Optimizing radiotherapy with immune checkpoint blockade in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer, and its incidence is rapidly increasing in North America and Western Europe as well as South-East Asia. Patients with advanced stage HCC have very poor outcomes;therefore, the discovery of new innovative approaches is urgently needed. Cancer immunotherapy has become a game-changer and revolutionized cancer treatment. A comprehensive understanding of tumor-immune interactions led to the development of immune checkpoint inhibitors (ICIs) as new therapeutic tools, which have been used with great success. Targeting immune checkpoint molecules such as programmed cell death-1 (PD-1) and cytotoxic T lymphocyteassociated protein-4 (CTLA-4) reinvigorates anti-tumor immunity by restoring exhausted T cells. Despite their effectiveness in several types of cancer, of the many immune suppressive mechanisms limit the efficacy of ICI monotherapy. Radiation therapy (RT) is an essential local treatment modality for a broad range of malignancies, and it is currently gaining extensive attention as a promising combination partner with ICIs because of its ability to trigger immunogenic cell death. The efficacy of combination approaches using RT and ICIs has been well documented in numerous preclinical and clinical studies on various types of cancers but not HCC. The application of ICIs has now expanded to HCC, and RT is recognized as a promising modality in HCC. This review will highlight the current roles of PD-1 and CTLA-4 therapies and their combination with RT in the treatment of cancers, including HCC. In addition, this review will discuss the future perspectives of the combination of ICIs and RT in HCC treatment.     

Therapeutic options for the management of pancreatic cancer

Since its initial characterization, pancreatic ductal adenocarcinoma has remained one of the most devastating and difficult cancers to treat. Pancreatic cancer is the fourth leading cause of death in the United States, resulting in an estimated 38460 deaths annually. With few screening tools available to detect this disease at an early stage, 94% of patients will die within five years of diagnosis. Despite decades of research that have led to a better understanding of the molecular and cellular signaling pathways in pancreatic cancer cells, few effective therapies have been developed to target these pathways. Other treatment options have included more sophisticated pancreatic cancer surgeries and combination therapies. While outcomes have improved modestly for these patients, more effective treatments are desperately needed. One of the greatest challenges in the future of treating this malignancy will be to develop therapies that target the tumor microenvironment and surrounding pancreatic cancer stem cells in addition to pancreatic cancer cells. Recent advances in targeting pancreatic stellate cells and the stroma have encouraged researchers to shift their focus to the role of desmoplasia in pancreatic cancer pathobiology in the hopes of developing newer-generation therapies. By combining novel agents with current cytotoxic chemotherapies and radiation therapy and personalizing them to each patient based on specific biomarkers, the goal of prolonging a patient’s life could be achieved. Here we review the most effective therapies that have been used for the treatment of pancreatic cancer and discuss the future potential of therapeutic options.     

Prognostic significance of tumor immune microenvironment and immunotherapy: Novel insights and future perspectives in gastric cancer

Despite a decrease in gastric cancer incidence, the development of novel biologic agents and combined therapeutic strategies, the prognosis of gastric cancer remains poor. Recently, the introduction of modern immunotherapy, especially using immune checkpoint inhibitors, led to an improved prognosis in many cancers. The use of immunotherapy was also associated with manageable adverse event profiles and promising results in the treatment of patients with gastric cancer, especially in heavily pretreated patients. These data have led to an accelerated approval of some checkpoint inhibitors in this setting. Understanding the complex relationship between the host immune microenvironment and tumor and the immune escape phenomenon leading to cancer occurrence and progression will subsequently lead to the identification of prognostic immune markers. Furthermore, this understanding will result in the discovery of both new mechanisms for blocking tumor immunosuppressive signals and pathways to stimulate the local immune response by targeting and modulating different subsets of immune cells. Due to the molecular heterogeneity of gastric cancers associated with differentclinico-biologic parameters, immune markers expression and prognosis, novel immunotherapy algorithms should be personalized and addressed to selected subsets of gastric tumors, which have been proven to elicit the best clinical responses. Future perspectives in the treatment of gastric cancer include tailored dual immunotherapies or a combination of immunotherapy with other targeted agents with synergistic antitumor effects.     

Personalized medicine in gastric cancer: Where are we and where are we going?

Despite improvements in adjuvant therapies for gastric cancer in recent years, the disease is characterized by high recurrence rates and a dismal prognosis. The major improvement in the treatment of recurrent or metastatic gastric cancer in recent years has been the incorporation of trastuzumab, a monoclonal antibody that inhibits human epidermal growth factor receptor 2(HER2) heterodimerization, after the demonstrated predictive value of the overexpression and/or amplification of this receptor. Beyond HER2, other genetic abnormalities have been identified, and these mutations may be targetable by tyrosine kinase inhibitors or monoclonal antibodies. The demonstration of four distinct molecular subtypes of gastric cancer by the Cancer Genome Atlas study highlight the enormous heterogeneity of the disease and its complex interplay between genetic and epigenetic alterations and provide a roadmap to implement genome-guided personalized therapy in gastric cancer. In the present review, we aim to discuss, from a clinical point of view, the genomic landscape of gastric cancer described in recent studies, the therapeutic insights derived from these findings, and the clinical trials that have been conducted and those in progress that take into account tailored therapies for gastric cancer.     

Gastrointestinal cancer stem cells as targets for innovative immunotherapy

The role of cancer stem cells in gastrointestinal cancer-associated death has been widely recognized. Gastrointestinal cancer stem cells(GCSCs) are considered to be responsible for tumor initiation, growth, resistance to cytotoxic therapies,recurrence and metastasis due to their unique properties. These properties make the current therapeutic trials against GCSCs ineffective. Moreover, recent studies have shown that targeting stem cell surface markers or stemness associated pathways might have an additional off-target effect on the immune system.Recent advances in oncology and precision medicine have opened alternative therapeutic strategies in the form of cancer immunotherapy. This approach differs from classical anti-cancer therapy through its mechanism of action involving the activation and use of a functional immune system against tumor cells, instead of aiming physically destruction of cancer cells through radio-or chemotherapy. New immunological approaches for GCSCs targeting involve the use of different immune cells and various immune mechanisms like targeting specific surface antigens, using innate immune cells like the natural killer and T cells, T-cell chimeric antigen receptor technology, dendritic cell vaccine, or immune checkpoint inhibitors. In this respect, better understandings of immune regulatory mechanisms that govern anti-tumor response bring new hope in obtaining long-term remission for cancer therapy.     

Immunotherapy in human colorectal cancer: challenges and prospective

Human colorectal cancer(CRC) is the third most commonly diagnosed malignancies and the prognosis for patients with recurrent or metastatic disease is extremely poor. Although new chemotherapeutic regimen improves survival rates, therapy with better efficacy and less adverse effects is drastically needed. Immunotherapy has been investigated in human CRC for decades with limited success. However, recent developments of immunotherapy, particularly immune checkpoint inhibitor therapy, have achieved promising clinical benefits in many types of cancer and revived the hope for utilizing such therapy in human CRC. In this review, we will discuss important immunological landscape within the CRC microenvironment and introduce immunoscore system to better describe immunophenotyping in CRC. We will also discuss different immunotherapeutic approaches currently utilized in different phases of clinical trials. Some of those completed or ongoing trials are summarized. Finally, we provide a brief prospective on the future human CRC immunotherapy.     

Current and emerging therapies in unresectable and recurrent gastric cancer

Gastric cancer is one of the most lethal cancers worldwide despite many advances and options in therapy. As it is often diagnosed at an advanced stage, prognosis is poor with a median overall survival of less than twelve months. Chemotherapy remains the mainstay of treatment for these patients but it confers only a moderate survival advantage. There remains a need for new targeted treatment options and a way to better define patient populations who will benefit from these agents. In the past few years, there has been a better understanding of the biology, molecular profiling, and heterogeneity of gastric cancer. Our increased knowledge has led to the identification of gastric cancer subtypes and to the development of new targeted therapeutic agents. There are now two new targeted agents, trastuzumab and ramucirumab, that have recently been approved for the treatment of advanced and metastatic gastric cancer. There are also many other actively investigated targets, including epidermal growth factor receptor, the phosphatadylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, c-Met, poly ADP-ribose polymerase, and immune checkpoint inhibition. In this review, we discuss the current management of advanced gastric cancer as well as emerging targeted therapies and immunotherapy.     

Engineering opportunities in cancer immunotherapy

Immunotherapy has great potential to treat cancer and prevent future relapse by activating the immune system to recognize and kill cancer cells. A variety of strategies are continuing to evolve in the laboratory and in the clinic, including therapeutic noncellular (vector-based or subunit) cancer vaccines, dendritic cell vaccines, engineered T cells, and immune checkpoint blockade. Despite their promise, much more research is needed to understand how and why certain cancers fail to respond to immunotherapy and to predict which therapeutic strategies, or combinations thereof, are most appropriate for each patient. Underlying these challenges are technological needs, including methods to rapidly and thoroughly characterize the immune microenvironment of tumors, predictive tools to screen potential therapies in patient-specific ways, and sensitive, information-rich assays that allow patient monitoring of immune responses, tumor regression, and tumor dissemination during and after therapy. The newly emerging field of immunoengineering is addressing some of these challenges, and there is ample opportunity for engineers to contribute their approaches and tools to further facilitate the clinical translation of immunotherapy. Here we highlight recent technological advances in the diagnosis, therapy, and monitoring of cancer in the context of immunotherapy, as well as ongoing challenges.     

Current status and perspectives of immune-based therapies for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a frequent cancer with a high mortality. For early stage cancer there are potentially curative treatments including local ablation, resection and liver transplantation. However, for more advanced stage disease, there is no optimal treatment available. Even in the case of a “curative” treatment, recurrence or development of a new cancer in the precancerous liver is common. Thus, there is an urgent need for novel and effective (adjuvant) therapies to treat HCC and to prevent recurrence after local treatment in patients with HCC. The unique immune response in the liver favors tolerance, which remains a genuine challenge for conventional immunotherapy in patients with HCC. However, even in this “immunotolerant” organ, spontaneous immune responses against tumor antigens have been detected, although they are insufficient to achieve significant tumor death. Local ablation therapy leads to immunogenic tumor cell death by inducing the release of massive amounts of antigens, which enhances spontaneous immune response. New immune therapies such as dendritic cell vaccination and immune checkpoint inhibition are under investigation. Immunotherapy for cancer has made huge progress in the last few years and clinical trials examining the use of immunotherapy to treat hepatocellular carcinoma have shown some success. In this review, we discuss the current status of and offer some perspectives on immunotherapy for hepatocellular carcinoma, which could change disease progression in the near future.     

Cancer of the esophagus and gastric cardia: recent advances.

Esophageal cancer and cancer of the gastric cardia, in particular adenocarcinomas, have shown a rapid and largely unexplained increase in incidence in many developed countries around the world. These diseases have a poor prognosis and current therapies have a modest impact on survival. This review presents recent advances in the epidemiology, etiology, diagnosis, staging, prevention and treatment of resectable and advanced disease. Although significant progress has been made in these areas of research and patient management over the past years, prognosis for most patients diagnosed with esophageal cancer or cancer of the gastric cardia remains poor. New diagnostic procedures, improved surgical procedures, combined treatment modalities and new treatment modalities are being evaluated and may be expected to contribute to improved patient outcomes and better palliation of symptoms in the future.     

Immunotherapy for colorectal cancer

The incidence of colorectal cancer(CRC)is on the rise,and the prognosis for patients with recurrent or metastatic disease is extremely poor.Although chemotherapy and radiation therapy can improve survival rates,it is imperative to integrate alternative strategies such as immunotherapy to improve outcomes for patients with advanced CRC.In this review,we will discuss the effect of immunotherapy for inducing cytotoxic T lymphocytes and the major immunotherapeutic approaches for CRC that are currently in clinical trials,including peptide vaccines,dendritic cell-based cancer vaccines,whole tumor cell vaccines,viral vector-based cancer vaccines,adoptive cell transfer therapy,antibody-based cancer immunotherapy,and cytokine therapy.The possibility of combination therapies will also be discussed along with the challenges presented by tumor escape mechanisms.     

Mechanisms and strategies to overcome immunotherapy resistance in hepatobiliary malignancies

Unprecedented advances have been achieved in hepatobiliary cancer treatment with immune checkpoint blockade (ICB). However, the efficacy of ICB in patients with hepatobiliary malignancies is still limited. Resistance to immunotherapies is often orchestrated by complicated tumor-host-microenvironment interactions but could also occur after initial efficacy, mostly when only partial responses are obtained. Clarification of cancer-resistance mechanisms will be beneficial to provide the rationale for the administration of personalized drugs. Here, we review the factors related to resistance to immune-targeted therapies in hepatobiliary malignancies and discuss the potential strategies for overcoming resistance and future directions of immunotherapy development.     

TCR gene-engineered cell therapy for solid tumors

The engineering of immune cells to target cancer cells (cellular immunotherapy) has been an exciting area of development in recent years. One type of cellular therapy, T cell receptor (TCR) gene engineered therapy, has shown particular promise in solid tumors. Through use of a heterodimer to recognize intracellular tumor antigens presented through the major histocompatibility complex (MHC), TCR T cells are able to evoke a cytotoxic response as well as a clinical response. In this review, we discuss the potential of TCR-based cellular therapies in solid tumors. While various challenges exist with this therapy, multiple clinical trials are ongoing, in attempt to mitigate these limitations.     

Colon cancer and the immune system： The role of tumor invading T cells

INTRODUCTION Colon cancer is still one of the leading causes of cancerdeath worldwide. In the United States approximately 145 290 new cases of colorectal cancer are diagnosed every year. With more than 56 000 deaths in the United States in 2005, colorecta…     

The progress and current status of immunotherapy in acute myeloid leukemia

Recently, there has been remarkable progress in basic and preclinical studies of acute myeloid leukemia (AML). The improved outcomes of AML can largely be attributed to advances in supportive care and hematopoietic cell transplantation as opposed to conventional chemotherapy. However, as the 5-year survival rate remains low due to a high incidence of relapse, novel and effective treatments are urgently needed. Increasing attention is focusing on identifying suitable immunotherapeutic strategies for AML. Here, we describe the immunological features, mechanisms of immune escape, and recent progress in immunotherapy for AML. Problems encountered in the clinic will also be discussed. Although current outcomes may be limited, ongoing preclinical or clinical efforts are aimed at improving immunotherapy modalities and designing novel therapies, such as vaccines, monoclonal antibody therapy, chimeric antibody receptor-engineered T cells (CAR-T), TCR-engineered T cells (TCR-T), and checkpoint inhibitors, which may provide promising and effective therapies with higher specificity and efficacy for AML.     

Immunotherapy for hepatocellular carcinoma: Current status and future perspectives

Hepatocellular carcinoma(HCC) is one of the world’s deadliest and fastestgrowing tumors, with a poor prognosis. HCC develops in the context of chronic liver disease. Curative resection, surgery(liver transplantation), trans-arterial chemoembolization, radioembolization, radiofrequency ablation and chemotherapy are common treatment options for HCC, however, they will only assist a limited percentage of patients. Current treatments for advanced HCC are ineffective and aggravate the underlying live...     

Diverse and precision therapies open new horizons for patients with advanced pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma(PDAC)is a common cause of cancer-related death,and most patients are with advanced disease when diagnosed.At present,despite a variety of treatments have been devel-oped for PDAC,few effective treatment options are available;on the other hand,PDAC shows significant resistance to chemoradiotherapy,targeted therapy,and immunotherapy due to its heterogeneous genetic profile,molecular signaling pathways,and complex tumor immune microenvironment.Nevertheless,over the past decades,there have been many new advances in the key theory and understanding of the in-trinsic mechanisms and complexity of molecular biology and molecular immunology in pancreatic can-cer,based on which more and more diverse new means and reasonable combination strategies for PDAC treatment have been developed and preliminary breakthroughs have been made.With the continuous ex-ploration,from surgical local treatment to comprehensive medical management,the research-diagnosis-management system of pancreatic cancer is improving.This review focused on the variety of treatments for advanced PDAC,including traditional chemotherapy,targeted therapy,immunotherapy,microenviron-ment matrix regulation as well as the treatment targeting epigenetics,metabolism and cancer stem cells.We pointed out the current research bottlenecks and future exploration directions.     

Gene therapy for gastric cancer： Is it promising？

Gastric cancer is one of the most common tumorsworldwide.The therapeutic outcome of conventionaltherapies is inefficient.Thus,new therapeutic strategiesare urgently needed.Gene therapy is a promisingmolecular alternative in the treatment of gastric cancer,including the replacement of defective tumor suppressorgenes,the inactivation of oncogenes,the introduction ofsuicide genes,genetic immunotherapy,anti-angiogeneticgene therapy,and virotherapy.Improved molecularbiological techniques and a better understanding ofgastric carcinogenesis have allowed us to validate avariety of genes as molecular targets for gene therapy.This review provides an update of the new developmentsin cancer gene therapy,new principles,techniques,strategies and vector systems,and shows how they maybe applied in the treatment of gastric cancer.