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Role of Immunotherapy in Gastroesophageal Cancers: Advances, Challenges and Future...
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Role of Immunotherapy in Gastroesophageal Cancers: Advances, Challenges and Future Strategies

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Immunology and Immunotherapy".

Deadline for manuscript submissions: closed (15 August 2023) | Viewed by 15104

Special Issue Editor

Dr. Ali Zaidi

E-Mail Website
Guest Editor
Esophageal and Lung Institute, Allegheny Health Network Institute, Pittsburgh, PA 15212, USA
Interests: esophageal cancer; development therapeutics; precision medicine; lung cancer; surveillance; early detection; disease monitoring; treatment response and immunotherapy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, the use of immunotherapy has led to significant advances in the gastroesophageal cancers treatment landscape with pivotal trials establishing PD-1 blockade as a new standard of care for selected patients, in both respectable and first-line metastatic settings. However, the survival outcomes for the advanced disease are still humbling due to the non-inflamed nature of these tumors, necessitating the development of combinatorial approaches to overcome the resistance to immunotherapy.The aim of our Special Issue is to provide a platform for original research and review articles focused on therapeutic approaches being developed for gastroesophageal cancers to improve the prognosis and survival rates of patients treated with immunotherapies, while addressing the challenges associated with an acquired resistance.

Dr. Ali H. Zaidi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • gastroesophageal cancers
  • PD1 blockade
  • immunotherapy
  • resistance
  • prognosis
  • survival
  • biomarkers

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Published Papers (7 papers)

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Research

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13 pages, 451 KiB  
Article
Adjuvant Immunotherapy in Curative Intent Esophageal Cancer Resection Patients: Real-World Experience within an Integrated Health System
by Hyunjee V. Kwak, Kian C. Banks, Yun-Yi Hung, Nathan J. Alcasid, Cynthia J. Susai, Ashish Patel, Simon Ashiku and Jeffrey B. Velotta
Cancers 2023, 15(22), 5317; https://doi.org/10.3390/cancers15225317 - 7 Nov 2023
Viewed by 1678
Abstract
Background: Adjuvant immunotherapy has been shown in clinical trials to prolong the survival of patients with esophageal cancer. We report our initial experience with immunotherapy within an integrated health system. Methods: A retrospective cohort study was performed reviewing patients undergoing minimally invasive esophagectomy [...] Read more.
Background: Adjuvant immunotherapy has been shown in clinical trials to prolong the survival of patients with esophageal cancer. We report our initial experience with immunotherapy within an integrated health system. Methods: A retrospective cohort study was performed reviewing patients undergoing minimally invasive esophagectomy at our institution between 2017 and 2021. The immunotherapy cohort was assessed for completion of treatment, adverse effects, and disease progression, with emphasis on patients who received surgery in 2021 and their eligibility to receive nivolumab. Results: There were 39 patients who received immunotherapy and 137 patients who did not. In logistic regression, immunotherapy was not found to have a statistically significant impact on 1-year overall survival after adjusting for age and receipt of adjuvant chemoradiation. Only seven patients out of 39 who received immunotherapy successfully completed treatment (18%), with the majority failing therapy due to disease progression or side effects. Of the 17 patients eligible for nivolumab, 13 patients received it (76.4%), and three patients completed a full course of treatment. Conclusions: Despite promising findings of adjuvant immunotherapy improving the survival of patients with esophageal cancer, real-life practice varies greatly from clinical trials. We found that the majority of patients were unable to complete immunotherapy regimens with no improvement in overall 1-year survival. Full article
(This article belongs to the Special Issue Role of Immunotherapy in Gastroesophageal Cancers: Advances, Challenges and Future Strategies)
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Review

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16 pages, 291 KiB  
Review
An Ailment with Which I Will Contend: A Narrative Review of 5000 Years of Esophagogastric Cancers and Their Treatments, with Special Emphasis on Recent Advances in Immunotherapeutics
by C. Beau Hilton, Steven Lander and Michael K. Gibson
Cancers 2024, 16(3), 618; https://doi.org/10.3390/cancers16030618 - 31 Jan 2024
Cited by 1 | Viewed by 1286
Abstract
Esophagogastric cancers are among the most common and deadly cancers worldwide. This review traces their chronology from 3000 BCE to the present. The first several thousand years were devoted to palliation, before advances in operative technique and technology led to the first curative [...] Read more.
Esophagogastric cancers are among the most common and deadly cancers worldwide. This review traces their chronology from 3000 BCE to the present. The first several thousand years were devoted to palliation, before advances in operative technique and technology led to the first curative surgery in 1913. Systemic therapies were introduced in 1910, and radiotherapy shortly thereafter. Operative technique improved massively over the 20th century, with operative mortality rates reducing from over 50% in 1933 to less than 5% by 1981. In addition to important roles in palliation, endoscopy became a key nonsurgical curative option for patients with limited-stage disease by the 1990s. The first nonrandomized studies on combination therapies (chemotherapy ± radiation ± surgery) were reported in the early 1980s, with survival benefit only for subsets of patients. Randomized trials over the next decades had similar overall results, with increasing nuance. Disparate conclusions led to regional variation in global practice. Starting with the first FDA approval in 2017, multiple immunotherapies now encompass more indications and earlier lines of therapy. As standards of care incorporate these effective yet expensive therapies, care must be given to disparities and methods for increasing access. Full article
(This article belongs to the Special Issue Role of Immunotherapy in Gastroesophageal Cancers: Advances, Challenges and Future Strategies)
17 pages, 304 KiB  
Review
The Evolving Landscape of Neoadjuvant Immunotherapy in Gastroesophageal Cancer
by Colum Dennehy, Alisha F. Khan, Ali H. Zaidi and Vincent K. Lam
Cancers 2024, 16(2), 286; https://doi.org/10.3390/cancers16020286 - 9 Jan 2024
Cited by 1 | Viewed by 3090
Abstract
Despite advances in treatment strategies and surgical approaches in recent years, improving survival outcomes in esophagogastric cancer (EGC) patients treated with curative intent remains a significant area of unmet need. The recent emergence of adjuvant immunotherapy as the standard of care for resected [...] Read more.
Despite advances in treatment strategies and surgical approaches in recent years, improving survival outcomes in esophagogastric cancer (EGC) patients treated with curative intent remains a significant area of unmet need. The recent emergence of adjuvant immunotherapy as the standard of care for resected EGC demonstrates the impact of immunotherapy in improving recurrence-free survival. Neoadjuvant and perioperative immunotherapies represent another promising approach with potential advantages over adjuvant therapy. Despite the promising results of early neoadjuvant immunotherapy studies, there are several challenges and future research needs. The optimal timing, duration and number of doses in relation to surgery and the optimal combination of immunotherapies are still unclear. In addition, rigorous correlative studies need to be performed to identify biomarkers for patient selection and treatment response prediction to maximize the benefits of neoadjuvant immunotherapy. In this review, we provide a concise summary of the current standard of care for resectable EGC and discuss the rationale for the use of immune checkpoint inhibitors in this setting and the pre-clinical and early clinical data of these novel therapies. Finally, we will examine the potential role and future direction of immunotherapy in the treatment paradigm and the perceived challenges and opportunities that lay ahead. Full article
(This article belongs to the Special Issue Role of Immunotherapy in Gastroesophageal Cancers: Advances, Challenges and Future Strategies)
20 pages, 323 KiB  
Review
Role of Immunotherapy in Gastroesophageal Cancers—Advances, Challenges and Future Strategies
by Emer Lynch, Austin G. Duffy and Ronan J. Kelly
Cancers 2023, 15(22), 5401; https://doi.org/10.3390/cancers15225401 - 14 Nov 2023
Viewed by 1623
Abstract
Background: Gastroesophageal cancers (GECs) carry considerable morbidity and mortality, and demonstrate geographical histological variances in addition to molecular heterogeneity. Consequently, the immunogenicity of the different subtypes, which can predict the likelihood of immunotherapy response, can vary. Immune checkpoint inhibitor (ICI) therapy has transformed [...] Read more.
Background: Gastroesophageal cancers (GECs) carry considerable morbidity and mortality, and demonstrate geographical histological variances in addition to molecular heterogeneity. Consequently, the immunogenicity of the different subtypes, which can predict the likelihood of immunotherapy response, can vary. Immune checkpoint inhibitor (ICI) therapy has transformed the treatment of many cancer types over the past decade but has been slower to gain a foothold in the treatment paradigm of GECs. Methods: This article reviews the existing evidence and use approvals for immunotherapies and immune-based treatments in GECs, in the neoadjuvant, adjuvant and metastatic disease settings. The challenges of and limitations to ICI application in current clinical practice are examined. Ongoing clinical trials and future directions of research are also considered. Conclusion: ICI therapy has become an established treatment option within GECs, both perioperatively and in advanced disease. However, nuances in terms of its use are not yet fully understood. Ongoing research proposes to broaden the application of immunotherapies in GECs with the potential to continue to improve outcomes. Full article
(This article belongs to the Special Issue Role of Immunotherapy in Gastroesophageal Cancers: Advances, Challenges and Future Strategies)
16 pages, 618 KiB  
Review
Regional Immunotherapy for Peritoneal Carcinomatosis in Gastroesophageal Cancer: Emerging Strategies to Re-Condition a Maladaptive Tumor Environment
by Catherine R. Lewis, Neda Dadgar, Samuel A. Yellin, Vera S. Donnenberg, Albert D. Donnenberg, David L. Bartlett, Casey J. Allen and Patrick L. Wagner
Cancers 2023, 15(20), 5107; https://doi.org/10.3390/cancers15205107 - 23 Oct 2023
Cited by 2 | Viewed by 2335
Abstract
Peritoneal carcinomatosis originating from gastric/gastroesophageal junction cancer (GC-PC) occurs in a defined subset of gastric cancer patients with unique clinical, pathologic, molecular and immunologic characteristics that create significant obstacles to effective treatment with modern therapy. Although systemic chemo- and immuno- therapy have yielded [...] Read more.
Peritoneal carcinomatosis originating from gastric/gastroesophageal junction cancer (GC-PC) occurs in a defined subset of gastric cancer patients with unique clinical, pathologic, molecular and immunologic characteristics that create significant obstacles to effective treatment with modern therapy. Although systemic chemo- and immuno- therapy have yielded disappointing results in GC-PC, recent advances in the characterization of GC-PC and peritoneal immune biology present new opportunities for targeted therapeutics. In this review article, we discuss the distinct properties of GC-PC and the peritoneal immune environment as they pertain to current and investigative treatment strategies. We discuss pre-clinical studies and clinical trials relevant to the modulation of the peritoneal environment as a therapeutic intervention in GC-PC. Finally, we present a road map for future combinatorial strategies based on the conception of the peritoneal cavity as a bioreactor. Within this isolated compartment, prevailing immunosuppressive conditions can be altered through regional interventions toward an adaptive phenotype that would support the effectiveness of regionally delivered cellular therapy products. It is hoped that novel combination strategies would promote efficacy not only in the sequestered peritoneal environment, but also via migration into the circulation of tumor-reactive lymphocytes to produce durable systemic disease control, thereby improving oncologic outcome and quality of life in patients with GC-PC. Full article
(This article belongs to the Special Issue Role of Immunotherapy in Gastroesophageal Cancers: Advances, Challenges and Future Strategies)
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20 pages, 1599 KiB  
Review
The Influence of the Microbiome on Immunotherapy for Gastroesophageal Cancer
by Neda Dadgar, Vinay Edlukudige Keshava, Moses S. Raj and Patrick L. Wagner
Cancers 2023, 15(18), 4426; https://doi.org/10.3390/cancers15184426 - 5 Sep 2023
Cited by 3 | Viewed by 2023
Abstract
Immunotherapy has shown promise as a treatment option for gastroesophageal cancer, but its effectiveness is limited in many patients due to the immunosuppressive tumor microenvironment (TME) commonly found in gastrointestinal tumors. This paper explores the impact of the microbiome on the TME and [...] Read more.
Immunotherapy has shown promise as a treatment option for gastroesophageal cancer, but its effectiveness is limited in many patients due to the immunosuppressive tumor microenvironment (TME) commonly found in gastrointestinal tumors. This paper explores the impact of the microbiome on the TME and immunotherapy outcomes in gastroesophageal cancer. The microbiome, comprising microorganisms within the gastrointestinal tract, as well as within malignant tissue, plays a crucial role in modulating immune responses and tumor development. Dysbiosis and reduced microbial diversity are associated with poor response rates and treatment resistance, while specific microbial profiles correlate with improved outcomes. Understanding the complex interactions between the microbiome, tumor biology, and immunotherapy is crucial for developing targeted interventions. Microbiome-based biomarkers may enable personalized treatment approaches and prediction of patient response. Interventions targeting the microbiome, such as microbiota-based therapeutics and dietary modifications, offer the potential for reshaping the gut microbiota and creating a favorable TME that enhances immunotherapy efficacy. Further research is needed to reveal the underlying mechanisms, and large-scale clinical trials will be required to validate the efficacy of microbiome-targeted interventions. Full article
(This article belongs to the Special Issue Role of Immunotherapy in Gastroesophageal Cancers: Advances, Challenges and Future Strategies)
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Other

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18 pages, 633 KiB  
Systematic Review
Role of Checkpoint Inhibitors in the Management of Gastroesophageal Cancers
by Frederic Karim, Adina Amin, Marie Liu, Nivetha Vishnuvardhan, Saif Amin, Raffey Shabbir, Brandon Swed and Uqba Khan
Cancers 2023, 15(16), 4099; https://doi.org/10.3390/cancers15164099 - 14 Aug 2023
Cited by 2 | Viewed by 2411
Abstract
Purpose: This article reviews the essential clinical trials that have led to these immunotherapy approvals and explores the use of predictive biomarkers, such as PD-L1 expression and MSI status, to identify patients who are most likely to benefit from immunotherapies. Methods: This case [...] Read more.
Purpose: This article reviews the essential clinical trials that have led to these immunotherapy approvals and explores the use of predictive biomarkers, such as PD-L1 expression and MSI status, to identify patients who are most likely to benefit from immunotherapies. Methods: This case review series describe findings from different clinical trials and contribute to the evolving understanding of the role of CPIs in managing advanced gastroesophageal cancers and may lead to improved treatment options and patient outcomes. Ongoing clinical trials also hold promise for expanding treatment options and improving patient outcomes in the future. Methods: The systematic review followed the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The protocol has not been registered. A systematic literature review was conducted to identify relevant clinical trials and studies that describe the role of immune checkpoint inhibitors in managing advanced gastroesophageal cancers. Electronic database (PubMed, Clinicaltrials.gov, Society of Immunotherapy of Cancer, Aliment Pharmacology & Therapeutics, BMC cancer, Molecular Cancer Research, Nature Reviews Molecular Cell Biology, American Association for Cancer Research, Science, Nature, Cancer Discovery, Journal of the National Cancer Institute, Advanced Immunology, Oncotarget, Nature Medicine, Nature Genetics, Gut, Pathology and Oncology Research, Journal of Clinical Oncology, The New England Journal of Medicine, Gastrointestinal oncology, JAMA Oncology, Journal of Gastrointestinal Oncology, Current Oncology, Annals of Oncology, The Lancet, JCO Oncology Practice, Future Oncology, Gastric Cancer, CA: A Cancer Journal for Clinicians, American Journal of Gastroenterology, Gastroenterology, Journal of the National Cancer Institute, International Journal of Epidemiology, Helicobacter, Gastroenterology Review) were searched using a combination of relevant keywords and MESH terms. The search encompassed articles published up to 5/2023. Additionally, manual searches of reference lists of selected articles and pertinent review papers were conducted to ensure comprehensive coverage of relevant studies. Studies were included if they provided insights into clinical trials evaluating the efficacy and safety of CPIs in treating advanced gastroesophageal cancers. Relevant case reviews and trials exploring combination therapies involving CPIs were also considered. Articles discussed in the utilization of predictive biomarkers were included to assess their impact on treatment outcomes. Data from selected studies were extracted to inform the narrative review. Key findings were summarized, including clinical trial designs, patient populations, treatment regimens, response rates, progression-free survival (PFS), overall survival (OS), and adverse events. The role of predictive biomarkers, particularly PD-L1 expression and MSI status, in identifying patients likely to benefit from CPIs was critically evaluated based on study results. Ongoing clinical trials investigating novel combination strategies and exploring the broader scope of CPIs in gastroesophageal cancers were also highlighted. The collected data were synthesized to provide a comprehensive overview of the crucial clinical trials that have contributed to the approval of CPIs for advanced gastroesophageal cancers. The role of CPIs in different lines of therapy, including first-line regimens, was discussed. Furthermore, the evolving landscape of predictive biomarkers was examined, emphasizing their potential significance in optimizing patient selection for CPI therapy. Ongoing clinical trials were reviewed to underscore the continuous efforts in expanding treatment options and improving patient outcomes in the future. Full article
(This article belongs to the Special Issue Role of Immunotherapy in Gastroesophageal Cancers: Advances, Challenges and Future Strategies)
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