Checkpoint Proteins for Optimizing the Treatment of Endometrial Cancer.

The dependence of cancer cells on the DNA damage response (DDR) pathway for the repair of endogenous- or exogenous-factor-induced DNA damage has been extensively studied in various cancer types, including endometrial cancer (EC). Targeting one or more DNA damage repair protein with small molecules has shown encouraging treatment efficacy in preclinical and clinical models. However, the genes coding for DDR factors are rarely mutated in EC, limiting the utility of DDR inhibitors in this disease. In the current review, we recapitulate the functional role of the DNA repair system in the development and progression of cancer. Importantly, we discuss strategies that target DDR proteins, including PARP, CHK1 and WEE1, as monotherapies or in combination with cytotoxic agents in the treatment of EC and highlight the compounds currently being evaluated for their efficacy in EC in clinic. Recent studies indicate that the application of DNA damage agents in cancer cells leads to the activation of innate and adaptive immune responses; targeting immune checkpoint proteins could overcome the immune suppressive environment in tumors. We further summarize recently revolutionized immunotherapies that have been completed or are now being evaluated for their efficacy in advanced EC and propose future directions for the development of DDR-based cancer therapeutics in the treatment of EC.

Polymorphic KIR3DL3 expression modulates tissue-resident and innate-like T cells.

Most human killer cell immunoglobulin-like receptors (KIR) are expressed by natural killer (NK) cells and recognize HLA class I molecules as ligands. KIR3DL3 is a conserved but polymorphic inhibitory KIR recognizing a B7 family ligand, HHLA2, and is implicated for immune checkpoint targeting. The expression profile and biological function of KIR3DL3 have been somewhat elusive, so we searched extensively for KIR3DL3 transcripts, revealing highly enriched expression in γδ and CD8+ T cells rather than NK cells. These KIR3DL3-expressing cells are rare in the blood and thymus but more common in the lungs and digestive tract. High-resolution flow cytometry and single-cell transcriptomics showed that peripheral blood KIR3DL3+ T cells have an activated transitional memory phenotype and are hypofunctional. The T cell receptor (TCR) usage is biased toward genes from early rearranged TCR-α variable segments or Vδ1 chains. In addition, we show that TCR-mediated stimulation can be inhibited through KIR3DL3 ligation. Whereas we detected no impact of KIR3DL3 polymorphism on ligand binding, variants in the proximal promoter and at residue 86 can reduce expression. Together, we demonstrate that KIR3DL3 is up-regulated alongside unconventional T cell stimulation and that individuals may vary in their ability to express KIR3DL3. These results have implications for the personalized targeting of KIR3DL3/HHLA2 checkpoint inhibition.

PVR expression in tumor microenvironment of advanced hepatocellular carcinoma.

e16113 Abstract Background: PVR (CD155)/TIGIT signaling has been investigated as a new immune checkpoint target in many cancers, including hepatocellular carcinoma (HCC). However, the expression and clinical significance of PVR, the ligand of TIGIT, have not been explored in the tumor microenvironment (TME) of advanced HCC. Methods: Patients with HCC who had adequate tumor tissues obtained at advanced stage were enrolled in the study. The membranous staining of PVR of tumor tissues, detected by immunohistochemistry (IHC), was semiquantitatively scored as IHC 0, 1, 2, or 3 if &lt; 1%, ≥1% but &lt; 5%, ≥5% but &lt; 10%, or ≥10% of tumor cells (TCs) and tumor-infiltrating immune cells (ICs) were PVR positive. The correlation of PVR expressions and other clinic-pathologic factors was analyzed. Results: Sixty-seven patients were included in the study. Among them, 57 (85.1%) were male, 32 (47.8%) were aged over 60 years, 48 (71.6%) were HBV-reactive, and 23 (34.3%) had been treated with sorafenib before obtaining tumor tissues. Thirteen (19.4%) and 18 (26.9%) tumor samples showed positive PVR expressions in TCs and ICs, respectively (TCs, IHC 1/2/3: 3/3/7; ICs, IHC 1/2/3: 7/3/8). The expressions of PVR in TCs or ICs were not associated with sex, age, HBV/HCV infection, previous sorafenib treatment, or overall survival of the patients. Notably, in both TCs and ICs, the intensities of PVR expression were inversely correlated with PD-L1 expression for patients with at least IHC ≥1 in either PVR or PD-L1 (TCs, n = 26, r = -0.6966, p &lt; 0.0001; ICs, n = 46, r = -0.4548, p = 0.0015). Conclusions: PVR expression can be identified in both TCs and ICs of TME of advanced HCC. The expressions of PVR and PD-L1 were inversely correlated. These findings may provide clinical implications for development of combination immunotherapy in advanced HCC. (This work is supported by grants from the Ministry of Science and Technology, Taiwan, MOST 110-2314-B-002-204-MY3). [Table: see text]

Phase 1 study of LB1410, a bivalent TIM-3/PD-1 bispecific antibody, in patients with advanced solid tumors or lymphoma.

TPS2663 Background: Cancer immunotherapies targeting PD-1 or PD-L1 have been proven effective in causing durable antitumor immune responses with less toxicity in many types of tumors. However, the response rate of anti-PD-1/PD-L1 treatments is far from satisfactory and most patients show primary or acquired resistance to the treatments. Tim-3, one of the next generation of immune checkpoint targets, co-expressed on exhausted T cells with PD-1. It is also expressed by innate immune populations, including NK and DC. Dual blocking PD-1 and Tim-3 not only on T cells but also on DC, NK cells may achieve better clinical benefit. LB1410 is a recombinant humanized anti-PD-1/TIM-3 bispecific antibody (BsAb) developed by L&amp;L Biopharma Co., Ltd. for the patients who are resistant to or refractory from PD-1/PD-L1 treatments. It blocked the immune checkpoint PD-1 and TIM-3-mediated immunosuppressive signal pathways simultaneously, showed better T/DC cell activity and in vivo anti-tumor efficacy compared to Tim-3 and PD-1 antibody combination in preclinical studies. Methods: This is a FIH, multicenter, non-randomized, open label, phase 1 study of LB1410 in Participants With Advanced Solid Tumor or Lymphoma（Keyplus-001）. The planned sample size is approximately 100 patients in two parts: part 1 dose escalation will evaluate safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and determine the maximum tolerated dose (MTD) and/or the recommended phase 2 dose (RP2D), and Part 2 dose expansion will further characterize the safety profile and preliminary tumor response in several cohorts including NSCLC, CRC, EC etc. Enrollment criteria include adults with life expectancy of &gt; 3 months, ECOG performance status 0-1，histologically or cytologically confirmed advanced and/or metastatic solid tumor malignancies or lymphoma for which standard treatment fails, or no standard treatment is available, or standard treatment is not applicable at this stage. Exclusion criteria include pregnancy, lactation, or breastfeeding, ongoing or recent evidence of significant autoimmune disease that required treatment with systemic immunosuppressive treatments. The primary endpoints are incidence of dose limiting toxicities and adverse events, MTD, and recommended phase 2 dose. Secondary objectives will evaluate PK parameters, preliminary antitumor activity, and immunogenicity of LB1410. Besides, the pharmacodynamics (PD) biomarkers related to LB1410 treatment, clinical activity will be explored. This clinical trial is in progress; cohorts 1 to 5 in dose escalation part have been completed. Clinical trial information: NCT05357651 .

Targeting immune checkpoints on tumor-associated macrophages in tumor immunotherapy.

Unprecedented breakthroughs have been made in cancer immunotherapy in recent years. Particularly immune checkpoint inhibitors have fostered hope for patients with cancer. However, immunotherapy still exhibits certain limitations, such as a low response rate, limited efficacy in certain populations, and adverse events in certain tumors. Therefore, exploring strategies that can improve clinical response rates in patients is crucial. Tumor-associated macrophages (TAMs) are the predominant immune cells that infiltrate the tumor microenvironment and express a variety of immune checkpoints that impact immune functions. Mounting evidence indicates that immune checkpoints in TAMs are closely associated with the prognosis of patients with tumors receiving immunotherapy. This review centers on the regulatory mechanisms governing immune checkpoint expression in macrophages and strategies aimed at improving immune checkpoint therapies. Our review provides insights into potential therapeutic targets to improve the efficacy of immune checkpoint blockade and key clues to developing novel tumor immunotherapies.