scholarly journals From Tumor Immunology to Immunotherapy in Gastric and Esophageal Cancer

2018 ◽  
Vol 20 (1) ◽  
pp. 13 ◽  
Author(s):  
David Vrána ◽  
Marcel Matzenauer ◽  
Čestmír Neoral ◽  
René Aujeský ◽  
Radek Vrba ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Esophageal Cancer ◽  
Checkpoint Inhibitors ◽  
Cell Cancer ◽  
Predictive Biomarkers ◽  
Molecular Classification ◽  
Novel Treatment ◽  
Predictive Role ◽  
Repair Genes

Esophageal and gastric cancers represent tumors with poor prognosis. Unfortunately, radiotherapy, chemotherapy, and targeted therapy have made only limited progress in recent years in improving the generally disappointing outcome. Immunotherapy with checkpoint inhibitors is a novel treatment approach that quickly entered clinical practice in malignant melanoma and renal cell cancer, but the role in esophageal and gastric cancer is still poorly defined. The principal prognostic/predictive biomarkers for immunotherapy efficacy currently considered are PD-L1 expression along with defects in mismatch repair genes resulting in microsatellite instability (MSI-H) phenotype. The new molecular classification of gastric cancer also takes these factors into consideration. Available reports regarding PD-1, PD-L1, PD-L2 expression and MSI status in gastric and esophageal cancer are reviewed to summarize the clinical prognostic and predictive role together with potential clinical implications. The most important recently published clinical trials evaluating checkpoint inhibitor efficacy in these tumors are also summarized.

scholarly journals How to Best Exploit Immunotherapeutics in Advanced Gastric Cancer: Between Biomarkers and Novel Cell-Based Approaches

2021 ◽  
Vol 10 (7) ◽  
pp. 1412
Author(s):  
Michele Ghidini ◽  
Angelica Petrillo ◽  
Andrea Botticelli ◽  
Dario Trapani ◽  
Alessandro Parisi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Clinical Implementation ◽  
T Cell Therapy ◽  
Dismal Prognosis

Despite extensive research efforts, advanced gastric cancer still has a dismal prognosis with conventional treatment options. Immune checkpoint inhibitors have revolutionized the treatment landscape for many solid tumors. Amongst gastric cancer subtypes, tumors with microsatellite instability and Epstein Barr Virus positive tumors provide the strongest rationale for responding to immunotherapy. Various predictive biomarkers such as mismatch repair status, programmed death ligand 1 expression, tumor mutational burden, assessment of tumor infiltrating lymphocytes and circulating biomarkers have been evaluated. However, results have been inconsistent due to different methodologies and thresholds used. Clinical implementation therefore remains a challenge. The role of immune checkpoint inhibitors in gastric cancer is emerging with data from monotherapy in the heavily pre-treated population already available and studies in earlier disease settings with different combinatorial approaches in progress. Immune checkpoint inhibitor combinations with chemotherapy (CT), anti-angiogenics, tyrosine kinase inhibitors, anti-Her2 directed therapy, poly (ADP-ribose) polymerase inhibitors or dual checkpoint inhibitor strategies are being explored. Moreover, novel strategies including vaccines and CAR T cell therapy are also being trialed. Here we provide an update on predictive biomarkers for response to immunotherapy with an overview of their strengths and limitations. We discuss clinical trials that have been reported and trials in progress whilst providing an account of future steps needed to improve outcome in this lethal disease.

scholarly journals New drug developments in metastatic gastric cancer

2018 ◽  
Vol 11 ◽  
pp. 175628481880807 ◽  
Author(s):  
Aaron C. Tan ◽  
David L. Chan ◽  
Wasek Faisal ◽  
Nick Pavlakis
Keyword(s):  
Gastric Cancer ◽  
Clinical Trials ◽  
Targeted Therapies ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Predictive Biomarkers ◽  
Metastatic Gastric Cancer ◽  
New Era

Metastatic gastric cancer is associated with a poor prognosis and novel treatment options are desperately needed. The development of targeted therapies heralded a new era for the management of metastatic gastric cancer, however results from clinical trials of numerous targeted agents have been mixed. The advent of immune checkpoint inhibitors has yielded similar promise and results from early trials are encouraging. This review provides an overview of the systemic treatment options evaluated in metastatic gastric cancer, with a focus on recent evidence from clinical trials for targeted therapies and immune checkpoint inhibitors. The failure to identify appropriate predictive biomarkers has hampered the success of many targeted therapies in gastric cancer, and a deeper understanding of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies. Identifying appropriate biomarkers for patient selection is essential for future clinical trials, for the most effective use of novel agents and in combination approaches to account for growing complexity of treatment options.

scholarly journals Individualizing Systemic Therapies in First Line Treatment and beyond for Advanced Renal Cell Carcinoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3750
Author(s):  
Yasir Khan ◽  
Timothy D. Slattery ◽  
Lisa M. Pickering
Keyword(s):  
Renal Cell ◽  
Checkpoint Inhibitors ◽  
Cell Cancer ◽  
Predictive Biomarkers ◽  
Therapeutic Options ◽  
Current Status ◽  
Vegf Receptor ◽  
Line Treatment ◽  
First Line ◽  
First Line Treatment

Therapeutic options for treating advanced renal cell cancer (RCC) are rapidly evolving. Vascular endothelial growth factor (VEGF)-directed therapy, predominantly VEGF receptor (VEGFr) tyrosine kinase inhibitors (TKIs) had been the most effective first line treatment since 2005 irrespective of International Metastatic RCC Database Consortium (IMDC) risk stratification. However, immune checkpoint inhibitors (ICI) have recently changed the treatment paradigm for advanced RCC particularly as the first-line systemic treatment modality. The combination of Ipilimumab and Nivolumab provides better disease control and long-term outcomes compared with the anti-VEGFr TKI Sunitinib for IMDC intermediate- to poor-risk patients and we now have the option of using ICI with TKI upfront for all IMDC risk groups. This poses a challenge for physicians, both to select the most suitable first line regimen and the most suitable subsequent therapy given the lack of data about sequencing in this setting. This treatment landscape is expected to become more complex with the emerging treatment options. Moreover, these therapeutic options cannot be generalized as significant variability exists between individual’s disease biologies and their physiologies for handling treatment adverse effects. Notable efforts are being made to identify promising predictive biomarkers ranging from neo-antigen load to gene expression profiling. These biomarkers need prospective validation to justify their utility in clinical practice and in treatment decision making. This review article discusses various clinicopathological characteristics that should be carefully evaluated to help select appropriate treatment and discusses the current status of biomarker-based selection.

Cetuximab, paclitaxel, carboplatin and radiation for esophageal and gastric cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4029-4029 ◽  
Author(s):  
M. Suntharalingam ◽  
T. Dipetrillo ◽  
P. Akerman ◽  
H. Wanebo ◽  
B. Daly ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Esophageal Cancer ◽  
Head And Neck Cancer ◽  
Head And Neck ◽  
Squamous Cell ◽  
Squamous Cell Cancer ◽  
Cell Cancer ◽  
Locally Advanced ◽  
Complete Response ◽  
Grade 3

4029 Background: Cetuximab is an IgG1, chimerized, monoclonal antibody that binds specifically to the epidermal growth factor receptor. Cetuximab improves survival when combined with radiation for patients with locally advanced head and neck cancer. We evaluated the safety and efficacy of the addition of cetuximab to concurrent chemoradiation for patients with esophageal and gastric cancer. Methods: Patients with adenocarcinoma or squamous cell cancer of the esophagus or stomach without distant organ metastases were eligible. Patients with locally advanced disease from mediastinal, celiac, portal and gastric lymphadenopathy were eligible. Surgical resection was not required. Clinical complete response was defined as no tumor on postreatment endoscopic biopsy. Patients received cetuximab, 400mg/m2 week #1 then 250 mg/m2/week for 5 weeks, paclitaxel, 50 mg/m2/week, and carboplatin, AUC =2 weekly for 6 weeks, with concurrent 50.4 Gy radiation. Results: Thirty-seven patients have been entered. The median age was 61 (range of 30–87). Thirty-four have esophageal cancer and 3 have gastric cancer. Of the patients with esophageal cancer, twenty-five have adenocarcinoma and nine have squamous cell cancer. Thus far, 30 patients have completed treatment and are evaluable for toxicity. There have been no grade 4 non-hematologic toxicities and 1 pt had grade 4 neutropenia (3%). Six patients (20%) had grade 3 esophagitis. Other grade 3 toxicities included dehydration (n=5), rash (n=9), and paclitaxel/cetuximab hypersensitivity reactions (n=2). Eighteen of 27 patients (67%) have had clinical complete response. Seven pts out of 16 (43%) who have gone to surgery have had a pathologic CR. Conclusions: Cetuximab can be safely administered with chemoradiation for patients with esophageal cancer. Consistent with the data in head and neck cancer, cetuximab increases cutaneous toxicity but does not increase mucositis/esophagitis when combined with chemoradiation. Further evaluation is ongoing. [Table: see text]

scholarly journals Molecular classification of gastric cancer

2016 ◽  
Vol 27 (5) ◽  
pp. 763-769 ◽  
Author(s):  
N.-Y. Chia ◽  
P. Tan
Keyword(s):  
Gastric Cancer ◽  
Molecular Classification

scholarly journals Immunotherapy in Advanced Gastric Cancer: An Overview of the Emerging Strategies

2018 ◽  
Vol 2018 ◽  
pp. 1-8 ◽  
Author(s):  
Helena Magalhães ◽  
Mário Fontes-Sousa ◽  
Manuela Machado
Keyword(s):  
Gastric Cancer ◽  
Advanced Gastric Cancer ◽  
Median Overall Survival ◽  
Systemic Disease ◽  
Treatment Strategies ◽  
Public Health Problem ◽  
Molecular Classification ◽  
Current Evidence ◽  
Curative Intent

Gastric cancer (GC) remains a public health problem, being the fifth most common cancer worldwide. In the western countries, the majority of patients present with advanced disease. Additionally, 65 to 75% of patients treated with curative intent will relapse and develop systemic disease. In metastatic disease, systemic treatment still represents the state of the art, with less than a year of median overall survival. The new molecular classification of GC was published in 2014, identifying four distinct major subtypes of gastric cancer, and has encouraged the investigation of new and more personalized treatment strategies. This paper will review the current evidence of immunotherapy in advanced gastric cancer.

scholarly journals New therapeutic options opened by the molecular classification of gastric cancer

2018 ◽  
Vol 24 (18) ◽  
pp. 1942-1961 ◽  
Author(s):  
Mihaela Chivu-Economescu ◽  
Lilia Matei ◽  
Laura G Necula ◽  
Denisa L Dragu ◽  
Coralia Bleotu ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Molecular Classification ◽  
Therapeutic Options

Characterization of tumor mutational burden (TMB), PD-L1, and DNA repair genes to assess correlation with immune checkpoint inhibitors (ICIs) response in metastatic renal cell carcinoma (mRCC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16079-e16079 ◽  
Author(s):  
Matthew Labriola ◽  
Jason Zhu ◽  
Rajan Gupta ◽  
Shannon McCall ◽  
Jennifer Jackson ◽  
...  
Keyword(s):  
Dna Repair ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Metastatic Tumor ◽  
Control Group ◽  
Personal Genome ◽  
Dna Repair Genes ◽  
Primary Tumors ◽  
Significant Difference ◽  
Repair Genes

e16079 Background: ICIs have revolutionized treatment for mRCC; however there are limited predictive biomarkers for response to ICIs. PD-L1 status is still controversial, demonstrating little predictive utility in mRCC. TMB is predictive for response to ICIs in melanoma and non-small cell lung cancer (NSCLC), but has not been validated in mRCC. Here, we assess the correlations between TMB and PD-L1 status with outcomes to ICI treatment in mRCC. Methods: 34 patients (pts) with mRCC who had previously received ICIs at Duke Cancer Institute were identified. Tumor samples were retrospectively evaluated using a Personal Genome Diagnostics Assay for somatic variants across > 500 genes, as well as TMB and microsatellite status. PD-L1 status was tested via the Dako 28-8 PD-L1 IHC assay. Deidentified clinical information was extracted from the medical record and tumor response was evaluated based on RECIST criteria. Results: Pts were grouped by overall response following ICI therapy into either progressive disease (“PD”, n = 18) or disease control group (“DC”, n = 16), defined as either stable disease, partial response, or complete response. Pts displayed a TMB range from 0.36 to 12.24 mutations/Mb with a mean score of 2.83 muts/Mb, with no significant difference between the PD and DC groups (mean 3.01 muts/Mb vs. 2.63 muts/Mb, p > 0.05). 9 of 32 evaluable samples were PD-L1 positive, with 4 in the PD group and 5 in the DC group. Notably, the DC group displayed a significant enrichment of mutations in genes affiliated with DNA repair (including BRCA1, BRCA2, FANCA, FANCB, FANCG, FANCM, MSH3, MSH6, RAD50, RAD51C, RAD51D, RAD54B, RECQL4, and SLX4; p = 0.0444). DNA damage gene mutations were found in 8/10 (80%) metastatic tumor specimens and 14/24 (58%) primary tumors. Conclusions: Overall, in this mRCC cohort, neither TMB nor PD-L1 correlated with patient outcomes or with ICI response. Furthermore, high TMB was not significantly associated with PD-L1 expression within the samples. The higher frequency of mutations in DNA repair genes in the DC group suggests potential use as a predictive signature for ICI response, warranting future prospective studies. Further studies with matched primary-metastatic samples would be beneficial to determine if DNA repair mutations occur more frequently in metastatic versus primary tumor specimens.

Characterization of tumor mutational burden (TMB), PD-L1, and DNA repair genes to assess correlation with immune checkpoint inhibitors (ICIs) response in metastatic renal cell carcinoma (mRCC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 589-589 ◽  
Author(s):  
Matthew Labriola ◽  
Jason Zhu ◽  
Rajan Gupta ◽  
Shannon McCall ◽  
Jennifer Jackson ◽  
...  
Keyword(s):  
Dna Repair ◽  
Checkpoint Inhibitors ◽  
Predictive Biomarkers ◽  
Clinical Information ◽  
Complete Response ◽  
Control Group ◽  
Personal Genome ◽  
Dna Repair Genes ◽  
Significant Difference ◽  
Repair Genes

589 Background: ICIs have revolutionized treatment for mRCC; however there are limited predictive biomarkers for response to ICIs. PD-L1 status is still controversial demonstrating little predictive utility in mRCC. TMB is predictive for response to ICIs in melanoma and non-small cell lung cancer (NSCLC), but has not been validated in mRCC. Here, we assess the correlations between TMB and PD-L1 status with outcomes to ICI treatment in mRCC. Methods: 34 patients (pts) with mRCC who had previously received ICI therapy at Duke Cancer Institute were identified. Tumor samples were retrospectively evaluated using a Personal Genome Diagnostics Assay for somatic variants across > 500 genes, as well as TMB and microsatellite status. Tumor samples were also analyzed with the Dako 28-8 PD-L1 IHC assay. Deidentified clinical information was extracted from the medical record and tumor response was evaluated based on RECIST criteria. Results: Pts were grouped by overall response following ICI therapy into either progressive disease (“PD”, n = 18) or disease control group (“DC”, n = 16), defined as either stable disease, partial response, or complete response. Pts displayed a TMB range from 0.36 to 12.24 mutations/Mb with a mean score of 2.83 muts/Mb, with no significant difference between the PD and DC groups (mean 3.01 muts/Mb vs. 2.63 muts/Mb, p > 0.05). 9 of 32 evaluable samples were PD-L1 positive, with 4 in the PD group and 5 in the DC group. Notably, the DC group displayed a significant enrichment of mutations in genes affiliated with DNA repair (including BRCA1, BRCA2, FANCA, FANCB, FANCG, FANCM, MSH3, MSH6, RAD50, RAD51C, RAD51D, RAD54B, RECQL4, and SLX4; p = 0.0444). Conclusions: Overall, in this mRCC cohort, neither TMB nor PD-L1 correlated with patient outcomes or with ICI response. Furthermore, high TMB was not significantly associated with PD-L1 expression within the samples. The higher frequency of mutations in DNA repair genes in the DC group suggests potential use as a predictive signature for ICI response, warranting future prospective studies.

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