Immunotherapy of kidney cancer

Renal cell carcinoma (RCC) accounts for 4% of all new cancer cases in males and 3% in females in the US. Compared to other solid tumors, it does not respond to traditional management modalities, such as chemotherapy and radiation therapy. However, it appears to be an immune-responsive tumor and several immunotherapeutic strategies have been investigated in the management of RCC with variable degrees of success. Active immunotherapy refers mainly to the use of vaccines, while adoptive (passive) immunotherapy includes the use of autologous immune cells, allogeneic immune cells (stem cell transplantation, donor lymphocyte infusion), as well as antibody delivery. Cytokine delivery with IL-2 has resulted in long-term disease-free survival in a small proportion of patients with metastatic disease. The continuous understanding of the mechanisms that underlie the immune complex networks has led to the identification of key molecules that play a major role in the immune response process. A panel of immuno-modulatory compounds that target such molecules has been tested in the preclinical and clinical setting. At the post-genomic era, the development of novel biomarkers can contribute to more accurate patient selection, resulting in higher responses and less toxicity of immunotherapeutic approaches.     

Combining cytotoxic and immune-mediated gene therapy to treat brain tumors

Glioblastoma (GBM) is a type of intracranial brain tumor, for which there is no cure. In spite of advances in surgery, chemotherapy and radiotherapy, patients die within a year of diagnosis. Therefore, there is a critical need to develop novel therapeutic approaches for this disease. Gene therapy, which is the use of genes or other nucleic acids as drugs, is a powerful new treatment strategy which can be developed to treat GBM. Several treatment modalities are amenable for gene therapy implementation, e.g. conditional cytotoxic approaches, targeted delivery of toxins into the tumor mass, immune stimulatory strategies, and these will all be the focus of this review. Both conditional cytotoxicity and targeted toxin mediated tumor death, are aimed at eliminating an established tumor mass and preventing further growth. Tumors employ several defensive strategies that suppress and inhibit anti-tumor immune responses. A better understanding of the mechanisms involved in eliciting anti-tumor immune responses has identified promising targets for immunotherapy. Immunotherapy is designed to aid the immune system to recognize and destroy tumor cells in order to eliminate the tumor burden. Also, immune-therapeutic strategies have the added advantage that an activated immune system has the capability of recognizing tumor cells at distant sites from the primary tumor, therefore targeting metastasis distant from the primary tumor locale. Pre-clinical models and clinical trials have demonstrated that in spite of their location within the central nervous system (CNS), a tissue described as 'immune privileged', brain tumors can be effectively targeted by the activated immune system following various immunotherapeutic strategies. This review will highlight recent advances in brain tumor immunotherapy, with particular emphasis on advances made using gene therapy strategies, as well as reviewing other novel therapies that can be used in combination with immunotherapy. Another important aspect of implementing gene therapy in the clinical arena is to be able to image the targeting of the therapeutics to the tumors, treatment effectiveness and progression of disease. We have therefore reviewed the most exciting non-invasive, in vivo imaging techniques which can be used in combination with gene therapy to monitor therapeutic efficacy over time.     

免疫治疗在头颈鳞癌中的研究进展

摘要： 尽管近年来外科手术和综合治疗手段在不断进步和发展， 但头颈鳞癌患者的5年生存率并未得到显著提高。因此， 提高头颈鳞癌治疗效率， 改善头颈鳞癌治疗手段迫在眉睫。作为一种颇具前景的新型疗法， 免疫治疗具有较低的毒性及高度特异性， 并且已逐渐被应用到包括头颈鳞癌在内的多种肿瘤的临床治疗之中。在头颈鳞癌的免疫治疗之中， 研究人员在单一细胞因子治疗的基础上进一步开发出了复合性系统疗法并取得了不错的疗效。另一方面， 包括蛋白/多肽-树突细胞疫苗在内的多种肿瘤疫苗治疗方法进入了大量临床试验研究中。此外， 针对PD-1 等免疫检查点的免疫疗法受到了广泛关注， 相关的抑制性抗体也已获批进行复发或转移性头颈鳞癌的治疗。本文旨在对以上多种免疫治疗手段在头颈鳞癌中的相关研究进展作一简要综述。     

Targeting tumours by adoptive transfer of immune cells

1. Surgery, radiotherapy and chemotherapy are the most widely used and well-established modalities for treating malignant diseases. Surgery is used to excise solid tumours and radiotherapy/chemotherapy are used for the treatment of liquid tumours and for solid tumours where there is a risk of micrometastases. A major drawback for both radiotherapy and chemotherapy is their lack of specificity for tumour cells. Both these treatments can destroy normal bone marrow cells and result in severe side-effects. 2. The impairment of haemapoiesis due to bone marrow destruction combined with the use of toxins in chemotherapy that inhibit the proliferation of immune cells leaves many patients immunocompromised. This complicates the development of prophylactic (vaccine) strategies for tumours where patients are undergoing conventional therapy. 3. An alternative approach is to expand and activate tumour-specific immune cells in vitro that can then be adoptively transferred back in large numbers. This is defined as adoptive immunotherapy and has the advantage of potentially bypassing the immuno-inhibitory effects of conventional therapies. 4. Transferred immune cells have been shown to mediate tumour regression in patients by both direct and indirect mechanisms. The immune cells used include tumour reactive T lymphocytes and dendritic cells, which elicit tumour specific responses. 5. Many novel cell-based immunotherapeutic strategies developed in murine tumour models are now being applied in human clinical trials. The malignancies targeted include melanoma, chronic myelogenous leukaemia and breast, ovarian, colon and kidney cancers. In the present review, we discuss these novel cell-based strategies and the implications they have for the future treatment of human malignancies.     

Cancer immunotherapy--revisited

Our insight into antitumour immune responses has increased considerably during the past decades, yet the development of immunotherapy as a treatment modality for cancer has been hampered by several factors. These include difficulties in the selection of the optimal dose and schedule, the methods of evaluation, and financial support. Although durable clinical remissions have been observed with various immunotherapeutic strategies, the percentage of patients who benefited from these interventions has remained too small to justify the general use of such strategies. However, the recent positive results of clinical trials with novel immunoactive drugs as well as the unexpected finding of a positive interaction between immunotherapy and chemotherapy may herald a new era for the immunotherapy of cancer.     

靶向间皮素免疫治疗实体瘤的研究进展

间皮素（Mesothelin）是一种肿瘤相关抗原,这一糖蛋白在超过30%的肿瘤组织中高表达,仅在少量正常组织中低水平表达,是目前研究较多的癌症免疫治疗靶点。目前有多种靶向Mesothelin的免疫治疗产品在临床试验中显示出很好的安全性,其中细胞治疗近年来发展最为迅速。本文将从Mesothelin的生物学特性、靶向Mesothelin免疫治疗药物的临床试验结果、Mesothelin CAR-T细胞免疫治疗面临的挑战和应对策略等几个方面,介绍以Mesothelin为靶点的实体瘤免疫治疗研究进展。     

Real Impact of Novel Immunotherapy Drugs in Cancer. The Experience of 10 Last Years

Intense research on immunotherapy has been conducted during recent years. As advances in the field have started changing the landscape of cancer therapy, it is necessary to assess the impact of immunotherapeutic modalities in the treatment of various cancers. Ten years ago, in 2011, ipilimumab was the first of the newest immunotherapeutic drugs against cancer to be approved by the FDA. Then several drugs followed and formed a therapeutic arsenal to fight cancer. Initial studies were performed on metastatic patients, but there are currently several studies in patients with potentially curable cancers. All these developments have created a new environment for oncology which we will present in this article. This review examines the current evidence related to the impact of immunotherapy on various cancers and discusses its potential clinical and research implications, including its effectiveness in comparison to other treatment modalities (chemotherapy, radiotherapy), its toxicity and prospective research opportunities. While constant updates and further research is critical to understand the impact of immunotherapy in cancer therapy, not only does it seem to be important to assess the current state of knowledge highlighting the success but also to determine the challenging aspects of cancer immunotherapy.     

c-erbB-2 as a target for immunotherapy

The c-erbB-2 proto-oncogene encodes a 185 kDa transmembrane Type 1 tyrosine kinase receptor whose amplification and/or overexpression has been linked with poor prognosis in a variety of cancers. The oncoprotein has been suggested to play a key role in tumour cell invasion, motility and metastasis, and in responsiveness to therapeutic agents. Over-expression of c-erbB-2 therefore identifies an important subset of patients with a high probability of relapse, but low probability of response to certain conventional therapies. The cell surface location of the oncoprotein, its stability of expression and low levels in normal adult tissues render it an attractive target for immunotherapeutic intervention. Although a ‘self’ antigen, there is evidence that c-erbB-2 p185 can induce both humoral and cell-mediated immune responses in cancer patients. Approaches to exploit p185 as an immunotherapeutic target include vaccination with peptides, plasmid DNA or vectors (viruses/bacteria) carrying the gene; with cytokines, co-stimulatory factors and superantigens being evaluated as adjuvants. Many monoclonal antibody (mAb)-based strategies are also in clinical development. Monoclonal antibodies can serve multiple functions; direct inhibition of c-erbB-2 activity, recruitment of host effector mechanisms and direct or indirect delivery of toxic payloads. Clinical trials in patients with late stage disease have shown that many of these approaches are safe, feasible and relatively non-toxic, and, in some cases, objective responses have been seen. As with all immunotherapy, the greatest benefit is likely to be obtained in patients with minimal residual disease in an adjuvant setting; such studies are awaited with interest.     

c-erbB-2 as a target for immunotherapy

The c-erbB-2 proto-oncogene encodes a 185 kDa transmembrane Type 1 tyrosine kinase receptor whose amplification and/or overexpression has been linked with poor prognosis in a variety of cancers. The oncoprotein has been suggested to play a key role in tumour cell invasion, motility and metastasis, and in responsiveness to therapeutic agents. Over-expression of c-erbB-2 therefore identifies an important subset of patients with a high probability of relapse, but low probability of response to certain conventional therapies. The cell surface location of the oncoprotein, its stability of expression and low levels in normal adult tissues render it an attractive target for immunotherapeutic intervention. Although a 'self' antigen, there is evidence that c-erbB-2 p185 can induce both humoral and cell-mediated immune responses in cancer patients. Approaches to exploit p185 as an immunotherapeutic target include vaccination with peptides, plasmid DNA or vectors (viruses/bacteria) carrying the gene; with cytokines, co-stimulatory factors and superantigens being evaluated as adjuvants. Many monoclonal antibody (mAb)-based strategies are also in clinical development. Monoclonal antibodies can serve multiple functions; direct inhibition of c-erbB-2 activity, recruitment of host effector mechanisms and direct or indirect delivery of toxic payloads. Clinical trials in patients with late stage disease have shown that many of these approaches are safe, feasible and relatively non-toxic, and, in some cases, objective responses have been seen. As with all immunotherapy, the greatest benefit is likely to be obtained in patients with minimal residual disease in an adjuvant setting; such studies are awaited with interest.     

Emerging immunotherapy for the treatment of esophageal cancer

Introduction: Esophageal cancer is the third most common cancer of the gastrointestinal tract. Despite new therapies, the prognosis for patients with these cancers remains poor with 5-year survival rates lower than 15%. Recently, immunotherapy has increasingly gained attention as a novel treatment strategy for advanced esophageal cancer.

Areas covered: Recent success of immunotherapy in treating other solid tumors has shed light on the utility of these approaches for esophageal cancers. Here, the authors focus on antibody-based, adoptive-cell-therapy-based, and vaccine-based immunotherapies, and briefly address their rationale, clinical data, and implications.

Expert opinion: Immunotherapy is now established to be a key treatment modality that can improve the outcomes of many cancer patients and appears to be ushering in a new era in cancer treatment. Checkpoint inhibitor drugs have shown preliminary favorable results in esophageal cancer treatment. Adoptive cell therapy and vaccine studies have also shown some promise in various clinical studies. Future endeavors will need to focus on identifying patients who are likely to benefit from immunotherapy, monitoring and managing immune responses and designing optimal combination strategies where immunotherapy agents are combined with other traditional treatment modalities.     

Challenges and strategies for successful clinical development of immune checkpoint inhibitors in glioblastoma

ABSTRACT

Introduction: Glioblastoma (GBM) remains an incurable tumor with median overall survival of 15 months with the best standard of care. Immune checkpoint inhibitors (CPI) have been the forefront of immunotherapy advances for treatment of various solid cancers. However, clinical development of CPI in GBM has been challenging due to factors associated with intracranial tumors such as limited space for an inflammatory response, difficulties with repeated sampling, and low tumor mutation burden and immunosuppressive mechanisms unique to GBM.

Areas covered: Herein, the authors review the clinical development of CPI in GBM, the challenges involved for their successful implementation, and discuss approaches to overcome these challenges.

Expert opinion: Strategies to improve clinical development of CPI in GBM need to carefully address multiple steps that are needed for successful activation and maintenance of tumor-specific immune responses. Multi-modality approaches are needed to achieve this goal and should focus on augmenting tumor T-cell infiltration, activating cytotoxic T-cells, and maintaining their effector function. CPI have been the most successful immunotherapy approach in the treatment of solid cancers and optimization of combinatorial approaches are needed for their successful implementation in GBM.     

Immune checkpoints in targeted-immunotherapy of pancreatic cancer: New hope for clinical development

Immunotherapy has been recently considered as a promising alternative for cancer treatment. Indeed, targeting of immune checkpoint (ICP) strategies have shown significant success in human malignancies. However, despite remarkable success of cancer immunotherapy in pancreatic cancer (PCa), many of the developed immunotherapy methods show poor therapeutic outcomes in PCa with no or few effective treatment options thus far. In this process, immunosuppression in the tumor microenvironment (TME) is found to be the main obstacle to the effectiveness of antitumor immune response induced by an immunotherapy method. In this paper, the latest findings on the ICPs, which mediate immunosuppression in the TME have been reviewed. In addition, different approaches for targeting ICPs in the TME of PCa have been discussed. This review has also synopsized the cutting-edge advances in the latest studies to clinical applications of ICP-targeted therapy in PCa.KEY WORDS: Immune checkpoint, Pancreatic cancer, Tumor microenvironment, Immunotherapy, Clinical development     

Nanomedicines modulating tumor immunosuppressive cells to enhance cancer immunotherapy

Cancer immunotherapy has veered the paradigm of cancer treatment. Despite recent advances in immunotherapy for improved antitumor efficacy, the complicated tumor microenvironment (TME) is highly immunosuppressive, yielding both astounding and unsatisfactory clinical successes. In this regard, clinical outcomes of currently available immunotherapy are confined to the varied immune systems owing in large part to the lack of understanding of the complexity and diversity of the immune context of the TME. Various advanced designs of nanomedicines could still not fully surmount the delivery barriers of the TME. The immunosuppressive TME may even dampen the efficacy of antitumor immunity. Recently, some nanotechnology-related strategies have been inaugurated to modulate the immunosuppressive cells within the tumor immune microenvironment (TIME) for robust immunotherapeutic responses. In this review, we will highlight the current understanding of the immunosuppressive TIME and identify disparate subclasses of TIME that possess an impact on immunotherapy, especially those unique classes associated with the immunosuppressive effect. The immunoregulatory cell types inside the immunosuppressive TIME will be delineated along with the existing and potential approaches for immunosuppressive cell modulation. After introducing the various strategies, we will ultimately outline both the novel therapeutic targets and the potential issues that affect the efficacy of TIME-based nanomedicines.     

进展期大肠癌免疫疗法的研究进展

目前,进展期大肠癌治疗缺乏有效手段,亟待研发新的治疗技术。近年来,免疫疗法已在血液系统肿瘤和黑素瘤的治疗中显示有显著疗效,且有多项免疫治疗技术试用于大肠癌治疗,包括肿瘤治疗性疫苗、免疫检查点抑制剂和过继细胞疗法等。其中,免疫检查点抑制剂抗程序性细胞死亡受体-1抗体已在DNA错配修复缺陷型大肠癌的治疗中显示有很好的疗效,但在血液系统肿瘤治疗中显示有显著疗效的嵌合抗原受体修饰的T细胞疗法却在大肠癌等实体瘤治疗中显示疗效欠佳,有一系列的问题需予解决。不过,免疫疗法已成为继手术、放疗和化疗后的第四大肿瘤疗法,将为进展期大肠癌治疗带来新的希望。     

纽约食管鳞状细胞癌1的研究进展

 纽约食管鳞状细胞癌1（New York esophageal squamous cell carcinoma 1,NY-ESO-1）是一种癌-睾丸抗原。其表达于多种肿瘤,但在正常组织中极少表达,且具有可同时诱导体液和细胞免疫应答的强免疫原性,因此被认为是一种肿瘤免疫治疗的理想抗原。此文概述了对NY-ESO-1与肿瘤的相关研究以及基于NY-ESO-1的免疫治疗的研究进展。     

Anti-tumor vaccines in head and neck cancer: targeting immune responses to the tumor

Immune therapies aiming at the destruction of a residual tumor and inducing tumor-specific memory responses are gaining acceptance among clinicians treating head and neck squamous cell carcinoma (HNSCC). This solid tumor lends itself remarkably well to currently popular vaccination strategies. Immune suppression is a hallmark of HNSCC, and its reversal accompanied by the vaccine-mediated restoration of antitumor immunity might be a promising approach to achieving improved survival of HNSCC patients. To date, few antitumor vaccines for HNSCC have been clinically evaluated. The reasons for this slow start are discussed, and the ongoing phase I clinical vaccination trials for HNSCC patients are briefly described. The emphasis is on dendritic cell (DC)-based vaccines, largely because of enhanced immunogenicity of epitopes presented by adoptively-transferred DC to responder T cells in vivo. Delivery of such antitumor vaccines in combination with conventional therapies and in the setting of a minimal residual disease to HNSCC patients takes advantage of exquisite specificity of the immune system at the time when tumor-induced suppression is reduced. Vaccine-driven generation, long-term survival and maintenance of tumor-specific immune cells are the objectives that antitumor vaccines have to realize to be clinically beneficial in HNSCC.     

Emerging antibody-targeted therapy in leukemia and lymphoma: current concepts and clinical implications

The success of immune-mediated therapies has encouraged studies on passive and active immunotherapy in leukemia and lymphoma. This review outlines the impact of increasing insights from basic immunology studies on the potentiation of effective immune responses and the identification of new antigens as targets for antibody (Ab)-targeted therapies. The principles of treatment in leukemia and lymphoma based on current knowledge on the classification of hematologic malignancies are reviewed, and discussed in the context of a rationale to implement new Ab-targeted immunotherapeutic approaches. An update is provided on the use of Ab-targeted therapies in clinical trials with emphasis on new emerging strategies to further expand the successful field of immunotherapy in leukemia and lymphoma.     

Pharmacological inhibition of TGFβ as a strategy to augment the antitumor immune response

There is considerable evidence suggesting that a variety of malignancies utilize the TGFβ cytokine to evade immune surveillance mechanisms to facilitate tumor growth and metastatic progression. The recently developed large- and small-molecule TGFβ inhibitors have demonstrated antitumor efficacy in several preclinical tumor models. Further investigation has revealed these agents to be critically dependent upon the host's immune system, suggesting that the inhibition of TGFβ may overcome the immunosuppressive tumor microenvironment and, ultimately, augment the antitumor immune response. These findings strongly support combining this strategy with other immunotherapeutic approaches for the treatment of metastatic cancer. This review discusses the immunoregulatory and antitumor properties of these pharmacological inhibitors of TGFβ signaling as either independent agents or in combination with various immunotherapeutic strategies, their potential side effects, as well as additional avenues of research that may be necessary for their eventual clinical application.     

Non-steroidal anti-inflammatory drugs, tumour immunity and immunotherapy

Non-steroidal anti-inflammatory drugs (NSAIDs) have received considerable importance in cancer chemoprevention over the last few years. They are now being considered as prospective candidates in cancer immunotherapy because of their striking immune-enhancing impact on various effector elements of anti-tumour immunity on one hand, and to augment the efficacy of different anti-cancer immunotherapeutic strategies on the other. This review specifically discusses the role of NSAIDs in anti-tumour immunity by describing their immunomodulatory effects on different immune cells including tumour-associated macrophages (TAM), dendritic cells (DC), natural killer (NK) cells, T effector cells, and T regulatory cells (Treg). Secondly, the therapeutic perspective of NSAIDs in combination with different anti-cancer immunotherapeutic approaches, in particular the cancer vaccines, tumour-specific monoclonal antibodies, and cytokine-based therapy, has been outlined. At the end, the impact of anti-inflammatories other than NSAIDs on tumour immunity and immunotherapy, and the immunopharmacological potential of selective E-prostanoid (EP) receptor antagonists with respect to cancer immunity have also been discussed briefly.