Markers of immune checkpoint inhibitor efficacy in the AACR Project GENIE database.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15091-e15091
Author(s):  
Yuanchu J Yang ◽  
Sam Rubinstein ◽  
Jeremy Lyle Warner
Keyword(s):  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Metastatic Breast ◽  
Copy Number Gain ◽  
Ductal Adenocarcinoma ◽  
Cancer Type ◽  
Reference Allele ◽  
Resected Nsclc ◽  
Tumor Types

e15091 Background: Although immune checkpoint inhibitors (ICIs) have been shown to be effective in many tumor types, some highly lethal cancers are not responsive to ICI. Potential biomarkers of ICI response include tumor mutational burden (TMB), which is thought to correlate with increased neoantigen production, and 9p24.1 copy number gain (CNG), which can result in over-expression of programmed death ligand 1 (PD-L1). 9p24.1 CNGs have been described in ICI-sensitive (ICI-S) hematologic malignancies (e.g., Hodgkin lymphoma), but are not well described in solid malignancy. We sought to investigate TMB and 9p24.1 CNG for ICI-S and ICI-resistant (ICI-R) tumor types in the publicly available AACR Project GENIE database, version 7.0. Methods: TMB was calculated by counting somatic mutations with tumor reference allele frequency ≥5% and sequencing depth ≥200X. Samples with < 0.5 MB sequenced were excluded. 9p24.1 CNG was extrapolated from gene-level data. Samples with two or more consecutive gene amplifications in the 9p24.1 region were determined to have 9p24.1 CNG. Samples whose sequencing assay did not include at least two genes in 9p24.1 were excluded. Using an overall response rate (ORR) of ≥10% to define ICI-S, we assessed three ICI-S cancers: hepatobiliary cancer (HBC), melanoma (MEL), non-small cell lung cancer (NSCLC); and two ICI-R types: metastatic breast cancer (MBC) & pancreatic ductal adenocarcinoma (PDAC). Groupwise TMB was compared using Wilcoxon rank-sum and 9p24.1 CNG was compared using Chi-squared. Results: MEL had the highest median TMB but a low 9p24.1 CNG rate; NSCLC had the highest rate of 9p24.1 CNG (Table). PDAC had both the lowest median TMB and 9p24.1 CNG rate. As a group, the ICI-S cancers had higher median TMB (p < .001) and 9p24.1 CNG rate (p < .001). Conclusions: Although rates of 9p24.1 CNG were low across the database as a whole, the NSCLC finding replicates findings described in early stage resected NSCLC (Inoue et al. 2016). Relatively high median TMB in MEL may explain ICI-sensitivity in this cancer type. The combination of low median TMB and low rates of 9p24.1 CNG in PDAC may explain the general lack of efficacy of ICIs in this disease. These findings demonstrate the utility of GENIE as a clinico-genomic database, and also highlight the need to identify better markers of responsiveness to these potentially effective but toxic therapies. [Table: see text]

scholarly journals Is There a Place for Immune Checkpoint Inhibitors in Vulvar Neoplasms? A State of the Art Review

2020 ◽  
Vol 22 (1) ◽  
pp. 190
Author(s):  
Fulvio Borella ◽  
Mario Preti ◽  
Luca Bertero ◽  
Giammarco Collemi ◽  
Isabella Castellano ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
State Of The Art ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Survival Rates ◽  
Younger Women ◽  
Multiple Tumor ◽  
Tumor Types

Vulvar cancer (VC) is a rare neoplasm, usually arising in postmenopausal women, although human papilloma virus (HPV)-associated VC usually develop in younger women. Incidences of VCs are rising in many countries. Surgery is the cornerstone of early-stage VC management, whereas therapies for advanced VC are multimodal and not standardized, combining chemotherapy and radiotherapy to avoid exenterative surgery. Randomized controlled trials (RCTs) are scarce due to the rarity of the disease and prognosis has not improved. Hence, new therapies are needed to improve the outcomes of these patients. In recent years, improved knowledge regarding the crosstalk between neoplastic and tumor cells has allowed researchers to develop a novel therapeutic approach exploiting these molecular interactions. Both the innate and adaptive immune systems play a key role in anti-tumor immunesurveillance. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in multiple tumor types, improving survival rates and disease outcomes. In some gynecologic cancers (e.g., cervical cancer), many studies are showing promising results and a growing interest is emerging about the potential use of ICIs in VC. The aim of this manuscript is to summarize the latest developments in the field of VC immunoncology, to present the role of state-of-the-art ICIs in VC management and to discuss new potential immunotherapeutic approaches.

scholarly journals Resistance to immune checkpoint inhibitors in advanced gastro-oesophageal cancers

2021 ◽  
Author(s):  
Mark A. Baxter ◽  
Fearghas Middleton ◽  
Hannah P. Cagney ◽  
Russell D. Petty
Keyword(s):  
Oesophageal Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Patient Specific ◽  
Cancer Type ◽  
Early Stage Disease ◽  
Treatment Paradigm ◽  
Research Challenge

AbstractImmune checkpoint inhibitors (ICIs) have altered the treatment paradigm across a range of tumour types, including gastro-oesophageal cancers. For patients with any cancer type who respond, ICIs can confer long-term disease control and significantly improve survival and quality of life, but for patients with gastro-oesophageal cancer, ICIs can be transformative, as durable responses in advanced disease have hitherto been rare, especially in those patients who are resistant to first-line cytotoxic therapies. Results from trials in patients with advanced-stage gastro-oesophageal cancer have raised hopes that ICIs will be successful as adjuvant and neoadjuvant treatments in early-stage disease, when the majority of patients relapse after potential curative treatments, and several trials are ongoing. Unfortunately, however, ICI-responding patients appear to constitute a minority subgroup within gastro-oesophageal cancer, and resistance to ICI therapy (whether primary or acquired) is common. Understanding the biological mechanisms of ICI resistance is a current major research challenge and involves investigation of both tumour and patient-specific factors. In this review, we discuss the mechanisms underlying ICI resistance and their potential specific applications of this knowledge towards precision medicine strategies in the management of gastro-oesophageal cancers in clinical practice.

scholarly journals Update on the role of pembrolizumab in patients with unresectable or metastatic colorectal cancer

2021 ◽  
Vol 14 ◽  
pp. 175628482110244
Author(s):  
Vanessa Wookey ◽  
Axel Grothey
Keyword(s):  
Colorectal Cancer ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Standard Of Care ◽  
Cancer Type ◽  
Cancer Therapies ◽  
Multiple Cancer ◽  
Multiple Treatment

Colorectal cancer (CRC) is the third most common cancer type in both men and women in the USA. Most patients with CRC are diagnosed as local or regional disease. However, the survival rate for those diagnosed with metastatic disease remains disappointing, despite multiple treatment options. Cancer therapies for patients with unresectable or metastatic CRC are increasingly being driven by particular biomarkers. The development of various immune checkpoint inhibitors has revolutionized cancer therapy over the last decade by harnessing the immune system in the treatment of cancer, and the role of immunotherapy continues to expand and evolve. Pembrolizumab is an anti-programmed cell death protein 1 immune checkpoint inhibitor and has become an essential part of the standard of care in the treatment regimens for multiple cancer types. This paper reviews the increasing evidence supporting and defining the role of pembrolizumab in the treatment of patients with unresectable or metastatic CRC.

scholarly journals Expression of Immune Checkpoint Regulators IDO, VISTA, LAG3, and TIM3 in Resected Pancreatic Ductal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2689
Author(s):  
Felix Popp ◽  
Ingracia Capino ◽  
Joana Bartels ◽  
Alexander Damanakis ◽  
Jiahui Li ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Immune Checkpoint ◽  
Patient Survival ◽  
Checkpoint Inhibitors ◽  
Tumor Infiltrating Lymphocytes ◽  
Ductal Adenocarcinoma ◽  
Lymph Node Status ◽  
Clinicopathologic Parameters ◽  
Survival Differences ◽  
Infiltrating Lymphocytes

Pancreatic cancer features elaborate mechanisms of immune evasion. The potential of new immune molecules was explored to restore the antitumor immune response. If these immune molecules are associated with poor survival, specific drugs could take effect. Here, we analyze the expression of VISTA, LAG3, IDO, and TIM3 on tumor-infiltrating lymphocytes (TILs) and its impact on patient survival. We analyzed 153 pancreatic cancer patients from the prospectively managed database of the multicentered PANCALYZE study. Immunohistochemistry on a tissue microarray assessed VISTA, LAG3, IDO, and TIM3 expression of TILs from the patients undergoing primary resection. Complementarily, we analyzed publicly available transcriptomic data (n = 903). Successful completion of chemotherapy, and lymph node status were independent predictors of survival in the multivariate analysis of the clinicopathologic parameters. Fifteen tumors were exclusively VISTA-positive, thirteen tumors expressed VISTA together with TIM3, and ten tumors expressed VISTA together with IDO. Patients featuring tumors with high numbers of IDO-positive TILs had better patient survival (p = 0.037). VISTA, LAG3, and TIM3 expression did not correlate with survival. The analysis of publicly available data did not show survival differences. Tumors rarely co-express more than two immune molecules at the same time, and VISTA is most frequently co-expressed. Although IDO generally inhibits T-cell proliferation, a high expression of IDO was associated with improved survival. We expect immune checkpoint inhibitors against VISTA, LAG3, and TIM3 to be inefficient in a clinical application.

scholarly journals Enhance the Immune Checkpoint Inhibitors Efficacy with Radiotherapy Induced Immunogenic Cell Death: A Comprehensive Review and Latest Developments

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 678 ◽  
Author(s):  
Adrien Procureur ◽  
Audrey Simonaggio ◽  
Jean-Emmanuel Bibault ◽  
Stéphane Oudard ◽  
Yann-Alexandre Vano
Keyword(s):  
Cell Death ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Tumor Antigens ◽  
Checkpoint Inhibitors ◽  
Mitotic Cell ◽  
Immunogenic Cell Death ◽  
Dna Damages ◽  
Multiple Tumor ◽  
Tumor Types

The immunogenic cell death (ICD) is defined as a regulated cell death able to induce an adaptive immunity. It depends on different parameters including sufficient antigenicity, adjuvanticity and favorable microenvironment conditions. Radiation therapy (RT), a pillar of modern cancer treatment, is being used in many tumor types in curative, (neo) adjuvant, as well as metastatic settings. The anti-tumor effects of RT have been traditionally attributed to the mitotic cell death resulting from the DNA damages triggered by the release of reactive oxygen species. Recent evidence suggests that RT may also exert its anti-tumor effect by recruiting tumor-specific immunity. RT is able to induce the release of tumor antigens, to act as an immune adjuvant and thus to synergize with the anti-tumor immunity. The advent of new efficient immunotherapeutic agents, such as immune checkpoint inhibitors (ICI), in multiple tumor types sheds new light on the opportunity of combining RT and ICI. Here, we will describe the biological and radiobiological rationale of the RT-induced ICD. We will then focus on the interest to combine RT and ICI, from bench to bedside, and summarize the clinical data existing with this combination. Finally, RT technical adaptations to optimize the ICD induction will be discussed.

scholarly journals Improving Immunotherapy Efficacy in Soft-Tissue Sarcomas: A Biomarker Driven and Histotype Tailored Review

2021 ◽  
Vol 12 ◽  
Author(s):  
Matthieu Roulleaux Dugage ◽  
Elise F. Nassif ◽  
Antoine Italiano ◽  
Rastislav Bahleda
Keyword(s):  
Soft Tissue ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Soft Tissue Sarcomas ◽  
Oncolytic Viruses ◽  
Cellular Therapies ◽  
M1 Macrophage ◽  
Synovial Sarcomas

Anti-PD-(L)1 therapies yield a disappointing response rate of 15% across soft-tissue sarcomas, even if some subtypes benefit more than others. The proportions of TAMs and TILs in their tumor microenvironment are variable, and this heterogeneity correlates to histotype. Tumors with a richer CD8+ T cell, M1 macrophage, and CD20+ cells infiltrate have a better prognosis than those infiltrated by M0/M2 macrophages and a high immune checkpoint protein expression. PD-L1 and CD8+ infiltrate seem correlated to response to immune checkpoint inhibitors (ICI), but tertiary lymphoid structures have the best predictive value and have been validated prospectively. Trials for combination therapies are ongoing and focus on the association of ICI with chemotherapy, achieving encouraging results especially with pembrolizumab and doxorubicin at an early stage, or ICI with antiangiogenics. A synergy with oncolytic viruses is seen and intratumoral talimogene laherpavec yields an impressive 35% ORR when associated to pembrolizumab. Adoptive cellular therapies are also of great interest in tumors with a high expression of cancer-testis antigens (CTA), such as synovial sarcomas or myxoid round cell liposarcomas with an ORR ranging from 20 to 50%. It seems crucial to adapt the design of clinical trials to histology. Leiomyosarcomas are characterized by complex genomics but are poorly infiltrated by immune cells and do not benefit from ICI. They should be tested with PIK3CA/AKT inhibition, IDO blockade, or treatments aiming at increasing antigenicity (radiotherapy, PARP inhibitors). DDLPS are more infiltrated and have higher PD-L1 expression, but responses to ICI remain variable across clinical studies. Combinations with MDM2 antagonists or CDK4/6 inhibitors may improve responses for DDLPS. UPS harbor the highest copy number alterations (CNA) and mutation rates, with a rich immune infiltrate containing TLS. They have a promising 15-40% ORR to ICI. Trials for ICB should focus on immune-high UPS. Association of ICI with FGFR inhibitors warrants further exploration in the immune-low group of UPS. Finally translocation-related sarcomas are heterogeneous, and although synovial sarcomas a poorly infiltrated and have a poor response rate to ICI, ASPS largely benefit from ICB monotherapy or its association with antiangiogenics agents. Targeting specific neoantigens through vaccine or adoptive cellular therapies is probably the most promising approach in synovial sarcomas.

Updates in the management and future landscape of urothelial carcinoma

2020 ◽  
pp. 107815522097102
Author(s):  
Kirollos S Hanna ◽  
Maren Campbell ◽  
Adam Kolling ◽  
Alex Husak ◽  
Sabrina Sturm ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Urothelial Carcinoma ◽  
Metastatic Disease ◽  
Checkpoint Inhibitors ◽  
Early Stage ◽  
Locally Advanced ◽  
The United States ◽  
Cancer Type ◽  
Antibody Drug Conjugate ◽  
Early Stage Disease

Urothelial carcinoma is the sixth most common cancer type in the United States. Although most patients present with early stage disease which is associated with improved outcomes, many will progress to locally advanced or metastatic disease. Immune checkpoint inhibitors have significantly impacted the treatment paradigm for patients and have resulted in improved survival rates. Despite their proven efficacy, many ongoing clinical trials continue to refine combinations with chemotherapy, sequencing of therapies and the role of ligand expression. Additionally, novel targets have been identified for advanced urothelial carcinoma and have led to the approval of the antibody-drug conjugate, enfortumab vedotin, and the fibroblast growth factor receptor-targeted, erdafitinib. Enrollment in a clinical trial is strongly encouraged for all stages of advanced or metastatic disease. Numerous ongoing clinical trials are likely to impact the treatment armamentarium for patients. In this manuscript, we highlight key updates in the clinical management for patients and outline ongoing trials.

scholarly journals Resisting Resistance to Immune Checkpoint Therapy: A Systematic Review

2020 ◽  
Vol 21 (17) ◽  
pp. 6176 ◽  
Author(s):  
Yolla Haibe ◽  
Ziad El Husseini ◽  
Rola El Sayed ◽  
Ali Shamseddine
Keyword(s):  
Immune Checkpoint ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Acquired Resistance ◽  
Immune Checkpoints ◽  
Therapeutic Approaches ◽  
Standard Chemotherapy ◽  
Primary Resistance ◽  
In The Beginning ◽  
Tumor Types

The treatment landscape in oncology has witnessed a major revolution with the introduction of checkpoint inhibitors: anti-PD1, anti-PDL1 and anti-CTLA-4. These agents enhance the immune response towards cancer cells instead of targeting the tumor itself, contrary to standard chemotherapy. Although long-lasting durable responses have been observed with immune checkpoints inhibitors, the response rate remains relatively low in many cases. Some patients respond in the beginning but then eventually develop acquired resistance to treatment and progress. Other patients having primary resistance never respond. Multiple studies have been conducted to further elucidate these variations in response in different tumor types and different individuals. This paper provides an overview of the mechanisms of resistance to immune checkpoint inhibitors and highlights the possible therapeutic approaches under investigation aiming to overcome such resistance in order to improve the clinical outcomes of cancer patients.

scholarly journals Immunmoduláló antitestek alkalmazása – az onkológia új fejezete

2016 ◽  
Vol 157 (Supplement 2) ◽  
pp. 9-16 ◽  
Author(s):  
Szilvia Szamosi ◽  
László Váróczy ◽  
Zoltán Szekanecz
Keyword(s):  
Metastatic Melanoma ◽  
Immune Checkpoint ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitors ◽  
Hematologic Malignancies ◽  
The United States ◽  
Clinical Development ◽  
Clinical Activity ◽  
The European Union ◽  
Tumor Types

In the past decade major advances in tumor immunology, a better understanding of antigen recognition by T-cells likewise discovering the regulatory inhibitory signals resulted in the development of new immunotherapies with promising durable responses in various solid tumor types and in hematologic malignancies. This review focuses on immunomodulatory antibodies, namely immune checkpoint inhibitor therapy. The prototype of this new class of immune stimulating agents was cytotoxic T-lymphocyte antigen-4 (CTLA-4) antagonists. After demonstrating enhanced survival, ipilimumab was approved first in the United States in 2011, further on in the European Union for second-line (2011) and for first-line therapy (2013) of metastatic melanoma. Additional T-cell intrinsic pathways were identified and targeted for clinical development. Antibodies blocking the PD-1 pathway also showed promising clinical activity and objective tumor response in several types of tumors, including metastatic melanoma, non-small- cell lung cancer. On the other hand antitumor activity is frequently accompanied by significant reversible immune-related adverse events. To explore potential new immune checkpoint targets bring forth several challanges. Future clinical development will involve identifying potential biomarkers anticipating responsiveness to pathway blockade and additional tumor types likely to respond to the therapy. Furthermore, combination strategies, immune checkpoint inhibitors combined with cancer vaccines, targeted inhibitors and traditional chemotherapies are being evaluated in pre-clinical studies. Orv. Hetil., 2016, 157(Suppl. 2), 9–16.

Incidence and characteristics of emergency department presentations during immune checkpoint inhibitor therapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e14164-e14164
Author(s):  
Daniel Arnold Smith ◽  
Kai Laukamp ◽  
Melanie Campbell ◽  
Robert Devita ◽  
Ariel Ann Nelson ◽  
...  
Keyword(s):  
Emergency Department ◽  
Overall Survival ◽  
Anticancer Agents ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Demographic Data ◽  
Cancer Type ◽  
Primary Cancer ◽  
Oncology Patients ◽  
Ed Visits

e14164 Background: Immune checkpoint inhibitors (ICIs) have emerged as a novel class of anticancer agents with unique response and toxicity profiles. Oncology patients undergoing ICI therapy can present acutely with cancer- or treatment-related complications, but knowledge of these acute clinical presentations is limited. The objective of this study was to investigate the features of emergency department (ED) presentations of patients undergoing ICI therapy. Methods: A retrospective chart review was performed of 1044 adult oncology patients at a single institution from 2010-2018 who underwent treatment with one or more ICI. The number of patient visits to the ED during and up to one month following ICI treatment was recorded, in addition to various clinical and demographic data. These data were compared based on stratification by number of ED visits (0 visits, 1 visit, or ≥2 visits) using Likelihood Ratio Chi-Square and Mann–Whitney U tests. Results: Mean age for the 1044 patients receiving ICI therapy was 64±13 years, with 57% males and 43% females. Primary cancer distribution included 42.0% lung, 24.2% melanoma, 6.9% head & neck, 5.1% kidney, 4.0% bladder, and 17.8% other malignancy. 83.4% of patients were treated with a single ICI, 14.9% with 2 ICIs, and 1.2% with 3-4 ICIs. 56.0% of patients had no ED visits during their treatment duration, 27.0% had 1 ED visit, and 17.0% had ≥2 ED visits. Patients with lung, kidney, and bladder cancer were more likely to present to the ED (p = < 0.001). Black ethnicity was the only demographic feature associated with more ED visits (p = 0.017). Patients receiving ≥2 ICIs or monotherapy with nivolumab, pembrolizumab, or atezolizumab more frequently presented to the ED compared to other ICIs (p = < 0.001). Patients with 1 or ≥2 ED visits had longer durations of ICI therapy (136±12 days and 216±15 days, respectively) compared to patients with no ED visits (127±8 days) (p = < 0.001). Patients with no ED visits also demonstrated better overall survival (p = < 0.001). Conclusions: More frequent ED visits during ICI therapy is statistically associated with several key clinical factors, including primary cancer type, ethnicity, specific ICI agent, ICI therapy duration, and overall survival.

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