The Clinical Application of Neoantigens in Esophageal Cancer.
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ABSTRACT:
SUBMITTER: Gu YM
PROVIDER: S-EPMC8353328 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Esophageal cancer is an exceedingly aggressive and malignant cancer that imposes a substantial burden on patients and their families. It is usually treated with surgery, chemotherapy, radiotherapy, and molecular-targeted therapy. Immunotherapy is a novel treatment modality for esophageal cancer wherein genetically engineered adoptive cell therapy is utilized, which modifies immune cells to attack cancer cells. Using chimeric antigen receptor (CAR) or T cell receptor (TCR) modified T cells yielded demonstrably encouraging efficacy in patients. CAR-T cell therapy has shown robust clinical results for malignant hematological diseases, particularly in B cell-derived malignancies. Natural killer (NK) cells could serve as another reliable and safe CAR engineering platform, and CAR-NK cell therapy could be a more generalized approach for cancer immunotherapy because NK cells are histocompatibility-independent. TCR-T cells can detect a broad range of targeted antigens within subcellular compartments and hold great potential for use in cancer therapy. Numerous studies have been conducted to evaluate the efficacy and feasibility of CAR and TCR based adoptive cell therapies (ACT). A comprehensive understanding of genetically-modified T cell technologies can facilitate the clinical translation of these adoptive cell-based immunotherapies. Here, we systematically review the state-of-the-art knowledge on genetically-modified T-cell therapy and provide a summary of preclinical and clinical trials of CAR and TCR-transgenic ACT.
| S-EPMC8630679 | biostudies-literature
Project description:Neoantigens, a type of tumor-specific antigens derived from non-synonymous mutations, have recently been characterized as attractive targets for cancer immunotherapy. Owing to the development of next-generation sequencing and utilization of machine-learning algorithms, it has become feasible to computationally predict neoantigens by depicting genetic alterations, aberrant post-transcriptional mRNA processing and abnormal mRNA translation events within tumor tissues. Consequently, neoantigen-based therapies such as cancer vaccines have been widely tested in clinical trials and have demonstrated promising safety and efficacy, opening a new era for cancer immunotherapy. We systematically summarize recent advances in the identification of both personalized and public neoantigens, neoantigen formulations and neoantigen-based clinical trials in this review. Moreover, we discuss future techniques and strategies for neoantigen-based cancer treatment either as a monotherapy or as a combination therapy with radiotherapy, chemotherapy or immune checkpoint inhibitors.
| S-EPMC8317330 | biostudies-literature
Project description:Background/aimsEndoscopic resection is a standard treatment for stage T1a esophageal cancer, with esophagectomy or radical radiation therapy (RT) performed for stage T1b lesions. This study aimed to compare treatment outcomes of each modality for clinical stage T1 esophageal cancer.MethodsIn total, 179 patients with clinical T1N0M0-stage esophageal cancer treated from 2006 to 2016 were retrospectively evaluated. Sixty-two patients with clinical T1a-stage cancer underwent endoscopic resection. Among 117 patients with clinical T1b-stage cancer, 82 underwent esophagectomy, and 35 received chemoradiotherapy or RT. We compared overall survival (OS) and recurrence-free survival (RFS) rates for each treatment modality.ResultsThe median follow-up time was 32 months (range, 1 to 120 months). The 5-year OS and RFS rates for patients with stage T1a cancer receiving endoscopic resection were 100% and 85%, respectively. For patients with stage T1b, the 5-year OS and RFS rates were 78% and 77%, respectively, for the esophagectomy group; 80% and 44%, respectively, for the RT alone group; and 96% and 80%, respectively, for the chemoradiation group. The esophagectomy group showed significantly higher RFS than the RT alone group (p=0.04). There was no significant difference in RFS between the esophagectomy and chemoradiation groups (p=0.922). Grade 4 or higher treatment-related complications occurred in four patients who underwent esophagectomy.ConclusionsEndoscopic resection appeared to be an adequate treatment for patients with T1a-stage esophageal cancer. The multidisciplinary approach involving chemoradiation was comparable to esophagectomy in terms of survival outcome without serious complications for T1b-stage esophageal cancer.
| S-EPMC6529170 | biostudies-literature
Project description:Tumor neoantigen is the truly foreign protein and entirely absent from normal human organs/tissues. It could be specifically recognized by neoantigen-specific T cell receptors (TCRs) in the context of major histocompatibility complexes (MHCs) molecules. Emerging evidence has suggested that neoantigens play a critical role in tumor-specific T cell-mediated antitumor immune response and successful cancer immunotherapies. From a theoretical perspective, neoantigen is an ideal immunotherapy target because they are distinguished from germline and could be recognized as non-self by the host immune system. Neoantigen-based therapeutic personalized vaccines and adoptive T cell transfer have shown promising preliminary results. Furthermore, recent studies suggested the significant role of neoantigen in immune escape, immunoediting, and sensitivity to immune checkpoint inhibitors. In this review, we systematically summarize the recent advances of understanding and identification of tumor-specific neoantigens and its role on current cancer immunotherapies. We also discuss the ongoing development of strategies based on neoantigens and its future clinical applications.
| S-EPMC6731555 | biostudies-literature
Project description:Mutation-derived neoantigens distinguish tumor from normal cells. T cells can sense the HLA-presented mutations, recognize tumor cells as non-self and destroy them. Therapeutically, immunotherapy antibodies can increase the virulence of the immune system by increasing T-cell cytotoxicity targeted toward neoantigens. Neoantigen vaccines act through antigen-presenting cells, such as dendritic cells, to activate patient-endogenous T cells that recognize vaccine-encoded mutations. Infusion of mutation-targeting T cells by adoptive cell therapy (ACT) directly increases the number and frequency of cytotoxic T cells recognizing and killing tumor cells. At the same time, publicly-funded consortia have profiled tumor genomes across many indications, identifying mutations in each tumor. For example, we find basal and HER2 positive tumors contain more mutated proteins and more TP53 mutations than luminal A/B breast tumors. HPV negative tumors have more mutated proteins than HPV positive head and neck tumors and in agreement with the hypothesis that HPV activity interferes with p53 activity, only 14% of the HPV positive mutations have TP53 mutations vs. 86% of the HPV negative tumors. Lung adenocarcinomas in smokers have over four times more mutated proteins relative to those in never smokers (median 248 vs. 61, respectively). With an eye toward immunotherapy applications, we review the spectrum of mutations in multiple indications, show variations in indication sub-types, and examine intra- and inter-indication prevalence of re-occurring mutation neoantigens that could be used for warehouse vaccines and ACT.
| S-EPMC6693295 | biostudies-literature
Project description:To address uncertainty of whether clinical stage groupings (cTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report data-simple descriptions of patient characteristics, cancer categories, and non-risk-adjusted survival-for clinically staged patients from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty-three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all-cause mortality from first management decision. Of 22,123 clinically staged patients, 8,156 had squamous cell carcinoma, 13,814 adenocarcinoma, 116 adenosquamous carcinoma, and 37 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (18.5-25 mg/kg2 , 47%), little weight loss (2.4?±?7.8 kg), 0-1 ECOG performance status (67%), and history of smoking (67%). Cancers were cT1 (12%), cT2 (22%), cT3 (56%), cN0 (44%), cM0 (95%), and cG2-G3 (89%); most involved the distal esophagus (73%). Non-risk-adjusted survival for squamous cell carcinoma was not distinctive for early cT or cN; for adenocarcinoma, it was distinctive for early versus advanced cT and for cN0 versus cN+. Patients with early cancers had worse survival and those with advanced cancers better survival than expected from equivalent pathologic categories based on prior WECC pathologic data. Thus, clinical and pathologic categories do not share prognostic implications. This makes clinically based treatment decisions difficult and pre-treatment prognostication inaccurate. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient characteristics, cancer categories, and treatment characteristics and should direct 9th edition data collection.
| S-EPMC5591441 | biostudies-literature
Project description:Background:Survival of patients with cT4 esophageal cancer is dismal. Although the optimal treatment strategy remains to be established, two treatment options are available for cT4 esophageal cancers: definitive chemoradiation (dCRT) and induction treatment followed by conversion surgery (CS). However, little is known concerning the differences in clinical outcome between patients with T4 esophageal tumors treated with dCRT and those eventually treated with CS. Methods:A systematic search of the scientific literature on PubMed/MEDLINE was carried out using the keywords "T4 esophageal cancer," "invading (involving) adjacent organ," "definitive chemoradiation," "induction therapy," "salvage surgery," and "conversion surgery," obtaining 28 reports published up to July 2018. Results/Conclusion:We found that CS was superior to dCRT with respect to local disease control and short-term survival; however, CS was associated with relatively higher perioperative mortality and morbidity. Alternatively, although dCRT might often cause fistula formation, a clinical complete response to dCRT is likely to lead to a better prognosis. Recent advances in chemotherapeutic agents have led to triple induction chemotherapy, with docetaxel, cisplatin, and 5-fluorouracil (DCF), which has shown promise as an initial induction treatment for cT4 esophageal cancer. Indeed, this regimen could control both local and systemic disease, which enables curative resection without preoperative CRT. Moreover, some appropriate changes in perioperative management and intensive systemic chemotherapy might enhance patient outcome. Randomized controlled trials with a large sample size are needed to establish the standard treatment for cT4 esophageal cancer.
| S-EPMC6422802 | biostudies-other
Project description:Platinum-based chemotherapy is considered a standard treatment option for patients with metastatic esophageal carcinoma. However, the overall survival of patients receiving such treatment is <1 year. A common presenting symptom of esophageal cancer is dysphagia, which has a substantial impact on quality of life. We have now retrospectively evaluated the efficacy and safety of palliative chemoradiotherapy for patients with stage IV esophageal cancer, most of whom are unfit for curative chemoradiotherapy. Fifty consecutive patients diagnosed with stage IV esophageal cancer were treated with concurrent chemoradiotherapy at Kindai University Hospital between April 2008 and December 2014. Most (90%) patients received a total radiation dose of at least 50 Gy, and the median number of treatment cycles per patient was four for the combination of 5-fluorouracil and cisplatin. The response of the primary tumor and the overall response were 80% and 44%, respectively. The dysphagia score was improved after chemoradiotherapy in 36 (72%) patients and did not change between before and after treatment in 14 (28%) patients. With a median follow-up time of 9.4 months from the start of chemoradiotherapy, the median progression-free survival and overall survival were 4.7 and 12.3 months, respectively. Three patients (T4b in two, T3 in one) developed esophagobronchial fistula after completion of chemoradiotherapy (n = 2) or after disease progression (n = 1), resulting in death in each case. Our results suggest that palliative chemoradioiotherapy was safe and contributed the improvement of dysphagia in patients with stage IV esophageal cancer.
| S-EPMC5655197 | biostudies-other
Project description:BackgroundCurrent prediction models of esophageal cancer (EC) are limited to predicting at a specific time point, and ignore changes in hazard ratios of predictive variables, known as time-varying effects. Our study aimed to investigate variables with time-varying effects in EC and to develop a prediction model that can update the 5-year predicted dynamic overall survival (DOS) probability during the follow-up period.MethodsFirstly, the clinicopathological information and survival data of 4,541 patients with EC was obtained from the Surveillance, Epidemiology, and End Results (SEER) database between 2007 and 2011 for modeling. Secondly, the time-varying effect of variables was assessed and the dynamic prediction model was developed based on the proportional baselines landmark supermodel.ResultsHere, we found that age at diagnosis, sex, location of primary tumor, histological type, chemotherapy, surgery, and T stage showed significant time-varying effects on overall survival. Thirdly, the prediction model was validated by an internal SEER validation cohort and a Chinese patient cohort, respectively, and achieved promising results as follows: area under the curve (AUC) =0.733 (internal validation) and 0.864 (external validation). The heuristic shrinkage factor was 0.995. Finally, several clear cases were selected as examples for model application to map the patient's 5-year DOS curves and to respectively demonstrate the impact of different variables' time-varying effect on survival.ConclusionsOverall, our results suggest that the existence of time-varying effect highlights the importance of updating the predicted survival probability during the follow-up period. Moreover, this prediction model can be used to assist doctors in making more-individualized treatment decisions based on a dynamic assessment of patient prognosis.
| S-EPMC8576729 | biostudies-literature
Project description:In this issue of JEM, Chheda et al. (https://doi.org/10.1084/jem.20171046) report that a conserved hotspot mutation associated with an aggressive form of brain cancer generates an immunogenic T cell epitope restricted by a common HLA subtype, thereby creating a "public" neoantigen.
| S-EPMC5748868 | biostudies-literature