Programmed Death Receptor Research Articles

Enfortumab Vedotin (Padcev)


 CADTH reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class.
 The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada's federal, provincial, and territorial governments, with the exception of Quebec.
 This review assesses enfortumab vedotin (Padcev), 1.25 mg/kg, 20 mg and 30 mg single-use vials for IV infusion.
 Indication: For the treatment of adult patients with unresectable locally advanced or metastatic urothelial cancer who have previously received a platinum-containing chemotherapy and programmed death receptor 1 (PD-1) or programmed death ligand 1 (PD-L1) inhibitor therapy.

Immunoexpression of Programmed Death-1 Receptor (PD-1) and Programmed Death-Ligand 1 (PD-L1) in Non-Small-Cell Lung Carcinoma and Its Correlation With Other Clinicopathological Parameters: A Cross-Sectional Study From North India.

AimTo study the prevalence of programmed death-1 receptor (PD-1) and programmed death-ligand 1 (PD-L1) positive cases in non-small-cell lung carcinoma (NSCLC) and their association with other clinicopathological parameters in a tertiary care setting in North India.Material and methodsOne hundred histologically proven NSCLC cases having sufficient tumor material from July 2016 to July 2018 were examined, and the prevalence of PD-1 and PD-L1 positivity in NSCLC was studied. In addition, H&E-stained sections were reviewed, and 100 consecutive cases meeting study criteria were identified as study cases. Histopathological categorization was done using a panel of immunohistochemical markers.Statistical analysis and resultsThe PD-1 positivity in lymphocytes was 29% (95% CI: 20.4%-38.9%). Membranous positivity for PD-L1 in tumor cells was 27% (95% CI: 18.6%-36.8%) and in tumor-infiltrating lymphocytes was 22% (95% CI: 14.3%-31.4%). There was no statistically significant association between PD-1 or PD-L1 status with age, gender, smoking, pleural effusion, clinical stage, histological type, or lymphocyte infiltration.ConclusionThe moderately high prevalence may justify routine testing for PD-1 or PD-L1 in NSCLC, which should preferably be carried out in all cases rather than any selected subsets. However, there was no significant correlation between PD-1 and PD-L1 with the clinical parameters studied.

CXCL13 as a Novel Immune Checkpoint for Regulatory B Cells and Its Role in Tumor Metastasis.

Tumor metastasis is the primary cause of mortality in patients with cancer. Several chemokines are identified as important mediators of tumor growth and/or metastasis. The level of CXCL13 has been reported to be elevated in serum or tumor tissues in patients, which mainly functions to attract B cells and follicular B helper T cells. However, the role of CXCL13 in cancer growth and metastasis is not fully explored. In the current study, we found that CXCL13 is not a strong mediator to directly promote tumor growth; however, the mice deficient in CXCL13 had far fewer pulmonary metastatic foci than did the wild-type mice in experimental pulmonary metastatic models. In addition, Cxcl13 -/- mice also had fewer IL-10-producing B cells (CD45+CD19+IL-10+) in the metastatic tumor immune microenvironment than those of wild-type C57BL/6 mice, resulting in an enhanced antitumor immunity. Notably, CXCL13 deficiency further improved the efficacy of a traditional chemotherapeutic drug (cyclophosphamide), as well as that of anti-programmed death receptor-1 immunotherapy. These results suggested that CXCL13 has an important role in regulating IL-10-producing B cells in tumor metastasis and might be a promising target for improving therapeutic efficiency and stimulating tumor immunity in future cancer therapy.

Burgeoning Exploration of the Role of Natural Killer Cells in Anti-PD-1/PD-L1 Therapy

Antibodies targeting programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) have been considered breakthrough therapies for a variety of solid and hematological malignancies. Although cytotoxic T cells play an important antitumor role during checkpoint blockade, they still show a potential killing effect on tumor types showing loss of/low major histocompatibility complex (MHC) expression and/or low neoantigen load; this knowledge has shifted the focus of researchers toward mechanisms of action other than T cell-driven immune responses. Evidence suggests that the blockade of the PD-1/PD-L1 axis may also improve natural killer (NK)-cell function and activity through direct or indirect mechanisms, which enhances antitumor cytotoxic effects; although important, this topic has been neglected in previous studies. Recently, some studies have reported evidence of PD-1 and PD-L1 expression in human NK cells, performed exploration of the intrinsic mechanism by which PD-1/PD-L1 blockade enhances NK-cell responses, and made some progress. This article summarizes the recent advances regarding the expression of PD-1 and PD-L1 molecules on the surface of NK cells as well as the interaction between anti-PD-1/PD-L1 drugs and NK cells and associated molecular mechanisms in the tumor microenvironment.

Efficacy and Safety of PD-1/PD-L1 Inhibitor Chemotherapy Combined with Lung Cancer Fang No. 1 in Relapsed and Refractory SCLC: A Retrospective Observational Study.

Background Relapsed and refractory small cell lung cancer (SCLC) accounts for about 15% of all lung cancers. The prognosis of patients is poor. The 5-year survival rate is almost 0. The average survival time of patients who refuse to receive treatment is only 2-4 months. For patients with extensive-stage SCLC, the current first-line treatment regimens are mainly platinum-containing double-drug chemotherapy. Poside combined with cisplatin/carboplatin and irinotecan combined with cisplatin/carboplatin are commonly used clinical regimens for the treatment of patients with extensive-stage SCLC. Although SCLC is very sensitive to radiotherapy and chemotherapy, most patients will develop recurrence and metastasis after initial treatment. Therefore, it is necessary to study clinically effective therapeutic drugs for relapsed and refractory SCLC. Objective To investigate the relationship between programmed death receptor-1 (programmed death receptor-1 (PD-1)) and programmed death receptor-ligand 1 (programmed death-ligand 1 (PD-L1)) inhibitors and Lung Cancer No. 1 efficacy and safety of Lung Cancer Fang No. 1 in the treatment of relapsed and refractory SCLC. Methods 80 patients with refractory SCLC were selected and randomly divided into control group and treatment group with 40 cases in each group. Among them, the control group received PD-1/PD-L1 inhibitor chemotherapy, and the treatment group received PD-1/PD-L1 inhibitor chemotherapy combined with Lung Cancer Fang No. 1 treatment. The differences in immune and tumor marker levels, clinical efficacy, and prognostic complications between the two groups before and after treatment were observed and compared. Results Before treatment, there was no significant difference in clinical improvement between the two groups. After treatment, the clinical symptom scores and body weight changes in the treatment group were significantly improved. The clinical symptom scores in the treatment group were lower than those in the control group, but the body weight changes were higher than those in the control group. The difference was statistically significant (P < 0.05). Before treatment, there was no significant difference in the levels of tumor markers between the two groups. After treatment, the levels of CYFRA21-1, CA125, and VGEF in the treatment group were significantly lower than those in the control group, and the difference was statistically significant (P < 0.05). There was no significant difference in the immune level between the two groups before treatment (P > 0.05), while the differences in CD4+, CD3+, and CD4+/CD8+ after treatment were significant, and the treatment group was higher than the control group, with statistical significance (P < 0.05). After treatment, the clinical efficacy of the two groups was significantly improved. The DCR90.00% of the treatment group was significantly higher than that of the control group, 67.50%, and the difference was statistically significant (P < 0.05). The analysis of complications after treatment showed that fatigue, anorexia, hypertension, hand-foot syndrome, diarrhea, leukopenia, thrombocytopenia, and urinary protein in the treatment group were significantly lower than those in the control group, and the difference was statistically significant (P < 0.05). Conclusion PD-1/PD-L1 inhibitor chemotherapy combined with Lung Cancer Fang No. 1 has a good and safe effect on SCLC patients. It has a good curative effect in improving the clinical symptoms of patients. It can stabilize the tumor, inhibit the development of lung cancer, improve the body's cellular immune function, adjust the level and expression of tumor markers, improve the body's material metabolism, and restore the balance of yin and yang in the body.

Clinical activity of PD-1 inhibition in the treatment of locally advanced or metastatic basal cell carcinoma

BackgroundBasal cell carcinoma (BCC) is the most common malignancy worldwide, yet the management of patients with advanced or metastatic disease is challenging, with limited treatment options. Recently, programmed death receptor...

PD59-12 MICROWAVE ABLATION COMBINED WITH ANTI-PD-1/CTLA-4 THERAPY INDUCES ANTI-TUMOR IMMUNE RESPONSE TO RENAL CELL CARCINOMA IN A MURINE MODEL

You have accessJournal of UrologyCME1 May 2022PD59-12 MICROWAVE ABLATION COMBINED WITH ANTI-PD-1/CTLA-4 THERAPY INDUCES ANTI-TUMOR IMMUNE RESPONSE TO RENAL CELL CARCINOMA IN A MURINE MODEL Run-Qi Guo, Jin-Zhao Peng, and Xiao-Guang Li Run-Qi GuoRun-Qi Guo More articles by this author , Jin-Zhao PengJin-Zhao Peng More articles by this author , and Xiao-Guang LiXiao-Guang Li More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002644.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Our current study was designed to investigate the characteristics of immune responses induced by MWA and dual immune checkpoint inhibitors (ICIs) in tumor tissues from tumor-bearing mice, with purpose of providing new insight into immune suppressive mechanisms limiting MWA efficacy and exploring the potential of dual ICIs in combination with MWA in cancer therapy. METHODS: First, untreated tumor assessment was performed to determine whether untreated tumor growth was suppressed. Mice with tumors established on the left kidney and right flank were randomly divided into 4 groups: the control group, the MWA group, the ICI group, and the MWA+ ICI group. Then, a rechallenge test was performed to determine whether systemic anti-tumor immunity was established. RESULTS: Although the volume of the untreated tumors continued to increase, tumor growth rates in the ICI group and the MWA+ICI group were significantly lower. CD8+ T cells were only significantly higher in the MWA+ICI group, while Treg cells were significantly lower in the MWA group, the ICI group and the MWA+ICI group. The MWA+ICI group also showed the highest amount of IFN-γ. Histopathologic studies revealed that cytotoxic T lymphocyte-associated antigen 4 expression (CTLA-4) in the distant tumor was significantly lower in the ICI group and the MWA+ICI group. MWA treatment led to an increase in programmed death ligand 1 (PD-L1)/ programmed death receptor 1 (PD-1) expression; however, after combining with ICI treatment, the expression decreased. In the tumor rechallenge test, tumor rejection was apparent in 16.7% of the mice in the MWA group, 50% of the mice in the ICI group, and 66.7% of the mice in the MWA+ICI group, whereas no mice in the control group showed tumor rejection. CONCLUSIONS: This study demonstrated that MWA induced systemic anti-tumor immunity was enhanced by combined use of anti PD-1/CTLA-4 therapy in a murine RENCA tumor model. The mice that received the combination therapy showed suppression of untreated tumor growth and tumor rejection. This treatment regimen is a potential clinical approach to enhance systemic anti-tumor immunity in patients with metastatic renal cell carcinoma. Source of Funding: This study was supported by Beijing Hospital Scientific Research Starting Foundation for PhD/MD under Grant BJ-2019-135 to Dr. Guo © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e1023 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Run-Qi Guo More articles by this author Jin-Zhao Peng More articles by this author Xiao-Guang Li More articles by this author Expand All Advertisement PDF DownloadLoading ...

Antibody-Drug Conjugates in Uro-Oncology.

Currently available treatment options for patients with refractory metastatic prostate, bladder, or kidney cancers are limited with the prognosis remaining poor. Advances in the pathobiology of tumors has led to the discovery of cancer antigens that may be used as the target for cancer treatment. Antibody-drug conjugates (ADCs) are a relatively new concept in cancer treatment that broaden therapeutic landscape. ADCs are examples of a 'drug delivery into the tumor' system composed of an antigen-directed antibody linked to a cytotoxic drug that may release cytotoxic components after binding to the antigen located on the surface of tumor cells. The clinical properties of drugs are influenced by every component of ADCs. Regarding uro-oncology, enfortumab vedotin (EV) and sacituzumab govitecan (SG) are currently registered for patients with locally advanced or metastatic urothelial cancer following previous treatment with an immune checkpoint inhibitor (iCPI; programmed death receptor-1 [PD-1] or programmed death-ligand 1 [PD-L1]) inhibitor) and platinum-containing chemotherapy. The EV-301 trial showed that EV significantly prolonged the overall survival compared with classic chemotherapy. The TROPHY-U-01 trial conducted to evaluate SG demonstrated promising results as regards the objective response rate and duration of response. The safety and efficacy of ADCs in monotherapy and polytherapy (mainly with iCPIs) for different cancer stages and tumor types are assessed in numerous ongoing clinical trials. The aim of this review is to present new molecular biomarkers, specific mechanisms of action, and ongoing clinical trials of ADCs in genitourinary cancers. In the expert discussion, we assess the place of ADCs in uro-oncology and discuss their clinical value.

The roaring 2020s: a new decade of systemic therapy for renal cell carcinoma.

The genomic and immunologic profiling of renal cell carcinoma (RCC) has provided the impetus for advancements in systemic treatments using combination therapy - either with immune check point inhibitor (ICI) + ICI or with ICI + targeted therapy. This approach has been examined in several landmark trials, treating both clear cell (ccRCC) and nonclear cell (nccRCC) histologies. In this review, we highlight systemic therapy advancements made in this new decade, the 2020s. Targeting the programmed death receptor 1/PD-L1 pathway has created more tolerable and effective immunotherapy regimens, expanding the applications of ICIs. These new applications, paired with trial data, include ICI monotherapy in nccRCC and adjuvant pembrolizumab in resected, high-risk RCC. In addition, ICI + ICI and ICI + TKI combination therapy have demonstrated oncologic efficacy in advanced ccRCC and sarcomatoid RCC. Similar progress has been noted regarding new targeted therapies. Along the hypoxia inducible factor pathway, belzutifan has received FDA approval in von Hippel-Lindau-associated RCC. In addition, in papillary RCC, agents such as cabozantinib target the MET proto-oncogene pathway and have demonstrated impressive oncologic outcomes. The 2020s utilize the molecular profiling of advanced RCC as a scaffold for recent trials in immunotherapy and targeted therapies. Going forward, emphasizing patient-reported outcomes and careful clinical trial construction remain critical to improve systemic therapy in RCC.

Companion Diagnostics: Lessons Learned and the Path Forward From the Programmed Death Ligand-1 Rollout.

Programmed death ligand-1 (PD-L1) immunohistochemistry companion diagnostic assays play a crucial role as predictive markers in patients being considered for immune checkpoint inhibitor therapy. However, because of a convergence of several factors, including recognition of increased types of cancers susceptible to immunotherapy, increasing numbers of immune checkpoint inhibitors, and release of multiple PD-L1 immunohistochemistry antibodies with differing reporting systems, this complex testing environment has led to significant levels of confusion for pathologists and medical oncologists. To identify which processes and procedures have contributed to the current challenges surrounding programmed death receptor-1 (PD-1)/PD-L1 companion diagnostics and to propose potential remedies to this issue. This is based upon input from key industrial stakeholders in conjunction with the College of American Pathologists Personalized Health Care Committee. A meeting of representatives of pharmaceutical and in vitro diagnostic companies along with the Personalized Health Care Committee reviewed the process of release of the PD-L1 companion diagnostic assays using a modified root cause analysis format. The modified root cause analysis envisioned an ideal circumstance of development and implementation of a companion diagnostic to identify shortcomings in the rollout of the PD-L1 assay and to suggest actions to improve future companion diagnostic assay releases. The group recommended improvements to key principles in companion diagnostics implementation related to multi-stakeholder communication, increased regulatory flexibility to incorporate postapproval medical knowledge, improved cross-disciplinary information exchange between medical oncology and pathology societies, and enhanced postmarket training programs. The rapidly changing nature of and increasing complexity associated with companion diagnostics require a fundamental review of processes related to their design, implementation, and oversight.

Prognostic and predictive impact of neutrophil‐to‐lymphocyte ratio and HLA‐I genotyping in advanced esophageal squamous cell carcinoma patients receiving immune checkpoint inhibitor monotherapy

BackgroundImmune checkpoint inhibitors (ICIs) have become standard‐of‐care in patients with pretreated advanced esophageal squamous cell carcinoma (ESCC). However, reliable biomarkers for clinical outcomes are lacking for ICIs. The exploration of effective biomarkers is therefore needed to optimize patient benefit in the treatment of ESCC.MethodsSixty‐nine patients with advanced ESCC enrolled at one center from two prospective trials were consecutively analyzed. NLR was dynamically collected and high‐resolution HLA‐I genotyping were performed on genomic DNA. Overall response rate (ORR), median progression‐free survival (mPFS) and median overall survival (mOS) were investigated.ResultsThirty‐three (47.8%) of 69 patients with baseline NLR ≥4 demonstrated significantly worse clinical outcomes (ORR 9.1% vs. 36.1%, p = 0.018; mPFS 1.8 vs. 3.2 months, hazard ratio [HR] 1.79, p = 0.026; mOS 7.4 vs. 11.0 months, HR 2.28, p = 0.008). An NLR decrease ≥20% at the first radiological evaluation was associated with longer OS (median, 14.0 vs. 7.9 months, p = 0.038). Eleven (15.9%) patients with HLA‐I homozygosity presented poorer clinical outcomes (ORR 0 vs. 27.6%, p = 0.056; mPFS 1.8 vs. 2.4 months, HR 3.37, p = 0.010; mOS 5.6 vs. 10.5 months, HR 3.97, p = 0.004). Patients with baseline NLR ≥4 and HLA‐I homozygosity had the worst outcome (ORR 0; mPFS 1.4 months; mOS 1.8 months) among all. The association between NLR, HLA‐I genotyping and clinical outcomes was independent of programmed death receptor ligand‐1 expression.ConclusionsNLR and HLA‐I genotyping could have predictive and prognostic value in patients with advanced ESCC receiving camrelizumab, and the combination of biomarkers may help to identify more patient benefit from immunotherapy.

Pyrazolones as inhibitors of immune checkpoint blocking the PD-1/PD-L1 interaction

Immuno-therapy has become a leading strategy to fight cancer. Over the past few years, immuno-therapies using checkpoint inhibitor monoclonal antibodies (mAbs) against programmed death receptor 1 (PD-1) and programmed death ligand 1 (PD-L1) have demonstrated improved survival compared with chemotherapy. We describe the microwave-assisted synthesis and the characterization of an innovative series of synthetic compounds endowed with nanomolar activity against PD-L1. The properties of the compounds were characterized using several biophysical techniques including microscale thermophoresis (MST) and fluorescence resonance energy transfer (FRET) measurements. A few small molecules demonstrated a high affinity for human PD-L1, potently disrupted the PD-L1:PD-1 interaction and inhibited Src homology region 2 domain-containing phosphatase (SHP2) recruitment to PD-1. More than 30 molecules from the pyrazolone family have been synthesized and 5 highly potent “PD-L1 silencing compounds” have been identified, based on in vitro measurements. Structure-activity relationships have been defined and ADME properties were evaluated. The phenyl-pyrazolone unit offers novel perspectives to design PD-L1-targeting agents, potentially useful to combat cancer and other pathologies implicating the PD-1/PD-L1 checkpoint.

Programmed death receptor ligand-2 (PD-L2) bearing extracellular vesicles as a new biomarker to identify early triple-negative breast cancer patients at high risk for relapse

PurposeBased on the tumor-promoting features of extracellular vesicles (EV) and PD-L1/2-bearing EV subpopulations (PD-L1/2EV), we evaluated their potential as surrogate markers for disease progression or eligibility criteria for PD-1 immune checkpoint inhibition (ICI) approaches in early triple-negative breast cancer (TNBC).MethodsAfter enrichment of EV from plasma samples of 56 patients before and 50 after chemotherapy (CT), we determined levels of EV particle number and PD-L1/2EV by nanoparticle tracking analysis or ELISA and associated the results with clinical status/outcome and the presence of distinct circulating tumor cells (CTC) subpopulations.ResultsCompared to healthy controls, patients had a tenfold higher EV concentration and significantly elevated PD L2EV but not PD L1EV levels. The most important clinical implications were found for PD-L2EV. High PD-L2EV levels were associated with a significantly reduced 3-year progression-free and overall survival (PFS and OS). A loss of PD-L2EV after CT was significantly more prominent in patients achieving pathological complete response (pCR). Increased pre-CT PD-L2EV levels were found in patients having NOTCH1-positive or ERBB3-positive CTC. The presence of ERBB3-positive CTC combined with high pre-CT PD-L2EV resulted in a shorter PFS.ConclusionThis study highlights PD L2EV as a promising biomarker for risk assessment of TNBC patients and represents the basic for additional studies introducing PD-L2EV as an eligibility criterion for PD-1 ICI approaches.

Effects and molecular mechanism of histone methyltransferase enhancer of zeste homolog 2 on regulating sepsis-induced T cell dysfunction

To investigate the effect and mechanism of histone methyltransferase enhancer of zeste homolog 2 (EZH2) on sepsis-induced T cell dysfunction. Twenty-four male C57BL/6 mice were divided into three groups randomly: sham operated group, sepsis model group [cecum ligation and puncture (CLP)+dimethyl sulfoxide (DMSO) group] and EZH2 selective inhibitor treated group (CLP+GSK126 group), with 8 mice in each group. Sepsis murine model was reproduced by CLP. CLP+DMSO group and CLP+GSK126 group were treated with DMSO or GSK126 (10 mg/kg) respectively right after surgery through intraperitoneal injection. The mice were sacrificed 24 hours after operation, and the mesenteric lymph nodes were collected. The expression of EZH2, apoptosis rates, cell proliferation marker ki-67 antigen positive T lymphocytes (ki-67+ cell), interferon-γ positive T lymphocytes (IFN-γ + cell), programmed death receptor-1 positive T lymphocytes (PD-1+ cell) and programmed death-ligand 1 positive T lymphocytes (PD-L1+ cell) were determined by flow cytometry. Compared with sham operated group, the expression of EZH2 in T lymphocytes was up-regulated on mesenteric lymph nodes of CLP+DMSO group. Compared with CLP+DMSO group, the ratio of CD3+ T lymphocytes in CLP+GSK126 group was up-regulated (0.70±0.02 vs. 0.50±0.07, P < 0.01), indicating that the EZH2 inhibitor could increase the number of T lymphocytes in lymph nodes of septic mice; the ratio of ki-67+ cells in CD4+ and CD8+ T lymphocytes in CLP+GSK126 group was increased (CD4+: 0.74±0.05 vs. 0.63±0.04, CD8+: 0.82±0.06 vs. 0.70±0.04, both P < 0.05), indicating that the EZH2 inhibitor could increase the ratio of T lymphocytes with high proliferative activity in lymph nodes of septic mice. However, no significant difference was found on both CD4+ and CD8+ T lymphocytes apoptosis rates in the mesenteric lymph nodes of mice between CLP+GSK126 group and CLP+DMSO group [CD4+: (21.53±2.87)% vs. (20.48±3.21)%, CD8+: (8.34±1.02)% vs. (7.71±1.38)%, both P > 0.05], indicating that no extra T lymphocytes apoptosis was induced by EZH2 inhibitor. Compared with CLP+DMSO group, the ratios of IFN-γ + CD4+ and IFN-γ + CD8+ T lymphocytes were increased in CLP+GSK126 group (IFN-γ +CD4+: 0.31±0.11 vs. 0.14±0.06, IFN-γ +CD8+: 0.30±0.10 vs. 0.13±0.06, both P < 0.05), suggesting that secretion of IFN-γ in lymph nodes by sepsis T lymphocytes was augmented after EZH2 inhibitor administration. Furthermore, compared with CLP+DMSO group, the ratio of PD-1+ cell in CD8+ T lymphocyte was down-regulated in CLP+GSK126 group (0.092±0.006 vs. 0.135±0.004, P < 0.01), suggesting that EZH2 inhibitor restrained the PD-1 expression on sepsis lymphoid node CD8+ T lymphocytes, however, it had no significant effect on PD-L1+ cells. EZH2, regulates sepsis-induced T lymphocyte dysfunction, possibly through modulating the expression of PD-1.

Suppression of the transforming growth factor-β signaling pathway produces a synergistic effect of combination therapy with programmed death receptor 1 blockade and radiofrequency ablation against hepatic carcinoma in mice

ABSTRACT Primary liver cancer (PLC) significantly affects the health of patients globally owing to its high morbidity and low survival rate. Radiofrequency ablation (RFA) has recently been introduced for the clinical treatment of PLC. However, significant immunosuppressive effects are induced by RFA, which limits its application. This study aimed to explore the potential of combination therapy with RFA by investigating the effects of siRNAs against programmed death receptor 1 (PD-1) and transforming growth factor-β (TGF-β) on the antitumor effect induced by RFA. We observed that compared with si-NC, cell viability was reduced, apoptosis rate was elevated, release of inflammatory factors and percentage of CD3+CD8+ cells were increased, and the PI3K/AKT/mTOR pathway was repressed in the co-culture of RFA-treated H22 cells and CD8+ T cells by transfection with si-PD-1 and si-TGF-β; these effects were further enhanced by co-transfection with si-PD-1 and si-TGF-β. Additionally, in H22 cell xenograft-bearing mice treated with RFA, compared with the si-NC group, repressed tumor growth, prolonged survival, increased production of inflammatory factors and expression of CD3 and CD8 in tumor tissues, and downregulation of the PI3K/AKT/mTOR pathway were observed in the si-PD-1 and si-TGF-β groups; these effects were further enhanced in the si-PD-1 + si-TGF-β group. Taken together, our data revealed that suppression of the TGF-β signaling pathway produced a synergistic antitumor effect of combination therapy with PD-1 blockade and RFA against PLC.

Computed Tomography Texture Analysis for Predicting Clinical Outcomes in Patients With Metastatic Renal Cell Carcinoma Treated With Immune Checkpoint Inhibitors.

The treatment responses of immune checkpoint inhibitors in metastatic renal cell carcinoma (mRCC) vary, requiring reliable prognostic biomarkers. We assessed the prognostic ability of computed tomography (CT) texture analysis in patients with mRCC treated with programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors. Sixty-eight patients with mRCC treated with PD-1/PD-L1 inhibitors between 2012 and 2019 were revaluated. Using baseline and first follow-up CT, baseline and follow-up texture models were developed to predict overall survival (OS) and progression-free survival (PFS) using least absolute shrinkage and selection operator Cox-proportional hazards analysis. Patients were divided into high-risk or low-risk group, and the survival difference was assessed using Kaplan-Meier and log-rank test. Multivariable Cox models were constructed by including only the clinical variables (clinical models) and by combining the clinical variables and the texture models (combined clinical-texture models), and their predictive performance was evaluated using Harrell's C-index. The baseline texture models distinguished longer- and shorter-term survivors for both OS (median, 60.1 vs. 17.0 months; P = .048) and PFS (5.2 vs. 2.8 months; P = .003). The follow-up texture models distinguished longer- and shorter-term overall survivors (40.3 vs. 15.2 months; P = .008) but not for PFS (5.0 vs. 3.6 months; P = .25). The combined clinical-texture model outperformed the clinical model in both predicting the OS (C-index, 0.70 vs. 0.63; P = .03) and PFS (C-index, 0.63 vs. 0.55; P = .04). CT texture analysis performed at baseline and early after starting PD-1/PD-L1 inhibitors is associated with clinical outcomes of patients with mRCC.

Regulation of Intrinsic Functions of PD-L1 by Post-Translational Modification in Tumors.

Tumor cells are eliminated by the immune system, including T lymphocytes and natural killer cells; however, many types of tumor cells acquire the immune tolerance by inhibiting T-cell activation and functions via immune checkpoint molecules. Immunotherapy targeting immune checkpoint molecules such as Programmed death receptor 1 (PD-1)/Programmed death ligand 1 (PD-L1) and cytotoxic T lymphocyte associated protein 4 (CTLA-4) have shown successful outcomes for multiple cancer treatments, however some patients show the lack of durable responses. Thus, discovering the chemical compounds or drugs manipulating the expression or function of immune checkpoint molecules are anticipated to overcome the drug resistance of immune checkpoint inhibitors. Function of inhibitory immune checkpoint molecules is often dysregulated by the transcriptional and post-translational levels in tumors. Here, this review focuses on the post-translational modification of intrinsic PD-L1 functions and regulators for PD-L1 transcription.

Optimism Bias in the Design of Phase III Randomized Control Trials Evaluating PD-1/PD-L1 Targeting Monoclonal Antibodies.

BackgroundMany randomized control trials (RCTs) evaluating programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) targeting monoclonal antibodies (mAbs) have been completed or are in progress. We examined hypothesized hazard ratios (HHRs) and observed hazard ratios (OHRs) from published RCTs evaluating these mAbs.MethodsPublications of RCTs evaluating at least one PD-1/PD-L1 targeting mAbs approved by the US Food and Drug Administration were identified through PubMed searches. The primary reports of RCTs were retrieved. Two investigators extracted HHR, OHR for the primary endpoint among other data elements independently. The differences (∆HR) in HHR and OHR were analyzed statistically. A separate search was conducted for secondary reports after longer follow-ups, the updated OHR was extracted.ResultsForty-nine RCTs enrolling 36 867 patients were included. The mean HHR and OHR were 0.672 and 0.738 respectively. The mean ∆HR was 0.067 (range: –0.300 to 0.895; 95% confidence interval (CI), 0.003-0.130). HHR was met or exceeded in 22 (45%) RCTs. OHR was ≥ 1.0 in 6 RCTs (12%). PD-L1 expression was not associated with the magnitude of effect. Of 18 RCTs with follow-up reports, the magnitude of benefit decreased in 8 RCTs with extended follow-ups.ConclusionThe majority of published RCTs evaluating PD-1/PD-L1 targeting mAbs did not achieve their hypothesized magnitude of benefit. The optimism bias requires attention from the cancer clinical research community given the number of these agents in development and the intense interest in evaluating these agents in a variety of disease settings.

Quality of biomarker defined subgroups in FDA approvals of PD-1/PD-L1 inhibitors 2014 to 2020.

PD-L1 expression is associated with differential response in cancers treated with checkpoint inhibitors. Clinical trials for Food and Drug Administration (FDA) approvals of programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) inhibitors include limited subgroup analyses based on PD-L1 expression. We aimed to define the characteristics of PD-L1 defined subgroups of clinical trials leading to FDA approvals for new indications of PD-1/PD-L1 inhibitors. FDA approvals for PD-1/PD-L1 inhibitors from January 2014 to December 2020 were identified and the clinical trials leading to each drug approval were reviewed. We collected key variables from publicly available information on FDA website and peer-reviewed publications of clinical trials. We assessed regulatory characteristics (approval date, approved drug[s], cancer type, line of therapy and biomarker-restricted approval criteria) of each approval. Clinical trials leading to approvals were reviewed for trial design (RCT vs single arm study, primary endpoint) and PD-L1 defined subgroup design (no subgroup analysis, single threshold 2-group analysis, nested subgroups and adjacent subgroups). We then compared regulatory and trials characteristics (trial design, primary endpoint and biomarker approval criteria) between studies with nested and adjacent subgroups. There were 60 approvals for PD-1/PD-L1 inhibitors between January 2014 and December 2020. Twelve of 60 (20%) did not include any PD-L1 subgroups. Twenty-five of 60 (42%) approvals reported only two subgroups, 14 (23%) included adjacent subgroups and 9 (15%) had nested subgroups. Twenty-five of 60 trials (42%) are single arm studies. Comparison of characteristics between trials with nested subgroup design and adjacent subgroup design did not show differences. We conclude that approvals for new indications of PD-1/PD-L1 inhibitors are based on studies that do not include comprehensive reporting of outcomes by PD-L1 biomarker subgroups.

Management of Dermatologic Events Associated With the Nectin-4-directed Antibody-Drug Conjugate Enfortumab Vedotin.

Enfortumab vedotin is a first-in-class Nectin-4-directed antibody-drug conjugate approved by the US Food and Drug Administration for the treatment of patients with locally advanced or metastatic urothelial cancer (la/mUC) previously treated with a platinum-based chemotherapy and a programmed death receptor-1/programmed death-ligand 1 (PD-1/L1) inhibitor, or patients with la/mUC who are ineligible for cisplatin-based chemotherapy and have previously received one or more prior lines of therapy. Enfortumab vedotin is the only drug to have demonstrated survival benefit versus chemotherapy in a randomized controlled trial in patients with la/mUC previously treated with platinum-based chemotherapy and a PD-1/L1 inhibitor. The development of dermatologic events following the administration of enfortumab vedotin is anticipated given the expression of Nectin-4 in epidermal keratinocytes and skin appendages (eg, sweat glands and hair follicles). There is the potential for rare but severe and possibly fatal cutaneous adverse reactions, including Stevens-Johnson syndrome and toxic epidermal necrosis, as described in the boxed warning of the US prescribing information for enfortumab vedotin. This manuscript describes the presumed pathophysiology and manifestations of dermatologic reactions related to enfortumab vedotin, and presents recommendations for prevention and treatment, to provide oncologists and other healthcare providers with an awareness of these potential adverse events to best anticipate and manage them.