Immune checkpoint of B7-H3 in cancer: from immunology to clinical immunotherapy

Journal of Hematology & Oncology, Journal Year: 2022, Volume and Issue: 15(1)

Published: Oct. 25, 2022

Immunotherapy for cancer is a rapidly developing treatment that modifies the immune system and enhances antitumor response. B7-H3 (CD276), member of B7 family plays an immunoregulatory role in T cell response, has been highlighted as novel potential target immunotherapy. shown to play inhibitory activation proliferation, participate tumor evasion influence both response behavior through different signaling pathways. expression found be aberrantly upregulated many types, association between poor prognosis established. targeting approaches rapidly, ongoing clinical trials are exploring safety efficacy profiles these therapies cancer. In this review, we summarize emerging research on function underlying pathways B7-H3, roles advances B7-H3-targeted therapy. Considering microenvironment characteristics results from preclinical models practice, indicates promising future immunotherapy, which might eventually contribute improvement immunotherapy will benefit patients.

Language: Английский

---

Dual checkpoint targeting of B7-H3 and PD-1 with enoblituzumab and pembrolizumab in advanced solid tumors: interim results from a multicenter phase I/II trial

Journal for ImmunoTherapy of Cancer, Journal Year: 2022, Volume and Issue: 10(4), P. e004424 - e004424

Published: April 1, 2022

Background Availability of checkpoint inhibitors has created a paradigm shift in the management patients with solid tumors. Despite this, most do not respond to immunotherapy, and there is considerable interest developing combination therapies improve response rates outcomes. B7-H3 (CD276) member B7 family cell surface molecules provides an alternative immune molecule therapeutically target alone or programmed death-1 (PD-1)–targeted therapies. Enoblituzumab, investigational anti-B7-H3 humanized monoclonal antibody, incorporates immunoglobulin G1 fragment crystallizable (Fc) domain that enhances Fcγ receptor-mediated antibody-dependent cellular cytotoxicity. Coordinated engagement innate adaptive immunity by targeting distinct members (B7-H3 PD-1) hypothesized provide greater antitumor activity than either agent alone. Methods In this phase I/II study, received intravenous enoblituzumab (3–15 mg/kg) weekly plus pembrolizumab (2 every 3 weeks during dose-escalation cohort expansion. Expansion cohorts included non–small lung cancer (NSCLC; inhibitor [CPI]–naïve post-CPI, death-ligand 1 [PD-L1] <1%), head neck squamous carcinoma (HNSCC; CPI-naïve), urothelial (post-CPI), melanoma (post-CPI). Disease was assessed using Response Evaluation Criteria Solid Tumors version 1.1 after 6 9 thereafter. Safety pharmacokinetic data were provided for all enrolled patients; efficacy focused on HNSCC NSCLC cohorts. Results Overall, 133 ≥1 dose study treatment. The maximum tolerated at 2 mg/kg reached. Intravenous (15 recommended II evaluation. Treatment-related adverse events occurred 116 (87.2%) grade ≥3 28.6%. One treatment-related death (pneumonitis). Objective responses 18 (33.3% [95% CI 13.3 59.0]) CPI-naïve 5 14 (35.7% 12.8 64.9]) NSCLC. Conclusions Checkpoint demonstrated acceptable safety Trial registration number NCT02475213 .

Language: Английский

---

New frontiers in immune checkpoint B7-H3 (CD276) research and drug development

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: March 2, 2023

B7-H3 (CD276), a member of the B7 family proteins, is key player in cancer progression. This immune checkpoint molecule selectively expressed both tumor cells and within microenvironment. In addition to its function, has been linked cell proliferation, metastasis, therapeutic resistance. Furthermore, drastic difference protein expression levels between normal tissues suggests that targeting with drugs would lead cancer-specific toxicity, minimizing harm healthy cells. These properties make promising target for therapy.Recently, important advances research drug development have reported, these new findings, including involvement cellular metabolic reprograming, stem enrichment, senescence obesity, expanded our knowledge understanding this molecule, which guiding future strategies B7-H3. review, we briefly discuss biology function development. We emphasize more on latest findings their underlying mechanisms reflect research. addition, improvements B-H3 inhibitors

Language: Английский

---

Unraveling the complexity of STAT3 in cancer: molecular understanding and drug discovery

Journal of Experimental & Clinical Cancer Research, Journal Year: 2024, Volume and Issue: 43(1)

Published: Jan. 20, 2024

Abstract Signal transducer and activator of transcription 3 (STAT3) is a transcriptional factor involved in almost all cancer hallmark features including tumor proliferation, metastasis, angiogenesis, immunosuppression, inflammation, metabolism reprogramming, drug resistance, stemness. Therefore, STAT3 has become promising therapeutic target wide range cancers. This review focuses on the up-to-date knowledge signaling cancer. We summarize both positive negative modulators together with hallmarks involving activities regulated by highlight its extremely sophisticated regulation immunosuppression microenvironment metabolic reprogramming. Direct indirect inhibitors preclinical clinical studies also have been summarized discussed. Additionally, we propose new strategies targeting STAT3-based combinations established chemotherapy, targeted therapy, immunotherapy combination therapy. These efforts may provide perspectives for therapy

Language: Английский

---

Interrogation of endothelial and mural cells in brain metastasis reveals key immune-regulatory mechanisms

Cancer Cell, Journal Year: 2024, Volume and Issue: 42(3), P. 378 - 395.e10

Published: Jan. 21, 2024

Brain metastasis (BrM) is a common malignancy, predominantly originating from lung, melanoma, and breast cancers. The vasculature key component of the BrM tumor microenvironment with critical roles in regulating metastatic seeding progression. However, heterogeneity major vascular components, namely endothelial mural cells, still poorly understood. We perform single-cell bulk RNA-sequencing sorted cell types detect multiple subtypes enriched specifically compared to non-tumor brain, including previously unrecognized immune regulatory subtypes. integrate human data mouse models, creating platform interrogate targets for treatment BrM. find that CD276 checkpoint molecule significantly upregulated vasculature, anti-CD276 blocking antibodies prolonged survival preclinical trials. This study provides important insights into complex interactions between cancer translational relevance designing therapeutic interventions.

Language: Английский

---

CD276-dependent efferocytosis by tumor-associated macrophages promotes immune evasion in bladder cancer

Nature Communications, Journal Year: 2024, Volume and Issue: 15(1)

Published: April 1, 2024

Interplay between innate and adaptive immune cells is important for the antitumor response. However, tumor microenvironment may turn suppressive, associated macrophages are playing a role in this transition. Here, we show that CD276, expressed on tumor-associated (TAM), play diminishing response against tumors. Using model of tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine BLCA male mice genetic ablation CD276 TAMs blocks efferocytosis enhances expression major histocompatibility complex class II (MHCII) TAMs. This increases CD4 + cytotoxic CD8 T cell infiltration tumor. Combined single RNA sequencing functional experiments reveal activates lysosomal signaling pathway transcription factor JUN to regulate AXL MerTK, resulting enhanced Proving principle, simultaneous blockade PD-1 restrain growth better than any components as intervention. Taken together, our study supports TAMs, which potentially targetable combination therapy.

Language: Английский

---

High B7-H3 expression with low PD-L1 expression identifies armored-cold tumors in triple-negative breast cancer

npj Breast Cancer, Journal Year: 2024, Volume and Issue: 10(1)

Published: Jan. 27, 2024

Triple-negative breast cancer (TNBC) is generally regarded as the most aggressive subtype among cancers, but exhibits higher chemotherapeutic and immunotherapeutic responses due to its unique immunogenicity. Thus, appropriate discrimination of subtypes critical for guiding therapeutic options in clinical practice. In this research, using multiple in-house public cohorts, we investigated expression features immuno-correlations B7-H3 checked anti-tumor effect monoclonal antibody a mouse model. We also developed novel classifier combining PD-L1 TNBC. was revealed be related immuno-cold accumulated collagen addition, targeting significantly suppressed TNBC growth, reversed armored-cold phenotype, boosted anti-PD-1 immunotherapy. patients with high low showed lowest immune infiltration, highest level, therapies, which mostly belong tumors. Overall, research provides subtyping strategy based on combination B7-H3/PD-L1 expression, leads approach management

Language: Английский

---

Advances in CAR T cell therapy: antigen selection, modifications, and current trials for solid tumors

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 15

Published: Jan. 6, 2025

Chimeric antigen receptor (CAR) T cell therapy has revolutionized the treatment of hematologic malignancies, achieving remarkable clinical success with FDA-approved therapies targeting CD19 and BCMA. However, extension these successes to solid tumors remains limited due several intrinsic challenges, including heterogeneity immunosuppressive tumor microenvironments. In this review, we provide a comprehensive overview recent advances in CAR aimed at overcoming obstacles. We discuss importance identification by emphasizing tumor-specific tumor-associated antigens development antigens. Furthermore, highlight key structural innovations, cytokine-armored CARs, protease-regulated CARs engineered chemokine receptors, enhance infiltration activity within microenvironment. Additionally, novel manufacturing approaches, such as Sleeping Beauty transposon system, mRNA-based transfection, vivo production, are discussed scalable solution improve accessibility therapies. Finally, address critical therapeutic limitations, cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity (ICANS), suboptimal persistence cells. An examination emerging strategies for countering limitations reveals that CRISPR-Cas9-mediated genetic modifications combination utilizing checkpoint inhibitors can functionality durability. By integrating insights from preclinical models, trials, innovative engineering review addresses their performance tumors.

Language: Английский

---

Transcriptomic datasets of cancer patients treated with immune-checkpoint inhibitors: a systematic review

Journal of Translational Medicine, Journal Year: 2022, Volume and Issue: 20(1)

Published: May 31, 2022

Abstract The availability of immune-checkpoint inhibitors (ICI) in the last decade has resulted a paradigm shift certain areas oncology. Patients can be treated either by monotherapy anti-CTLA-4 (tremelimumab or ipilimumab), anti-PD-1 (nivolumab pembrolizumab), anti-PD-L1 (avelumab atezolizumab durvalumab) as combination therapy and anti-PD-1. To maximize clinical treatment benefit cancer immunotherapy, prediction actual immune response identification application clinically useful biomarkers will required. Whole transcriptomic datasets patients with ICI could provide basis for large-scale discovery ranking such potential biomarker candidates. In this review, we summarize currently available data from different biological sources (whole blood, fresh-frozen tissue, FFPE) obtained methods (microarray, RNA-Seq, RT-qPCR). We directly include only results trials other investigations where an was administered. are grouped based on administered also most important individual cohorts. discuss limitations shortcomings datasets. Finally, subset animal studies is reviewed to overview vivo investigations. Our review swift reference researchers aiming find suitable study their investigation, thus saving significant amount time.

Language: Английский

---

Reigniting hope in cancer treatment: the promise and pitfalls of IL-2 and IL-2R targeting strategies

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: July 29, 2023

Abstract Interleukin-2 (IL-2) and its receptor (IL-2R) are essential in orchestrating immune responses. Their function expression the tumor microenvironment make them attractive targets for immunotherapy, leading to development of IL-2/IL-2R-targeted therapeutic strategies. However, dynamic interplay between IL-2/IL-2R various cells their dual roles promoting activation tolerance presents a complex landscape clinical exploitation. This review discusses pivotal IL-2 IL-2R tumorigenesis, shedding light on potential as diagnostic prognostic markers manipulation cancer. It underlines necessity balance anti-tumor activity with regulatory T-cell expansion evaluates strategies such dose optimization selective targeting enhanced effectiveness. The article explores recent advancements field, including developing genetically engineered variants, combining therapies other cancer treatments, benefits multidimensional approach integrating molecular profiling, immunological analyses, data. concludes that deeper understanding interactions within is crucial realizing full IL-2-based therapies, heralding promise improved outcomes patients.

Language: Английский

---