Monoclonal antibodies targeting immune checkpoints have revolutionized oncology. Yet, the effectiveness of these treatments varies significantly among patients, and they are associated with unexpected adverse events, including hyperprogression. The murine research model used in drug development fails to recapitulate both the functional human immune system and the population heterogeneity. Hence, a novel model is urgently needed to study the consequences of immune checkpoint blockade. Dogs appear to be uniquely suited for this role. Approximately 1 in 4 companion dogs dies from cancer, yet no antibodies are commercially available for use in veterinary oncology. Here we characterize two novel antibodies that bind canine PD-1 with sub-nanomolar affinity as measured by SPR. Both antibodies block the clinically crucial PD-1/PD-L1 interaction in a competitive ELISA assay. Additionally, the antibodies were tested with a broad range of assays including Western Blot, ELISA, flow cytometry, immunofluorescence and immunohistochemistry. The antibodies appear to bind two distinct epitopes as predicted by molecular modeling and peptide phage display. Our study provides new tools for canine oncology research and a potential veterinary therapeutic.
- MeSH
- antigeny CD274 imunologie antagonisté a inhibitory metabolismus MeSH
- antigeny CD279 * imunologie antagonisté a inhibitory metabolismus MeSH
- epitopy imunologie MeSH
- inhibitory kontrolních bodů imunologie farmakologie MeSH
- lidé MeSH
- monoklonální protilátky * imunologie MeSH
- nádory imunologie veterinární farmakoterapie MeSH
- nemoci psů imunologie farmakoterapie MeSH
- psi MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- psi MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- srovnávací studie MeSH
Immune checkpoint blockade (ICB) using monoclonal antibodies against programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1) is the treatment of choice for cancer immunotherapy. However, low tissue permeability, immunogenicity, immune-related adverse effects, and high cost could be possibly improved using alternative approaches. On the other hand, synthetic low-molecular-weight (LMW) PD-1/PD-L1 blockers have failed to progress beyond in vitro studies, mostly due to low binding affinity or poor pharmacological characteristics resulting from their limited solubility and/or stability. Here, we report the development of polymer-based anti-human PD-L1 antibody mimetics (α-hPD-L1 iBodies) by attaching the macrocyclic peptide WL12 to a N-(2-hydroxypropyl)methacrylamide copolymer. We characterized the binding properties of iBodies using surface plasmon resonance, enzyme-linked immunosorbent assay, flow cytometry, confocal microscopy, and a cellular ICB model. We found that the α-hPD-L1 iBodies specifically target human PD-L1 (hPD-L1) and block the PD-1/PD-L1 interaction in vitro, comparable to the atezolizumab, durvalumab, and avelumab licensed monoclonal antibodies targeting PD-L1. Our findings suggest that iBodies can be used as experimental tools to target hPD-L1 and could serve as a platform to potentiate the therapeutic effect of hPD-L1-targeting small molecules by improving their affinity and pharmacokinetic properties.
BACKGROUND: The anti-PD-1 monoclonal antibody pembrolizumab has been shown to be associated with a good response in patients with metastatic gastric cancer. Excellent therapeutic results of pembrolizumab have been shown in patients with tumours showing a high microsatellite instability (MSI) and Epstein–Barr virus (EBV) positivity. GOAL: This is a retrospective study of 40 bioptic specimens from the patients, who underwent gastrectomy for gastric carcinoma. The goal of the study was to identify biomarkers (EBV, MLH-1, PDL-1 expression) that are potentially relevant for selecting the patients, who may benefit from PD-1 inhibition therapy. METHODS: Immunohistochemical (IHC) expression of PDL-1 and MSI, cytogenetic FISH amplification of the HER-2/neu gene and polymerase chain reaction of EBV RNA, including charge quantification, were performed in selected patients with metastatic or advanced gastric cancer. RESULTS: EBV-encoded RNA was detected in nine patients. None of them exhibited Her-2 overexpression or CMV infection. PD-L1 was detected in twelve patients. Ten patients were MLH1 positive. All nine cases of EBV infection showed a high expression of PD-L1 and MLH-1 (Tab. 1, Ref. 14).
- MeSH
- antigeny CD274 analýza imunologie MeSH
- biologické markery * analýza MeSH
- exprese genu MeSH
- infekce virem Epsteina-Barrové diagnóza imunologie MeSH
- klinické laboratorní techniky metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- mikrosatelitní nestabilita MeSH
- MutL homolog 1 analýza imunologie MeSH
- nádory žaludku * imunologie patofyziologie MeSH
- odběr biologického vzorku MeSH
- receptor erbB-2 analýza imunologie MeSH
- retrospektivní studie MeSH
- senioři MeSH
- výběr pacientů MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- Publikační typ
- práce podpořená grantem MeSH
- MeSH
- antigeny CD274 imunologie MeSH
- lidé MeSH
- nemalobuněčný karcinom plic * diagnóza MeSH
- patologové * psychologie MeSH
- prognóza MeSH
- průzkumy a dotazníky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- komentáře MeSH
- souhrny MeSH
BACKGROUND: The programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) pathway is important in metastatic renal cell carcinoma (mRCC). However, some dissimilarities between anti-PD-1 and anti-PD-L1 inhibitors have emerged. We aimed to assess differences between anti-PD-1 and anti-PD-L1 combination immunotherapies as first-line treatments in mRCC patients. METHODS: Multiple databases (PubMed, Web of Science, and Scopus) were searched for articles published until March 2021. Studies were eligible if they compared overall survival (OS), progression-free survival (PFS), objective response rates (ORR), complete response rates (CRR), and adverse events. RESULTS: Five studies met the eligibility criteria. PD-1 combination therapy was associated with significantly better OS and PFS and higher ORR and CRR than sunitinib (hazard ratio [HR]: 0.60, 95% confidence interval [CI]: 0.40-0.89; HR: 0.52, 95% CI: 0.37-0.75; odds ratio [OR]: 3.20, 95% CI: 2.18-4.68; and OR: 3.05, 95% CI: 2.13-4.37, respectively; P < 0.001). For all oncological outcomes, anti-PD-1 agents were superior to anti-PD-L1 agents based on HR and OR (OS: HR = 0.88, PFS: HR = 0.76, ORR: OR = 1.85, and CRR: OR = 2.24). Conversely, anti-PD-L1 agents were superior to anti-PD-1 agents in their safety profiles. In network meta-analyses, pembrolizumab plus lenvatinib seemed the worst tolerated anti-PD-1 combination therapy. CONCLUSIONS: Our analysis indicates the superior oncologic benefits of first-line anti-PD-1 combination therapies over anti-PD-L1 combination therapies in mRCC patients. This biological difference is of vital importance for clinical treatment decision making and the design of future rational combination therapy trials in mRCC.
- MeSH
- antigeny CD274 antagonisté a inhibitory imunologie MeSH
- antigeny CD279 antagonisté a inhibitory imunologie MeSH
- inhibitory kontrolních bodů aplikace a dávkování škodlivé účinky terapeutické užití MeSH
- karcinom z renálních buněk farmakoterapie imunologie MeSH
- klinické zkoušky, fáze III jako téma MeSH
- lidé MeSH
- nádory ledvin farmakoterapie imunologie MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky terapeutické užití MeSH
- randomizované kontrolované studie jako téma MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- systematický přehled MeSH
Durvalumab je plně humanizovaná IgGκ monoklonální protilátka, která selektivně blokuje ligand receptoru programované buněčné smrti (PD‑L1). V Evropské unii je registrován ke konsolidační léčbě lokálně pokročilého inoperabilního nemalobuněčného karcinomu plic (NSCLC) bez progrese po chemoradiační terapii (CRT).
Durvalumab is a fully humanized IgGκ monoclonal antibody that selectively blocks programmed cell death ligand 1 (PD‑L1). In European Union, it is registered for consolidation treatment of non‑small cell lung cancer (NSCLC) which has not progressed following platinum‑based chemoradiation therapy (CRT).
- Klíčová slova
- durvalumab,
- MeSH
- antigeny CD274 antagonisté a inhibitory imunologie MeSH
- autoimunitní nemoci chemicky indukované etiologie MeSH
- inhibitory kontrolních bodů * farmakologie škodlivé účinky terapeutické užití MeSH
- intersticiální plicní nemoci chemicky indukované etiologie farmakoterapie MeSH
- kolitida chemicky indukované etiologie farmakoterapie MeSH
- léková dermatitida etiologie farmakoterapie MeSH
- lékové postižení jater etiologie farmakoterapie MeSH
- lidé MeSH
- monoklonální protilátky farmakokinetika škodlivé účinky terapeutické užití MeSH
- nefritida chemicky indukované etiologie farmakoterapie MeSH
- nemalobuněčný karcinom plic * farmakoterapie MeSH
- nemoci endokrinního systému chemicky indukované etiologie farmakoterapie MeSH
- nežádoucí účinky léčiv etiologie farmakoterapie MeSH
- Check Tag
- lidé MeSH
Onkologická onemocnění představují jedny z nejběžnějších a zároveň nejzávažnějších chorob známých v klinické medicíně. Ke klíčovému pokroku v onkologii poslední doby patří klinická implementace personalizované a precizní onkologie a znovuobrození imunoterapie. Precizní onkologie spočívá v individualizaci léčby pro každého pacienta a pro každý nádor na základě molekulární charakteristiky nádorové choroby a genové výbavy konkrétního nemocného. Personalizovaná onkologie znamená léčbu přizpůsobenou charakteristice a jedinečnosti každého pacienta. Adresný přístup ke každému nemocnému a individualizace léčby s respektováním jedinečných znaků nádorového onemocnění i hostitele nemoci představuje budoucnost onkologie.
Oncological diseases represent one of the most common and at the same time the most serious diseases known to clinical medicine. Clinical implementation of personalized and precise oncology and re‑discovery of immunotherapy comprises a key advance in oncology in recent years. Precise oncology is grounded in individualization of therapy for each patient and each tumor based on molecular characteristics of oncological disease and genetic make‑up of a specific patient. Personalized medicine means a therapy adjusted to the characteristics and uniqueness of each patient. Directed approach to each patient and individualization of therapy with respect to both unique markers of oncological disease and disease host represents the future of oncology.
- MeSH
- antigeny CD274 antagonisté a inhibitory imunologie MeSH
- cílená molekulární terapie metody MeSH
- imunoterapie * metody MeSH
- individualizovaná medicína trendy MeSH
- inhibitory kontrolních bodů * terapeutické užití MeSH
- kombinovaná farmakoterapie MeSH
- kritéria léčebné odpovědi MeSH
- lidé MeSH
- nádory farmakoterapie imunologie MeSH
- oprava chybného párování bází DNA imunologie MeSH
- prediktivní hodnota testů MeSH
- protinádorové látky imunologicky aktivní MeSH
- T-lymfocyty imunologie účinky léků MeSH
- Check Tag
- lidé MeSH
BACKGROUND: The diagnosis of advanced lung cancer is made with minimally invasive procedures. This often results in the availability of cytological material only for subtype determination and companion diagnostic testing, with the latter being technically and clinically validated on histological material only. Thus, the primary objective of the MO29978 clinical study was to assess programmed death ligand 1 (PD-L1) protein expression on cytology samples as surrogates for histology samples in patients with lung cancer. METHODS: Formalin-fixed, paraffin-embedded histological samples and cytological cell blocks from 190 patients were analyzed with immunohistochemical assays using the rabbit monoclonal anti-PD-L1 antibody clones SP142 and SP263. PD-L1 expression was quantified on both tumor cells (TC) and tumor-infiltrating immune cells (IC). Overall concordance, sensitivity, specificity, and accuracy, with a 1% cutoff used for both assays, were assessed for PD-L1 expression on TC and IC. RESULTS: In non-small cell lung cancer histology and cytology samples measured with the PD-L1 (SP142) antibody (n = 173), the intraclass correlation coefficients were 0.40 and 0.06 on TC and IC, respectively. With SP142 and SP263, accuracies of 74.1% for TC and 51.9% for IC and accuracies of 75.2% for TC and 61.2% for IC, respectively, were reported. CONCLUSIONS: Overall, this study has demonstrated that PD-L1 analysis on TC is feasible in cytological material, but quantification is challenging. Tumor tissue should be preferred over cell block cytology for PD-L1 immunohistochemical analysis unless laboratories have validated their cytology preanalytical approaches and demonstrated the comparability of histology and cytology for TC PD-L1 results.
- MeSH
- antigeny CD274 imunologie metabolismus MeSH
- cytodiagnostika metody MeSH
- imunohistochemie metody MeSH
- lidé MeSH
- mezinárodní agentury MeSH
- monoklonální protilátky imunologie MeSH
- nádorové biomarkery imunologie metabolismus MeSH
- nádory plic diagnóza metabolismus MeSH
- nemalobuněčný karcinom plic diagnóza metabolismus MeSH
- prospektivní studie MeSH
- ROC křivka MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- multicentrická studie MeSH
Introduction: One of the hallmarks of cancerogenesis is the ability of tumor cells to evade the immune system. They can achieve it by abusing inhibitory immune checkpoint pathways, which, under normal circumstances, maintain peripheral tolerance during infection. Immune checkpoint inhibitors, especially anti-PD-1/PD-L1 monoclonal antibodies, currently represent a widely discussed treatment option not only in solid oncology, but in hematology-oncology as well.Areas covered: The manuscript is focused on clinical research concerning PD-1/PD-L1 blockade in lymphoma and multiple myeloma in order to identify the patients who would profit the most from this treatment modality. The authors reviewed articles on the topic on PubMed and relevant clinical trials on clinicaltrials.gov before October 2019.Expert opinion: So far, nivolumab and pembrolizumab have been approved for treating patients with relapsed/refractory classical Hodgkin lymphoma and primary mediastinal B cell lymphoma. Nevertheless, monotherapy alone is not curative and a combinational approach is needed. Modern treatment strategies and combinations are comprehensively summarized in this manuscript. There is no approved immune checkpoint inhibitor for the multiple myeloma indication. Although the combination of PD-1/PD-L1 inhibitors with immunomodulatory agents initially seemed promising, unexpected immune related toxicities have stopped any further development. Novel strategies and more potent combinations in myeloma and lymphoma are further discussed in the manuscript.
- MeSH
- antigeny CD274 antagonisté a inhibitory imunologie MeSH
- antigeny CD279 antagonisté a inhibitory imunologie MeSH
- B-buněčný lymfom farmakoterapie imunologie patologie MeSH
- Hodgkinova nemoc farmakoterapie imunologie patologie MeSH
- humanizované monoklonální protilátky terapeutické užití MeSH
- lidé MeSH
- mnohočetný myelom farmakoterapie imunologie patologie MeSH
- nádorové proteiny antagonisté a inhibitory imunologie MeSH
- nádory mediastina farmakoterapie imunologie patologie MeSH
- nivolumab terapeutické užití MeSH
- protinádorové látky imunologicky aktivní terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- audiovizuální média MeSH
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
PURPOSE: In multiple oncological settings, expression of the coinhibitory ligand PD-L1 by malignant cells and tumor infiltration by immune cells expressing coinhibitory receptors such as PD-1, CTLA4, LAG-3, or TIM-3 conveys prognostic or predictive information. Conversely, the impact of these features of the tumor microenvironment on disease outcome among high-grade serous carcinoma (HGSC) patients remains controversial. EXPERIMENTAL DESIGN: We harnessed a retrospective cohort of 80 chemotherapy-naïve HGSC patients to investigate PD-L1 expression and tumor infiltration by CD8+ T cells, CD20+ B cells, DC-LAMP+ dendritic cells as well as by PD-1+, CTLA4+, LAG-3+, and TIM-3+ cells in relation with prognosis and function orientation of the tumor microenvironment. IHC data were complemented with transcriptomic and functional studies on a second prospective cohort of freshly resected HGSC samples. In silico analysis of publicly available RNA expression data from 308 HGSC samples was used as a confirmatory approach. RESULTS: High levels of PD-L1 and high densities of PD-1+ cells in the microenvironment of HGSCs were strongly associated with an immune contexture characterized by a robust TH1 polarization and cytotoxic orientation that enabled superior clinical benefits. Moreover, PD-1+TIM-3+CD8+ T cells presented all features of functional exhaustion and correlated with poor disease outcome. However, although PD-L1 levels and tumor infiltration by TIM-3+ cells improved patient stratification based on the intratumoral abundance of CD8+ T cells, the amount of PD-1+ cells failed to do so. CONCLUSIONS: Our data indicate that PD-L1 and TIM-3 constitute prognostically relevant biomarkers of active and suppressed immune responses against HGSC, respectively.
- MeSH
- antigen CTLA-4 imunologie metabolismus MeSH
- antigeny CD274 imunologie metabolismus MeSH
- buněčný receptor 2 viru hepatitidy A imunologie metabolismus MeSH
- CD8-pozitivní T-lymfocyty imunologie MeSH
- dospělí MeSH
- epiteliální ovariální karcinom imunologie metabolismus patologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- membránové glykoproteiny asociované s lyzozomy imunologie metabolismus MeSH
- míra přežití MeSH
- nádorové biomarkery imunologie metabolismus MeSH
- nádorové proteiny imunologie metabolismus MeSH
- prognóza MeSH
- regulace genové exprese u nádorů * MeSH
- retrospektivní studie MeSH
- senioři MeSH
- serózní cystadenokarcinom imunologie metabolismus patologie MeSH
- tumor infiltrující lymfocyty imunologie MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
