Project description:In recent years, progress in our understanding of immune-modulatory signaling pathways in immune cells and the tumor microenvironment (TME) has led to rejuvenated interest in cancer immunotherapy. In particular, immunotherapy targeting the immune checkpoint receptors such as cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4), programmed cell-death 1 (PD-1), and programmed cell-death ligand 1 (PD-L1) have demonstrated clinical activity in a wide variety of tumors, including gynecological cancers. This review will focus on the emerging clinical data on the therapeutic role of immune checkpoint inhibitors, and potential strategies to enhance the efficacy of this class of compounds, in the context of gynecological cancers. It is anticipated that future biomarker-directed clinical trials will provide further insights into the mechanisms underlying response and resistance to immunotherapy, and help guide our approach to designing therapeutic combinations that have the potential to enhance the benefit of immunotherapy in patients with gynecologic cancers.
Project description:The expansion of our understanding of tumor immunity and the recent success of new cancer immunotherapy has reignited the hope that we can treat cancer effectively with immunotherapeutic approaches. Immune checkpoint inhibitors have shown significant efficacy in the treatment of some solid and hematologic malignancies. Encouraged by recent success in some other types of malignancies, many clinical trials are ongoing to evaluate the efficacy of immune checkpoint inhibitors in gastrointestinal (GI) malignancies. In this review, we briefly discuss theoretical background and current status of immune checkpoint inhibitors in GI cancers. We summarize the key studies and present the ongoing clinical trials involving immune checkpoint inhibitors in GI cancers.
Project description:Gastroesophageal cancers (GEC) have a poor survival rate of 20-30% at 5 years, often due to delayed presentations. Neoadjuvant chemoradiotherapy (CRT) followed by surgery or peri-operative chemotherapy and surgery are widely used as the standard of care for patients with resectable GEC. Immune checkpoint inhibitors (ICIs) have improved survival in metastatic and recurrent GEC which led to their application in resectable GEC. Based on the pivotal CheckMate 577 study results, the Food and Drug Administration (FDA) approved nivolumab for patients with completely resected high-risk esophageal or gastroesophageal junction cancer (GEJC). Several ongoing trials with many ICIs could potentially improve resectable GEC outcomes. This review explores the rationale for using ICIs in resectable GEC and discusses the significance of reported clinical trials. Finally, we will examine some ongoing clinical trials and the challenges as well as prospects of ICIs in resectable GEC.
Project description:Gastrointestinal (GI) cancers account for a large proportion of cancer deaths worldwide and pose a major public health challenge. Immunotherapy is considered to be one of the prominent and successful approaches in cancer treatment in recent years. Among them, immune checkpoint inhibitor (ICI) therapy, has received widespread attention, and many clinical findings support the feasibility of ICIs, with sustained responses and significantly prolonged lifespan observed in a wide range of tumors. However, patients treated with ICIs have not fully benefited, and therefore, the identification and development of biomarkers for predicting ICI treatment response have received further attention and exploration. From tumor genome to molecular interactions in the tumor microenvironment, and further expanding to circulating biomarkers and patient characteristics, the exploration of biomarkers is evolving with high-throughput sequencing as well as bioinformatics. More large-scale prospective and specific studies are needed to explore biomarkers in GI cancers. In this review, we summarize the known biomarkers used in ICI therapy for GI tumors. In addition, some ICI biomarkers applied to other tumors are included to provide insights and further validation for GI tumors. Moreover, we present single-cell analysis and machine learning approaches that have emerged in recent years. Although there are no clear applications yet, it can be expected that these techniques will play an important role in the application of biomarker prediction.
Project description:Among all malignant tumors that threaten human health, virus-related tumors account for a large proportion. The treatment of these tumors is still an urgent problem to be resolved. The immune system is the "guard" of the human body, resisting the invasion of foreign substances such as viruses. Studies have shown that immunotherapy has clinical significance in the treatment of a variety of tumors. In particular, the emergence of immune checkpoint inhibitors (ICIs) in recent years has opened a new door to cancer therapy. Considering the potential role of ICIs in the treatment of virus-related cancers, we focused on their therapeutic effect in virus-associated cancers and explored whether the therapeutic effect in virus-associated cancers was related to virus infection status. Although there is no clear statistical significance indicates that ICIs are more effective in virus-associated cancers than non-virus infections, the efficacy of checkpoint inhibitors in the treatment of virus-related cancers is promising. We believe that this research provides a good direction for the implementation of individualized precision medicine.
Project description:Following the administration of immune checkpoint inhibitors, an unexpected pattern of response designated as hyperprogression may be observed in certain patients. This paradoxical response corresponds to an acceleration in tumor growth and a dramatic decrease of patient survival. The reported incidence rates of hyperprogressive disease are highly variable, ranging between 4 and 29%. In this review, we have performed a literature search on hyperprogressive disease, including both retrospective studies and case reports, and discuss potential predictive biomarkers as well as potential mechanisms associated with immune-checkpoint inhibitor associated hyperprogression.
Project description:BackgroundCheckpoint inhibitors have transformed the treatment of cancer in adults. This class of drugs has demonstrated encouraging results in various malignancies such as metastatic melanoma, bladder cancer, renal cancer, and non-small cell lung carcinoma. However, researchers have only begun investigating the effectiveness and tolerability of checkpoint inhibitors in pediatric patients.MethodsWe conducted a review of PubMed indexed literature and clinicaltrials.gov using combinations of the keywords checkpoint, inhibitor, pediatric, CTLA-4 (cytotoxic T lymphocyte antigen-4), PD-1 (programmed cell death-1), and PD-L1 (programmed cell death receptor-1 ligand) to find every recently completed and ongoing trial evaluating checkpoint inhibitors in patients younger than 21 years old. Pertinent articles and clinical trials discussing the role of immune checkpoint inhibitors in the pediatric population were selected for final analysis and manuscript citation.ResultsThis review presents an overview of the cellular mechanisms involved in checkpoint inhibition and of studies evaluating checkpoint inhibitors in humans. The review also details results and side effects from studies conducted with pediatric patients, current pediatric clinical trials, and future implications.ConclusionImmune checkpoint inhibitors have the potential to further therapeutic advances in pediatric oncology; however, we need more clinical trials and combination drug strategies targeted toward pediatric cancers.
Project description:In the recent few years, significant efforts have been undertaken for the development of different immunotherapeutic approaches against cancer. In this context, immune checkpoint inhibitors (ICIs), a novel class of immunotherapeutic drugs with the potential to unleash the immune system, have emerged as authentic game-changers for managing patients with various cancers, including gastrointestinal malignancies. Although the majority of gastrointestinal cancers are generally considered poorly immunogenic, basic research findings and data from clinical trials have proven that subset(s) of patients with various digestive tract cancers are highly responsive to ICI-based therapy. In this context, a better understanding on the role of various DNA repair pathway alterations, especially the evidence supporting the significant importance of DNA mismatch repair deficiencies and the efficacy of the anti-programmed cell death 1 drugs, have led to US Food and Drug Administration approval of 2 anti-programmed cell death 1 antibodies (pembrolizumab and nivolumab) for the treatment of patients with microsatellite instability. This review aims to provide a comprehensive and up-to-date summary for the role of DNA mismatch repair deficiency in cancer, and its importance in the development of ICI therapy. In addition, we provide insights into the spectrum of various genetic alterations underlying ICI resistance, together with the important influence that the tumor microenvironment plays in mediating the therapeutic response to this new class of drugs. Finally, we provide a comprehensive yet succinct glimpse into the most exciting preclinical discoveries and ongoing clinical trials in the field, highlighting bench-to-beside translational impact of this exciting area of research.
Project description:Background: A large proportion of patients eventually experience disease progression despite treatment with immune checkpoint inhibitors (ICIs), but subsequent treatment options are limited for this population. Retreatment with the same or different types of ICIs is a possible strategy, but the clinical efficacy and safety data are limited. This systematic review aims to evaluate the efficacy and safety of ICIs retreatment in patients with solid tumors after disease progression to previous ICIs.Methods: We searched MEDLINE, EMBASE, the Cochrane Library, and major meeting libraries for prospective studies. The primary outcomes included the objective response rate (ORR), disease control rate (DCR), median overall survival (mOS), and the incidence of grade ?3 immune-related adverse events (irAEs).Results: We identified 22 prospective studies including 1865 patients. For disease progression after CTLA-4 inhibitors, three studies evaluated anti-CTLA-4 retreatment. The ORR was 12-23%, the DCR was 48.4-67.7%, and the mOS was 12?months. The incidence of grade ?3 irAEs was 5.9-25%. Four studies evaluated anti-programmed cell death protein 1 (PD-1) retreatment. The ORR was 22-36%, the DCR was 40-64%, and the mOS was 13.4-20.6?months. The incidence of grade ?3 irAEs was <10%. For disease progression after PD-(L)1 inhibitors, 13 studies evaluated anti-PD-(L)1 retreatment. The ORR was 5-53%, the DCR was 38-83%, and the mOS was 13.9?months. The incidence of grade ?3 irAEs was 0-15% for patients retreated with single anti-PD-(L)1 agent, but was higher (0-64%) for those retreated with ICIs combined with other agents. Two studies evaluated anti-cytotoxic T-lymphocyte associated protein 4 (CTLA-4) retreatment. The ORR was 0-22.4%, the DCR was 50-72%, and the mOS was 4-21?months. The incidence of grade ?3 irAEs was 26-61%.Conclusion: Retreatment with ICIs is feasible for cancer patients considering its encouraging efficacy and tolerable safety. Further prospective trials are needed to explore more promising strategies and identify suitable populations for retreatment.
Project description:Monoclonal antibodies targeting the PD-1/PD-L1 immune checkpoint have considerably improved the treatment of some cancers, but novel drugs, new combinations, and treatment modalities are needed to reinvigorate immunosurveillance in immune-refractory tumors. An option to elicit antitumor immunity against cancer consists of using approved and marketed drugs known for their capacity to modulate the expression and functioning of the PD-1/PD-L1 checkpoint. Here, we have reviewed several types of drugs known to alter the checkpoint, either directly via the blockade of PD-L1 or indirectly via an action on upstream effectors (such as STAT3) to suppress PD-L1 transcription or to induce its proteasomal degradation. Specifically, the repositioning of the approved drugs liothyronine, azelnidipine (and related dihydropyridine calcium channel blockers), niclosamide, albendazole/flubendazole, and a few other modulators of the PD-1/PD-L1 checkpoint (repaglinide, pimozide, fenofibrate, lonazolac, propranolol) is presented. Their capacity to bind to PD-L1 or to repress its expression and function offer novel perspectives for combination with PD-1 targeted biotherapeutics. These known and affordable drugs could be useful to improve the therapy of cancer.