Radiotherapy and immune checkpoint blockades: a snapshot in 2016.
Ontology highlight
ABSTRACT:
SUBMITTER: Koo T
PROVIDER: S-EPMC5207372 | biostudies-literature | 2016 Dec
REPOSITORIES: biostudies-literature
Publications
Radiotherapy and immune checkpoint blockades: a snapshot in 2016.
Radiation oncology journal 20161228 4
Immune checkpoint blockades including monoclonal antibodies (mAbs) of cytotoxic T-lymphocyte antigen-4 (CTLA-4), programmed death-1 (PD-1), and programmed death-ligand 1 (PD-L1) have been emerged as a promising anticancer therapy. Several immune checkpoint blockades have been approved by US Food and Drug Administration (FDA), and have shown notable success in clinical trials for patients with advanced melanoma and non-small cell lung cancer. Radiotherapy is a promising combination partner of imm ...[more]
Similar Datasets
Project description:Immune checkpoint blockades (ICBs) have revolutionized cancer therapy by inducing durable clinical responses, but only a small percentage of patients can benefit from ICB treatments. Many studies have established various biomarkers to predict ICB responses. However, different biomarkers were found with diverse performances in practice, and a timely and unbiased assessment has yet to be conducted due to the complexity of ICB-related studies and trials. In this study, we manually curated 29 published datasets with matched transcriptome and clinical data from more than 1400 patients, and uniformly preprocessed these datasets for further analyses. In addition, we collected 39 sets of transcriptomic biomarkers, and based on the nature of the corresponding computational methods, we categorized them into the gene-set-like group (with the self-contained design and the competitive design, respectively) and the deconvolution-like group. Next, we investigated the correlations and patterns of these biomarkers and utilized a standardized workflow to systematically evaluate their performance in predicting ICB responses and survival statuses across different datasets, cancer types, antibodies, biopsy times, and combinatory treatments. In our benchmark, most biomarkers showed poor performance in terms of stability and robustness across different datasets. Two scores (TIDE and CYT) had a competitive performance for ICB response prediction, and two others (PASS-ON and EIGS_ssGSEA) showed the best association with clinical outcome. Finally, we developed ICB-Portal to host the datasets, biomarkers, and benchmark results and to implement the computational methods for researchers to test their custom biomarkers. Our work provided valuable resources and a one-stop solution to facilitate ICB-related research.
| S-EPMC10452274 | biostudies-literature
Project description:The immune checkpoint blockade therapy has completely transformed cancer treatment modalities because of its unprecedented and durable clinical responses in various cancers. With the increasing use of immune checkpoint blockades in clinical practice, a large number of patients develop acquired resistance. However, the knowledge about acquired resistance to immune checkpoint blockades is limited and poorly summarized. In this review, we clarify the principal elements of acquired resistance to immune checkpoint blockades. The definition of acquired resistance is heterogeneous among groups or societies, but the expert consensus of The Society for Immunotherapy of Cancer can be referred. Oligo-progression is the main pattern of acquired resistance. Acquired resistance can be derived from the selection of resistant cancer cell clones that exist in the tumor mass before therapeutic intervention or gradual acquisition in the sensitive cancer cells. Specifically, tumor intrinsic mechanisms include neoantigen depletion, defects in antigen presentation machinery, aberrations of interferon signaling, tumor-induced exclusion/immunosuppression, and tumor cell plasticity. Tumor extrinsic mechanisms include upregulation of other immune checkpoints. Presently, a set of treatment modalities is applied to patients with similar clinical characteristics or resistance mechanisms for overcoming acquired resistance, and hence, further research is required.
| S-EPMC8236848 | biostudies-literature
Project description:Small cell lung cancer (SCLC) is one of the deadliest cancer types in the world. Despite the high response rate to frontline platinum-containing doublets, relapse is inevitable for the majority of patients and the prognosis is poor. Topotecan, which has limited efficacy, has remained the standard second-line therapy for approximately three decades. Although SCLC has a high mutation burden, the clinical efficacy of immune checkpoint blockades (ICBs) in SCLC is far less pronounced than that in non-small cell lung cancer (NSCLC). Only atezolizumab in combination with chemotherapy improved overall survival over chemotherapy alone in the phase III CheckMate 133 trial and has recently received FDA approval as first-line therapy. Most studies concerning ICBs in SCLC are limited to early-phase studies and found that ICBs were not superior to traditional chemotherapy. Why is there such a large difference between SCLC and NSCLC? In this review, comparative analyses of previous studies indicate that SCLC is even more immunodeficient than NSCLC and the potential immune escape mechanisms in SCLC may involve the low expression of PD-L1 and the downregulation of major histocompability complex (MHC) molecules and regulatory chemokines. In consideration of these immune dysfunctions, we speculate that chemotherapy and radiotherapy prior to immunotherapy, the combination of ICBs with antiangiogenic treatment, and selecting tumor mutation burden in combination with PD-L1 expression as biomarkers could be promising strategies to improve the clinical efficacy of immunotherapy for SCLC.
| S-EPMC6599302 | biostudies-literature
Project description:The Wnt/?-catenin (?-cat) pathway plays a critical role in cancer. Using hydrocarbon-stapled peptide technologies, we aim to develop potent, selective inhibitors targeting this pathway by disrupting the interaction of ?-cat with its coactivators B-cell lymphoma 9 (BCL9) and B-cell lymphoma 9-like (B9L). We identified a set of peptides, including hsBCL9CT-24, that robustly inhibits the activity of ?-cat and suppresses cancer cell growth. In animal models, these peptides exhibit potent anti-tumor effects, favorable pharmacokinetic profiles, and minimal toxicities. Markedly, these peptides promote intratumoral infiltration of cytotoxic T cells by reducing regulatory T cells (Treg) and increasing dendritic cells (DCs), therefore sensitizing cancer cells to PD-1 inhibitors. Given the strong correlation between Treg infiltration and APC mutation in colorectal cancers, it indicates our peptides can reactivate anti-cancer immune response suppressed by the oncogenic Wnt pathway. In summary, we report a promising strategy for cancer therapy by pharmacological inhibition of the Wnt/?-cat signaling.
| S-EPMC6506245 | biostudies-literature
Project description:Radiotherapy (RT) is used routinely as a standard treatment for more than 50% of patients with malignant tumors. The abscopal effect induced by local RT, which is considered as a systemic anti-tumor immune response, reflects the regression of non-irradiated metastatic lesions at a distance from the primary site of irradiation. Since the application of immunotherapy, especially with immune checkpoint inhibitors, can enhance the systemic anti-tumor response of RT, the combination of RT and immunotherapy has drawn extensive attention by oncologists and cancer researchers. Nevertheless, the exact underlying mechanism of the abscopal effect remains unclear. In general, we speculate that the immune mechanism of RT is responsible for, or at least associated with, this effect. In this review, we discuss the anti-tumor effect of RT and immune checkpoint blockade and discuss some published studies on the abscopal effect for this type of combination therapy. In addition, we also evaluate the most appropriate time window for the combination of RT and immune checkpoint blockade, as well as the optimal dose and fractionation of RT in the context of the combined treatment. Finally, the most significant purpose of this review is to identify the potential predictors of the abscopal effect to help identify the most appropriate patients who would most likely benefit from the combination treatment modality.
| S-EPMC6097415 | biostudies-literature
Project description:Hepatocellular carcinoma (HCC) is the fifth most common cancer, and its incidence is rapidly increasing in North America and Western Europe as well as South-East Asia. Patients with advanced stage HCC have very poor outcomes; therefore, the discovery of new innovative approaches is urgently needed. Cancer immunotherapy has become a game-changer and revolutionized cancer treatment. A comprehensive understanding of tumor-immune interactions led to the development of immune checkpoint inhibitors (ICIs) as new therapeutic tools, which have been used with great success. Targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T lymphocyte-associated protein-4 (CTLA-4) reinvigorates anti-tumor immunity by restoring exhausted T cells. Despite their effectiveness in several types of cancer, of the many immune suppressive mechanisms limit the efficacy of ICI monotherapy. Radiation therapy (RT) is an essential local treatment modality for a broad range of malignancies, and it is currently gaining extensive attention as a promising combination partner with ICIs because of its ability to trigger immunogenic cell death. The efficacy of combination approaches using RT and ICIs has been well documented in numerous preclinical and clinical studies on various types of cancers but not HCC. The application of ICIs has now expanded to HCC, and RT is recognized as a promising modality in HCC. This review will highlight the current roles of PD-1 and CTLA-4 therapies and their combination with RT in the treatment of cancers, including HCC. In addition, this review will discuss the future perspectives of the combination of ICIs and RT in HCC treatment.
| S-EPMC6543238 | biostudies-literature
Project description:The common gamma receptor-dependent cytokines and their JAK-STAT pathways play important roles in T cell immunity and have been demonstrated to be related with response to immune checkpoint blockades (ICBs). PTPRD and PTPRT are phosphatases involved in JAK-STAT pathway. However, their clinical significance for non-small cell lung cancer (NSCLC) treated with ICBs is still unclear. Genomic and survival data of NSCLC patients administrated with anti-PD-1/PD-L1 or anti-CTLA-4 antibodies (Rizvi2015; Hellmann2018; Rizvi2018 Samstein2019) were retrieved from publicly accessible data. Genomic, survival and mRNA data of 1007 patients with NSCLC were obtained from The Cancer Genome Atlas (TCGA). PTPRD/PTPRT mutation was significantly associated with better progression-free survival (PFS) in three independent Rizvi2015, Hellmann2018 and Rizvi2018 cohorts. The median PFS for PTPRD/PTPRT mutant-type vs. wild-type NSCLC patients were not reached vs. 6.3 months (Rizvi2015, HR = 0.16; 95% CI, 0.02-1.17; P=0.03), 24.0 vs. 5.4 months (Hellmann2018, HR, 0.49; 95% CI, 0.26-0.94; P=0.03), 5.6 vs. 3.0 months (Rizvi2018, HR = 0.64; 95% CI, 0.44-0.92; P=0.01) and 6.8 vs. 3.5 months (Pooled cohort, HR, 0.54; 95% CI, 0.39-0.73; P<0.0001) respectively. PTPRD/PTPRT mutation was an independent predictive factor for PFS in pooled cohort (P = 0.01). Additionally, PTPRD/PTPRT mutation associated with better overall survival (OS) in Samstein2019 cohort (19 vs. 10 months, P=0.03). While similar clinical benefits were not observed in patients without ICBs treatment (TCGA cohort, P=0.78). In the further exploratory analysis, PTPRD/PTPRT mutation was significantly associated with increased tumor mutation burden and higher mRNA expression of JAK1 and STAT1. Gene Set Enrichment Analysis revealed prominent enrichment of signatures related to antigen processing and presentation in patients with PTPRD/PTPRT mutation. This work suggested that PTPRD/PTPRT mutation might be a potential positive predictor for ICBs in NSCLC. These results need to be further confirmed in future.
| S-EPMC8192300 | biostudies-literature
Project description:AimThis meta-analysis aimed to compare the efficacy and safety of immune checkpoint blockade for the treatment of ocular melanoma.MethodsWe searched the PubMed, EMBASE, and Cochrane Library databases up to July 2021. Effect sizes (ESs) and corresponding 95% confidence intervals (CIs) were used to compare the outcomes. Efficacy outcomes included complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), objective response rate (ORR), overall survival (OS), progression free survival (PFS). Safety outcomes included adverse events (AEs) and serious adverse event (SAEs).ResultsA total of 16 eligible articles with 848 ocular melanoma patients were included. ICB treatment significantly improved CR (ES=0.02, 95%CI: 0.00-0.03, P=0.023), PR (ES=0.07, 95%CI: 0.05-0.09, P=0.000), SD (ES=0.31, 95%CI: 0.17-0.46, P=0.000), PD (ES=0.69, 95%CI: 0.61-0.77, P=0.000), ORR (ES=0.10, 95%CI: 0.04-0.15, P=0.000), OS (ES=9.68, 95%CI: 7.28-12.07, P=0.000) and PFS (ES=2.88, 95%CI: 2.69-3.07, P=0.000) in patients with ocular melanoma. Moreover, ICB therapies were associated with reduced AEs (ES=0.48, 95%CI: 0.30-0.67, P=0.000) and SAEs (ES=0.31, 95%CI: 0.18-0.45, P=0.000).ConclusionsICB therapy showed good efficacy and safety in treating patients with ocular melanoma.
| S-EPMC8685375 | biostudies-literature
Project description:Immune checkpoint blockade (ICB) immunotherapy induces potent antitumor immunity across multiple solid tumors, although few patients respond well to this therapy. An emerging biomarker for predicting responsiveness to ICB immunotherapy is tumor mutational burden (TMB). Although several surrogate biomarkers, including deficient mismatch repair, TP53/KRAS mutations, and comutations in DNA damage response pathways, have been shown to be effective for predicting the response to checkpoint blockade immunotherapy, each is positive for only a small cohort of candidates, and many potential responders to ICB are inevitably missed. Here, we found that titin (TTN), which is frequently detected in solid tumors, is associated with increased TMB and correlated with objective response to ICB. In 7 public clinical cohorts, all patients with mutated TTN showed longer progression-free survival or overall survival than those with wild-type status. Furthermore, an improved objective response rate and higher TMB were identified in cohorts with accessible information. Identification of TTN mutation as a predictor of improved outcomes in response to ICBs provides a clinically feasible assessment for estimating TMB and ICB therapy outcomes.
| S-EPMC6542599 | biostudies-literature
Project description:BACKGROUND:Immune checkpoint inhibitors (ICIs) for solid tumors, including those targeting programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), have shown impressive clinical efficacy, however, most patients do not achieve durable responses. One major therapeutic obstacle is the immunosuppressive tumor immune microenvironment (TIME). Thus, we hypothesized that a strategy combining tumor-directed radiation with TIME immunomodulation could improve ICI response rates in established solid tumors. METHODS:Using a syngeneic mouse model of human papillomavirus (HPV)-associated head and neck cancer, mEER, we developed a maximally effective regimen combining PD-1 and CTLA-4 inhibition, tumor-directed radiation, and two existing immunomodulatory drugs: cyclophosphamide (CTX) and a small-molecule inducible nitric oxide synthase (iNOS) inhibitor, L-n6-(1-iminoethyl)-lysine (L-NIL). We compared the effects of the various combinations of this regimen on tumor growth, overall survival, establishment of immunologic memory, and immunologic changes with flow cytometry and quantitative multiplex immunofluorescence. RESULTS:We found PD-1 and CTLA-4 blockade, and radiotherapy alone or in combination, incapable of clearing established tumors or reversing the unfavorable balance of effector to suppressor cells in the TIME. However, modulation of the TIME with cyclophosphamide (CTX) and L-NIL in combination with dual checkpoint inhibition and radiation led to rejection of over 70% of established mEER tumors and doubled median survival in the B16 melanoma model. Anti-tumor activity was CD8+ T cell-dependent and led to development of immunologic memory against tumor-associated HPV antigens. Immune profiling revealed that CTX/L-NIL induced remodeling of myeloid cell populations in the TIME and tumor-draining lymph node and drove subsequent activation and intratumoral infiltration of CD8+ effector T cells. CONCLUSIONS:Overall, this study demonstrates that modulation of the immunosuppressive TIME is required to unlock the benefits of ICIs and radiotherapy to induce immunologic rejection of treatment-refractory established solid tumors.
| S-EPMC6693252 | biostudies-literature