Using Combination therapy to overcome diverse challenges of Immune Checkpoint Inhibitors treatment

International Journal of Biological Sciences, Год журнала: 2024, Номер 20(10), С. 3911 - 3922

Опубликована: Янв. 1, 2024

Immune checkpoint inhibitors (ICIs) have heralded a new era in immunotherapy, representing pivotal breakthrough cancer treatment. Their impact is profound, with ICIs standing as some of the most prescribed anticancer therapies today. Notably, their ability to induce long-term remission even after treatment cessation provides genuine hope for achieving durable cures. However, despite these strides, challenges persist landscape oncology, including resistance phenomena, immune-related adverse events, and suboptimal response rates. In challenges, combination therapy emerges promising approach, poised enhance outcomes address limitations inherent single-agent ICI therapy. By synergistically targeting multiple pathways, holds potential augment therapeutic efficacy while mitigating toxicity impeding emergence mechanisms. Understanding intricacies underlying development events paramount devising novel refined strategies. A timeline showing FDA approvals shown

Язык: Английский

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Targeting LSD1 in cancer: Molecular elucidation and recent advances

Cancer Letters, Год журнала: 2024, Номер 598, С. 217093 - 217093

Опубликована: Июль 4, 2024

Язык: Английский

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Immune checkpoint inhibitors in cancer patients with autoimmune disease: Safety and efficacy

Human Vaccines & Immunotherapeutics, Год журнала: 2025, Номер 21(1)

Опубликована: Фев. 2, 2025

The utilization of immune-checkpoint inhibitors (ICIs) in cancer immunotherapy frequently leads to the occurrence immune-related adverse events (irAEs), making it generally not recommended for patients with preexisting autoimmune diseases. Hence, we conducted a meta-analysis on safety and efficacy ICIs diseases provide further insights. PubMed, EMBASE, Cochrane Library were systematically searched until December 20, 2024. main summary measures used pooled rate risk ratio (RR) 95% confidential interval (CI), which analyzed using R statistic software. A total 52 articles included study. When received treatment, overall incidence was 0.610 (95% CI: 0.531-0.686) any grade irAEs, 0.295 0.248-0.343) flares, 0.325 0.258-0.396) de novo 0.238 0.174-0.309) ≥3 0.143 0.109-0.180) discontinuation due immunotoxicity. Compared those without diseases, experienced higher any-grade irAEs (RR: 1.23, 1.12-1.35) immunotoxicity (1.40, 1.11-1.78). However, no statistically significant differences observed objective response (ORR), disease control (DCR), survival (OS), progression-free (PFS) between two groups. During are common among but severe is relatively low. effective this population, should be strictly monitored when avoid

Язык: Английский

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Case Report: Severe Immune‐Related Adverse Event Under Pembrolizumab Therapy for Discoid Lupus Erythematosus‐Related Squamous Cell Carcinoma

International Journal of Rheumatic Diseases, Год журнала: 2025, Номер 28(2)

Опубликована: Фев. 1, 2025

Discoid lupus erythematosus (DLE) is an autoimmune condition and the most common subtype of chronic cutaneous erythematosus, accounting for 50%–85% cases [1]. DLE can be individual disease only involving skin or present as part manifestations systemic (SLE). occurs a localized form (80%) with lesions on face, ears, scalp disseminated (20%) above below neck [2]. In small proportion cases, progress to squamous cell carcinoma (SCC). It generally accepted that inflammation has important role in carcinogenesis, consistent local inflammatory stimuli resulting scarring seen contributory increased risk SCC [3]. recent years, advanced been increasingly treated immune checkpoint inhibitors (ICIs). Immune-related adverse events (irAEs) are range complications associated use ICIs. The irAEs seems patients preexisting diseases [4, 5]. Cytotoxic T lymphocyte-associated antigen 4 programmed death protein 1 (PD-1) molecules play crucial autoantigen tolerance. By inhibiting these molecules, ICIs enhance not anticancer immunity but also responses, potentially exacerbating conditions inducing new diseases. Studies have shown equally effective need close monitoring flare-ups [6, 7]. Here, we report case DLE-related who developed severe irAE after introduction pembrolizumab, anti-PD-1 monoclonal antibody. A 50-year-old man presented nine-month history multiple lower lip papillomatous nodules (Figure 1A). He had 25-year SLE. At onset SLE, he erythema multiforme, polyarthritis, recurrent meningitis positive serum antinuclear anti-RNP antibodies, remission was induced by high-dose prednisolone (60 mg/day). For last 15 polyarthritis well-controlled maintenance therapy 12–13 mg/day azathioprine 100 mg/day. However, refractory dorsum his hands including 1B,C). Addition hydroxychloroquine ineffective, reduction glucocorticoids difficult. Serum anti-dsDNA antibody tests were negative hypocomplementemia found clinical course. During those 9 months, underwent cryotherapy, did improve. Due uncertain nature, biopsy lesion performed differentiate between benign malignant processes. histological examination revealed 1D,E). staged T2N2M0 due lymph node metastasis left submandibular region. cetuximab, anti-epidermal growth factor receptor antibody, radiation therapy, computed tomography scan month treatment showed lung liver metastases. Cetuximab withdrawn five courses administration over because progressive disease. Pembrolizumab indicated metastatic SCC. After first dose pembrolizumab 200 mg, fever 38°C–40°C elevated CRP levels around 10 mg/dL. test remained negative, complement titers unchanged. active persistent both before initiation pembrolizumab. mononuclear counts cerebrospinal fluid, combined exclusion infectious other causes, led diagnosis aseptic meningitis, suggesting relapse irAE. Increasing 60 methylprednisolone pulse improve levels. one uncontrolled glucocorticoids. Combined chemotherapy 5-fluorouracil cisplatin (FP therapy) introduced 24 days expectation controlling well malignancy cytostatic drugs. FP decrease improvement rash 2A). Since then, continued under careful observation flare systematic review about 75% diseases, experience their baseline develop novel ICI [8]. sample size heterogeneity included patients, any factors biomarkers predict identified [9]. spite frequency, controlled manageable without discontinuation: Therefore, considered acceptable safety profile even [10]. Nevertheless, our could glucocorticoid required discontinuation Canceration autoreactive cells [3], therefore, share DLE. induce escape from expressing 1-ligand (PD-L1). restore anti-SCC PD-1/PD-L1 binding, which cross-reactive responses activating 2B). addition, development high IFN-γ-induced cytokines [11]. upregulated IFN-γ signature similar may conclusion, immunotherapy arising requires meticulous attention potential irAEs. All authors followed up patient collected data. Conceptualization, H.A. H.N.; visualization, H.A., H.N., K.H., J.K., S.S.; supervision, M.K., H.U., H.T. H.N. wrote original draft, edited it. approved final version. We acknowledge allowing us publish all personal photography information. Informed consent attained publication this report. declare no conflicts interest. data underlying article will shared reasonable request corresponding author.

Язык: Английский

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Rheumatic Immune-Related Adverse Events due to Immune Checkpoint Inhibitors—A 2023 Update

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5643 - 5643

Опубликована: Март 15, 2023

With the aging of population, malignancies are becoming common complications in patients with rheumatoid arthritis (RA), particularly elderly patients. Such often interfere RA treatment. Among several therapeutic agents, immune checkpoint inhibitors (ICIs) which antagonize immunological brakes on T lymphocytes have emerged as a promising treatment option for variety malignancies. In parallel, evidence has accumulated that ICIs associated numerous immune-related adverse events (irAEs), such hypophysitis, myocarditis, pneumonitis, and colitis. Moreover, not only exacerbate pre-existing autoimmune diseases, but also cause de novo rheumatic disease–like symptoms, arthritis, myositis, vasculitis, currently termed irAEs. Rheumatic irAEs differ from classical diseases multiple aspects, should be individualized based severity. Close collaboration oncologists is critical preventing irreversible organ damage. This review summarizes current regarding mechanisms management focus vasculitis. Based these findings, potential strategies against discussed.

Язык: Английский

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Nanoparticles overcome adaptive immune resistance and enhance immunotherapy via targeting tumor microenvironment in lung cancer

Frontiers in Pharmacology, Год журнала: 2023, Номер 14

Опубликована: Март 24, 2023

Lung cancer is one of the common malignant cancers worldwide. Immune checkpoint inhibitor (ICI) therapy has improved survival lung patients. However, ICI leads to adaptive immune resistance and displays PD-1/PD-L1 blockade in cancer, leading less response Tumor microenvironment (TME) an integral tumor microenvironment, which involved immunotherapy resistance. Nanomedicine been used enhance cancer. In this review article, we described association between TME We also highlighted importance Moreover, discussed how nanoparticles are regulation improve efficacy immunotherapy, including SGT-53, AZD1080, Nanomodulator NRF2, Cisplatin nanoparticles, Au@PG, DPAICP@ME, SPIO NP@M-P, NBTXR3 ARAC Nano-DOX, MS NPs, Nab-paclitaxel, GNPs-hPD-L1 siRNA. Furthermore, concluded that targeting by could be helpful overcome

Язык: Английский

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Targeting the TRIM14/USP14 Axis Enhances Immunotherapy Efficacy by Inducing Autophagic Degradation of PD-L1

Cancer Research, Год журнала: 2024, Номер 84(17), С. 2806 - 2819

Опубликована: Июнь 26, 2024

Immunotherapy has greatly improved cancer treatment in recent years by harnessing the immune system to target cells. The first immunotherapeutic agent approved FDA was IFNα. Treatment with IFNα can lead effective activation and attenuate tumor evasion, but persistent been shown elicit immunosuppressive effects. Here, we identified an autophagy-dependent mechanism which triggers evasion upregulating PD-L1 suppress antitumor activity of CD8+ T Mechanistically, increased transcription TRIM14, recruited deubiquitinase USP14 inhibit autophagic degradation PD-L1. removed K63-linked ubiquitin chains from PD-L1, impairing its recognition cargo receptor p62 (also known as SQSTM1) for subsequent degradation. Combining inhibitor IU1 anti-CTLA4 effectively suppressed growth without significant toxicity. This work suggests a strategy targeting selective autophagy abolish PD-L1-mediated evasion. Significance: IFNα-induced TRIM14 suppresses immunity recruiting indicating that this axis could be approach treating cancer.

Язык: Английский

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The evolving role of lenvatinib at the new era of first-line hepatocellular carcinoma treatment

Clinical and Molecular Hepatology, Год журнала: 2023, Номер 29(4), С. 909 - 923

Опубликована: Май 25, 2023

Emergence of multi-targeted kinase inhibitors (MTIs) and immune checkpoint (ICI) have changed the landscape management in hepatocellular carcinoma (HCC). Combination therapy involving ICI has superseded sorafenib as first-line treatment option for advanced HCC due to their superior response rates survival benefits based on recently published phase III trials. However, role lenvatinib remains uncertain no prospective trials compared its efficacy with HCC. Several retrospective studies shown that may not be inferior combination. Indeed, a growing body evidence suggests is associated outcome non-viral patients, questioning supremacy all patients rendering potential preferred option. Furthermore, high-burden intermediate-stage HCC, accumulating supports lenvatinib, or combination transarterial chemoembolization (TACE), over TACE alone. In this Review, we describe latest surrounding evolving

Язык: Английский

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Integrated genetic analyses of immunodeficiency-associated Epstein-Barr virus- (EBV) positive primary CNS lymphomas

Acta Neuropathologica, Год журнала: 2023, Номер 146(3), С. 499 - 514

Опубликована: Июль 26, 2023

Abstract Immunodeficiency-associated primary CNS lymphoma (PCNSL) represents a distinct clinicopathological entity, which is typically Epstein-Barr virus-positive (EBV + ) and carries an inferior prognosis. Genetic alterations that characterize EBV-related lymphomagenesis remain unclear precluding molecular classification targeted therapies. In this study, comprehensive genetic analysis of 22 EBV PCNSL, therefore, integrated clinical pathological information with exome RNA sequencing (RNASeq) data. PCNSL germline controls carried median 55 protein-coding single nucleotide variants (SNVs; range 24–217) 2 insertions/deletions (range 0–22). landscape was largely shaped by aberrant somatic hypermutation 41.01% 31.79–53.49%) SNVs mapping to its target motifs. Tumors lacked established (MYD88, CD79B, PIM1) copy number (CDKN2A, HLA loss) driving − PCNSL. Instead, were characterized SOCS1 mutations (26%), predicted disinhibit JAK/STAT signaling, mutually exclusive gain-of-function NOTCH pathway (26%). Copy gains enriched on 11q23.3, locus directly for chromosomal aberrations EBV, includes SIK3 known protect from cytotoxic T-cell responses. Losses covered 5q31.2 (STING), critical sensing viral DNA, 17q11 (NF1). Unsupervised clustering RNASeq data revealed two transcriptional groups, shared strong expression CD70 IL1R2, previously linked tolerogenic tumor microenvironments. Correspondingly, deconvolution bulk elevated M2-macrophage, T-regulatory cell, mast cell monocyte fractions in addition novel insights into the pathobiology provide rationale exploration therapies including JAK-, NOTCH- CD70-directed approaches.

Язык: Английский

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The role of lenvatinib in the era of immunotherapy of hepatocellular carcinoma

Journal of Liver Cancer, Год журнала: 2023, Номер 23(2), С. 262 - 271

Опубликована: Авг. 17, 2023

Hepatocellular carcinoma (HCC) frequently presents as advanced stage with poor prognosis and high mortality. Systemic treatment is the of choice for disease. In 2007, first multi-kinase inhibitor (MKI) sorafenib was approved shown to modestly prolong overall survival (OS). The progress systemic therapy has been slow afterwards until 2018 when lenvatinib, another MKI, be non-inferior on median OS first-line HCC. Since then, remarkable achieved HCC, including development second-line targeted treatment, regorafenib, cabozantinib ramucirumab from 2017 2019. A growing focus placed immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1), its ligand PD-L1, cytotoxic T-lymphocyte-associated protein 4. These ICIs have proven their potency in treating HCC both initial subsequent line therapy. At present, regimens atezolizumab combined bevacizumab, well combination tremelimumab durvalumab, are recommended treatments based positive phase III clinical trials. With advancement ICIs, it anticipated that role MKIs will evolve. this article, one most commonly used chosen reviewed.

Язык: Английский

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