Immune checkpoint blockade in hematological malignancies: current state and future potential

Frontiers in Oncology, Год журнала: 2024, Номер 14

Опубликована: Янв. 23, 2024

Malignant cells are known to evade immune surveillance by engaging checkpoints which negative regulators of the system. By restoring T-lymphocyte mediated anti-tumor effect, checkpoint inhibitors (ICI) have revolutionized treatment solid tumors but met rather modest success in hematological malignancies. Currently, only FDA approved indications for ICI therapy classic hodgkin lymphoma and primary mediastinal B cell lymphoma. Multiple clinical trials assessed alone combination with standard care treatments other lymphomas, plasma neoplasms myeloid were noted limited efficacy. These mostly focused on PD-1/PDL-1 CTLA-4 inhibitors. Recently, there has been an effort target like LAG-3, TIM-3, TIGIT along improving strategies inhibition. Drugs targeting macrophage checkpoint, CD47, also being tested. Long term safety efficacy data from these ongoing studies eagerly awaited. In this comprehensive review, we discuss mechanism inhibitors, key takeaways reported results completed therapies context

Язык: Английский

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Next-Generation Therapeutic Antibodies for Cancer Treatment: Advancements, Applications, and Challenges

Molecular Biotechnology, Год журнала: 2024, Номер unknown

Опубликована: Сен. 2, 2024

Язык: Английский

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Revolutionary Cancer Therapy for Personalization and Improved Efficacy: Strategies to Overcome Resistance to Immune Checkpoint Inhibitor Therapy

Cancers, Год журнала: 2025, Номер 17(5), С. 880 - 880

Опубликована: Март 4, 2025

Cancer remains a significant public health issue worldwide, standing as primary contributor to global mortality, accounting for approximately 10 million fatalities in 2020 [...].

Язык: Английский

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Development of small molecule drugs targeting immune checkpoints

Cancer Biology and Medicine, Год журнала: 2024, Номер unknown, С. 1 - 18

Опубликована: Май 9, 2024

Immune checkpoint inhibitors (ICIs) are used to relieve and refuel anti-tumor immunity by blocking the interaction, transcription, translation of co-inhibitory immune checkpoints or degrading checkpoints. Thousands small molecule drugs biological materials, especially antibody-based ICIs, actively being studied antibodies currently widely used. Limitations, such as efficacy, poor membrane permeability, unneglected tolerance issues remain evident but thought be overcome drugs. Recent structural studies have broadened scope candidate molecules, well innovative chemical inhibitors. By way comparison, drug-based ICIs represent superior oral bioavailability favorable pharmacokinetic features. Several ongoing clinical trials exploring synergetic effect other therapeutic strategies based on multiple ICI functions, including regulation, anti-angiogenesis, cell cycle regulation. In this review we summarized current progression mechanism underlying proteins, which will lay foundation for further exploration.

Язык: Английский

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Optimizing asymmetric antibody purification: a semi-automated process and its digital integration

mAbs, Год журнала: 2025, Номер 17(1)

Опубликована: Март 3, 2025

Over the past decades, immunization and display technologies have considerably increased potential for generating new binders against cell surface targets. Concomitantly, complexity of biologic therapeutic drugs has also increased, with asymmetric formats such as bispecific antibodies or antibody fusion proteins making supply molecules preclinical drug discovery more challenging. The purification those is crucial, an efficient platform research units should multiple aims. First, it needs to deliver highest quality activities at a fast pace in order increase screening capacities. Second, protein sufficient yield cover project requirements minimize repetition production cycles. Through case study antibody, we describe semi-automated digitalized aiming accelerating optimizing discovery. We show how automation repetitive tasks digitalization process can lead throughput context complex purifications, including cation exchange chromatography separation step. Furthermore, highlight leads enhanced data capture accessibility, facilitating decision-making along process. With maximal 36 per week proving consistency delivered, this represents step forward

Язык: Английский

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Cadonilimab plus chemotherapy as first-line treatment for persistent, recurrent, or metastatic cervical cancer: a cost-effectiveness analysis

Frontiers in Immunology, Год журнала: 2025, Номер 16

Опубликована: Апрель 3, 2025

Immunotherapy has made significant advancements in cervical cancer (CC) treatment; however, its efficacy remains limited programmed death ligand 1 (PD-L1)-negative patients. Cadonilimab, the first bispecific antibody targeting both (PD-1) and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), demonstrated superior manageable safety as a first-line treatment for persistent, recurrent, or metastatic CC (p/r/m CC) phase III COMPASSION-16 trial. Notably, it showed survival benefits PD-L1-negative This study aimed to evaluate cost-effectiveness from perspective of Chinese healthcare system. A partitioned model was developed based on data derived The utilized 3-week cycle length 10-year time horizon. primary outcomes included costs, quality-adjusted life-years (QALYs), incremental ratio (ICER), net monetary benefit (INMB), health (INHB). Additionally, sensitivity analyses, scenario subgroup analyses were performed. cadonilimab plus chemotherapy regimen provided an additional 0.61 QALYs compared alone, at cost $42,486.54. yielded ICER $70,220.88/QALY, exceeding willingness-to-pay threshold $38,042/QALY. corresponding INMB INHB -$19,469.55 -0.51 QALYs, respectively. Consequently, not deemed be cost-effective. Sensitivity that results remained consistent when each parameter varied within predetermined range, indicating model's robustness. Subgroup no positive correlation between economic PD-L1 expression levels. patients who did receive bevacizumab, emerged cost-effective alternative. In China, is considered standard general p/r/m population. However, represents option ineligible bevacizumab therapy.

Язык: Английский

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Bispecific Antibodies in Hematologic and Solid Tumors: Current Landscape and Therapeutic Advances

American Society of Clinical Oncology Educational Book, Год журнала: 2025, Номер 45(3)

Опубликована: Апрель 8, 2025

Bispecific antibodies (bsAbs) have emerged as a novel class of therapeutics, offering dual-targeting strategy to enhance the therapeutic efficacy monoclonal antibodies, which is often limited by tumor heterogeneity and occurrence resistance mechanisms. By simultaneously engaging two distinct antigens or pathways, bsAbs disrupt multiple signaling cascades simultaneously, preventing escape mechanisms more durable response. Furthermore, they can optimize immune activation, improving cell recruitment strategies. In particular, T-cell engager facilitate cell–mediated destruction linking T cells antigens. Instead, dual checkpoint inhibitors (CPIs) activation blocking inhibitory signals. Additionally, targeting growth factors receptor tyrosine kinases offer solutions for overcoming drug in solid tumors. Although shown remarkable success hematologic malignancies, their expansion into tumors faces key challenges, including heterogeneity, penetration, risk on-target, off-tumor toxicities. Addressing these challenges requires innovative engineering strategies, optimized delivery mechanisms, careful patient selection maximize benefit while mitigating adverse effects. The clinical trials has led approval both with numerous agents development. Combination strategies chemotherapy, targeted agents, CPIs could represent promising further expand potential. As research progresses, are expected play role reshaping future precision oncology, effective tailored treatment options.

Язык: Английский

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A mechanistic quantitative systems pharmacology model platform for translational efficacy evaluation and checkpoint combination design of bispecific immuno-modulatory antibodies

Frontiers in Pharmacology, Год журнала: 2025, Номер 16

Опубликована: Апрель 10, 2025

Over the past 2 decades, tumor immunotherapies have witnessed remarkable advancements, especially with emergence of immune checkpoint-targeting bispecific antibodies. However, a quantitative understanding dynamic cross-talking mechanisms underlying different checkpoints as well optimal dosing and target design antibodies still remain challenging to researchers. To address this challenge, we here developed multi-scale systems pharmacology (QSP) model platform that integrates diverse array their interactive functions. The has been calibrated validated against an extensive collection multiscale experimental datasets covering 20+ monoclonal antibody treatments at over 60 administered dose levels. Based on high-throughput simulations, QSP comprehensively screened characterized potential efficacy combination designs, model-based preclinical population-level simulations revealed target-specific dose-response relationships alternative strategies can maintain anti-tumor treatment while reducing frequencies. Model also pointed out combining lead significantly enhanced efficacy. Our mechanistic serve integrated precision medicine simulation guide translational research clinical development immuno-modulatory

Язык: Английский

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Immune checkpoint ligands expressed on mature high endothelial venules predict poor prognosis of NSCLC: have a relationship with CD8+ T lymphocytes infiltration

Frontiers in Immunology, Год журнала: 2024, Номер 15

Опубликована: Фев. 8, 2024

Background An insufficient number of intratumoral CD8 + T lymphocytes is a major barrier to antitumor immunity and immunotherapy. High endothelial venules (HEVs) are the sites through which enter tumors; however, molecular mechanism HEVs mediate lymphocyte infiltration remains poorly understood. Methods Forty-two patients with stage IIIA lung adenocarcinoma, who underwent surgery, were recruited. Multiplex immunohistochemical staining was conducted on tumor tissues detect immune checkpoint ligands (ICLs) expressed in HEVs, blood vessels, lymphatics. A new ICL score model constructed evaluate ligand expression. The relationship between score, tumor-infiltrating cell frequency, survival investigated. Results Mature but not vessels or lymphatics, mediated infiltration. However, ICLs mature could negatively regulate entry into tertiary lymphoid structures (TLSs). In addition, according results obtained using our total model, expression observed be predictor both survival, high > 1 represent weak 2 predicts poor survival. Conclusion Using we discovered that indicative subset TLSs, as well patient cancer.

Язык: Английский

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The role of immunotherapy sensitizers and novel immunotherapy modalities in the treatment of cancer

Frontiers in Oncology, Год журнала: 2024, Номер 14

Опубликована: Фев. 27, 2024

The importance of the immune system in response against cancer has always been a subject intense investigation. advent checkpoint inhibitors transformed landscape oncologic treatments, while expanding understanding this disease’s pathophysiology. Consequently, many therapies are being investigated, with interventions directed at different steps and pathways response. Relevantly, immunotherapy sensitizers have arisen as approaches focused on synergistic effects combination, or combination other treatment modalities, such chemotherapy radiation therapy. Concomitantly, novel modalities also development. Approaches focusing from tumor intrinsic to microenvironment ex-vivo interventions, CAR-T cell tumor-infiltrating lymphocytes important examples. Although those were initially envisioned standalone options, their demonstrated promising results early-phase vitro studies clinical trials. possibility coupling well techniques, further strengthen concept sensitizers, allowing for deeper more robust responses treatment. This review aims present an overview concepts these sensitizing mechanisms that basis multitude therapeutic strategies. Novel presented, potential combining them sensitizer interventions. Understanding complexity underlying principles may be key future breakthroughs improved patient outcomes.

Язык: Английский

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