NK cell-based cancer immunotherapy

The identification of spontaneous antitumor immune responses in cancer patients and the demonstration that an intact immune system can prevent against certain forms of malignancies invigorated research efforts in the development of cancer immunotherapies. To date, numerous and diversified approaches are being investigated, thereby providing new means by which to mobilize the cellular and molecular elements of the immune system in order to destroy established cancers. While it is appreciated that tumor-specific cytotoxic T lymphocytes play a critical role in successful immunotherapy, it is becoming increasingly apparent that cellular components of both the innate and the adaptive arms of the immune system can control tumor growth. In particular, natural killer (NK) cells are emerging as key players in the cross-talk between innate and adaptive immunity. With the uncovering of the regulatory mechanisms governing NK cell biology, new immunotherapies based on the harnessing of NK cell antitumor activity are now being developed. In this review, we summarize the role of NK cells in the control of tumor growth and discuss potential cancer therapies incorporating NK cell-mediated antitumor activity.     

Novel immunotherapeutic strategies for invasive fungal disease

Infectious diseases still represent a major cause of mortality in man. Failure of the immune system to eradicate pathogens may result in serious invasive infections. Increasing numbers of immunocompromised patients, ineffective treatment and the emergence of drug-resistant pathogens represent the underlying problems. The focus of this review is on the pathogenesis of systemic fungal disease and the development of novel immunotherapeutic approaches. A comprehensive understanding of host-pathogen interactions is required for manipulation of immune responses to direct anti-fungal immunity. The potential of growth factor- and antibody-based therapeutics for invasive fungal disease are discussed. Recent advances in antibody technology may provide new strategies for developing antibody-based anti-fungal therapies. Development of fungal disease is related primarily to impaired host defense mechanisms, which emphasizes the importance of immunorestorative therapy in immunocompromised individuals. Controlled comparative clinical research is needed to evaluate the efficacy of novel immunotherapies, which provide prospects for the future management of invasive fungal disease.     

Cancer vaccines entering Phase III clinical trials

The last 10 years have seen a growth in the number of tumour antigens identified from immune responses raised in patients. The discovery that tumours can be recognised by the immune system stimulated a great deal of work characterising the molecular mechanisms underlying immune recognition. This in turn has led to an impressive array of immunological approaches to the generation of cancer vaccines; these range from molecularly defined T cell epitopes, antibody-based vaccines, cytokine therapies, immune modulators and DNA vaccines, to whole cell vaccines and, more recently, combinations of these methods. Many of these approaches have entered Phase I/II trials and have shown interesting clinical results. Moreover, they have extended our knowledge of the immune system and our understanding of the mechanisms required to design a successful cancer vaccine. This review outlines some of the approaches that have led to some of these vaccines entering Phase III clinical trials, discusses their modes of action and reports on their current status in trial.     

Cancer vaccines entering Phase III clinical trials

The last 10 years have seen a growth in the number of tumour antigens identified from immune responses raised in patients. The discovery that tumours can be recognised by the immune system stimulated a great deal of work characterising the molecular mechanisms underlying immune recognition. This in turn has led to an impressive array of immunological approaches to the generation of cancer vaccines; these range from molecularly defined T cell epitopes, antibody-based vaccines, cytokine therapies, immune modulators and DNA vaccines, to whole cell vaccines and, more recently, combinations of these methods. Many of these approaches have entered Phase I/II trials and have shown interesting clinical results. Moreover, they have extended our knowledge of the immune system and our understanding of the mechanisms required to design a successful cancer vaccine. This review outlines some of the approaches that have led to some of these vaccines entering Phase III clinical trials, discusses their modes of action and reports on their current status in trial.     

Blockade of insulin-like growth factor type-1 receptor with cixutumumab (IMC-A12): a novel approach to treatment for multiple cancers

Insulin-like growth factor type-1 receptor (IGF-1R) plays a central role in cell proliferation and survival and is overexpressed in many tumor types. Notably, IGF-1R-mediated signaling confers resistance to diverse cytotoxic, hormonal, and biologic agents, suggesting that therapies targeting IGF-1R may be effective against a broad range of human malignancies. Cixutumumab (IMC-A12; ImClone Systems) is a fully human immunoglobulin G1 (IgG1) monoclonal antibody that specifically inhibits IGF-1R signaling. Binding of cixutumumab to IGF-1R results in receptor internalization and degradation. Because cixutumumab is an IgG1 monoclonal antibody, it may induce additional cytotoxicity via immune effector mechanisms such as antibody-dependent cellular cytotoxicity. In preclinical studies, cixutumumab monotherapy resulted in growth inhibition of multiple experimental cancers. Moreover, cixutumumab safely enhanced the tumor growth inhibitory and cytotoxic effects of a broad range of chemotherapeutics, and modulated the action of agents that target hormone receptors and signal transduction, which may have implications for cancer therapy. Herein, we review published preclinical and clinical data for cixutumumab and provide a comprehensive overview of selected clinical studies.     

Paraneoplastic neurological syndromes - diagnosis and management

Paraneoplastic neurological syndromes (PNS) are rare nervous system dysfunctions in cancer patients, which are not due to a local effect of the tumour or its metastases. PNS in adults are mainly associated with lung cancer, especially small cell lung cancer, lymphoma and gynaecological tumours. In some cases an overlapping of different clinical syndromes can be observed. Since autoantibodies directed against tumour and nervous system tissue can be observed, an autoimmune aetiology has been suspected in PNS patients. Currently, one group of patients exhibit surface-binding receptor or ion channel autoantibodies which are thought to be pathogenic and many of these patients respond well to immunotherapies. Another group of PNS is associated with highly specific autoantibodies directed against intracellular onconeuronal antigens. The latter group seem to be T-cell-mediated and do not respond well to immunotherapies. The childhood PNS, especially the neuroblastoma-associated opsoclonus-myoclonus syndrome also respond to immunosuppressive therapies, plasmapheresis and intravenous immunoglobulins. The current review summarizes recent developments in physiopathology, diagnosis and treatment of paraneoplastic neurological syndromes.     

The role of CD33 as therapeutic target in acute myeloid leukemia

CD33 is a myeloid differentiation antigen that is displayed on acute myeloid leukemia (AML) blasts in most patients and, possibly, leukemic stem cells in some, and has thus served as target for antibody-based therapies for many years. Validation for this approach comes from the antibody–drug conjugate, gemtuzumab ozogamicin, which improves survival of some patients with AML when added to induction chemotherapy. Still, CD33 is a challenging target because of its low expression and slow internalization; these characteristics limit antibody-dependent cell-mediated cytotoxicity and intracellular drug accumulation and, consequently, the activity of unlabeled and toxin-carrying antibodies. Very promising preclinical data are now available from an improved antibody–drug conjugate and CD33-targeted strategies that redirect immune effector cells to eradicate the leukemia, most notably bispecific antibodies and chimeric antigen receptor T-cell immunotherapy. In parallel to their clinical testing, efforts will be needed to identify the patients that most likely benefit from such agents and the disease stage in which they are most efficacious. With enhanced activity of CD33-directed therapies, toxic effects on normal hematopoiesis will increase and require excellent supportive care measures, or even rescue with donor cells, to minimize morbidity and mortality from expected cytopenias and to optimize treatment outcomes with these therapeutics.     

Cancer immunotherapy: sipuleucel-T and beyond

In April 2010, sipuleucel-T became the first anticancer vaccine approved by the United States Food and Drug Administration. Different from the traditional chemotherapy agents that produce widespread cytotoxicity to kill tumor cells, anticancer vaccines and immunotherapies focus on empowering the immune system to overcome the tumor. The immune system consists of innate and adaptive components. The CD4(+) and CD8(+) T cells are the most crucial components of the adaptive arm of the immune system that act to mediate antitumor responses. However, T-cell responses are regulated by intrinsic and extrinsic mechanisms, which may interfere with effective antitumor responses. Many anticancer immunotherapies use tumor-associated antigens as vaccines in order to stimulate an immune response against tumor cells. Sipuleucel-T is composed of autologous mononuclear cells incubated with a fusion protein consisting of a common prostate cancer antigen (prostatic acid phosphatase) linked to an adjuvant (granulocyte-macrophage colony-stimulating factor). It is postulated that when the vaccine is infused into the patient, the activated antigen-presenting cells displaying the fusion protein will induce an immune response against the tumor antigen. In a recent randomized, double-blind, placebo-controlled, phase III clinical trial, sipuleucel-T significantly improved median overall survival by 4.1 months in men with metastatic castration-resistant prostate cancer compared with placebo. Although overall survival was improved, none of the three phase III clinical trials found a significant difference in time to disease progression. This, along with cost and logistic issues, has led to an active discussion. Although sipuleucel-T was studied in the metastatic setting, its ideal place in therapy is unknown, and clinical trials are being conducted in patients at different stages of disease and in combination with radiation therapy, antiandrogen therapy, and chemotherapy. Various other anticancer vaccines and immunotherapies for other tumor types are currently under investigation and in clinical trials. These immunotherapies were formulated to incorporate tumor-associated antigens aimed at stimulating effector T-cell responses or to block regulatory mechanisms that suppress the function of effector T cells. Additional studies will determine how these therapies can best improve clinical outcomes in patients with cancer.     

靶向B淋巴细胞的治疗策略

在一些自身免疫性疾病和B细胞淋巴瘤中,B淋巴细胞（简称B细胞）表现为异常活化或恶性增殖。靶向B细胞的免疫治疗包括直接治疗策略和间接治疗策略。直接治疗策略采用抗CD20抗体、抗CD22抗体等与B细胞特异性结合,诱导B细胞凋亡或通过抗体的Fc段介导的抗体依赖的细胞毒作用、补体依赖的细胞毒作用发挥直接的清除作用。间接治疗策略通过干扰其他免疫细胞（如T细胞）与B细胞的作用,阻断B细胞活化所需的第二信号;或者靶向一些能促进B细胞活化、增殖、分化的因子,通过拮抗这些因子的功能间接影响B细胞的功能。本文将简要介绍B细胞靶向治疗策略。     

Dendritic cells and T cells in immunotherapy

Autologous cellular immunotherapies have been used experimentally in humans to treat many types of cancer. These therapies are divided into two principal types: active cellular immunotherapies that rely on autologous dendritic cells or other antigen presenting cells; and adoptive T-cell therapies, in which large numbers of antigen-specific T lymphocytes are propagated ex vivo and then infused back into the patient. With the FDA approval of the antigen presenting cell vaccine sipuleucel-T for prostate cancer, active immunization has become an accepted approach for the treatment of established cancer.     

Symphony of nanomaterials and immunotherapy based on the cancer–immunity cycle

The immune system is involved in the initiation and progression of cancer. Research on cancer and immunity has contributed to the development of several clinically successful immunotherapies. These immunotherapies often act on a single step of the cancer–immunity cycle. In recent years, the discovery of new nanomaterials has dramatically expanded the functions and potential applications of nanomaterials. In addition to acting as drug-delivery platforms, some nanomaterials can induce the immunogenic cell death (ICD) of cancer cells or regulate the profile and strength of the immune response as immunomodulators. Based on their versatility, nanomaterials may serve as an integrated platform for multiple drugs or therapeutic strategies, simultaneously targeting several steps of the cancer–immunity cycle to enhance the outcome of anticancer immune response. To illustrate the critical roles of nanomaterials in cancer immunotherapies based on cancer–immunity cycle, this review will comprehensively describe the crosstalk between the immune system and cancer, and the current applications of nanomaterials, including drug carriers, ICD inducers, and immunomodulators. Moreover, this review will provide a detailed discussion of the knowledge regarding developing combinational cancer immunotherapies based on the cancer–immunity cycle, hoping to maximize the efficacy of these treatments assisted by nanomaterials.     

Combining radiation and cancer gene therapy: a potential marriage of physical and biological targeting?

The development and progression of cancer is marked by the acquisition of specific genetic hallmarks that endow tumour cells with a survival advantage over their normal tissue counterparts. In the process, tumours frequently develop resistance to radiotherapy and chemotherapy, and acquire the ability to evade the host immune response. Cancer gene therapy (CGT) represents an ideal therapeutic tool to target one or more of these underlying genetic abnormalities, and restore some form of order, to the otherwise autonomous and discordant microenvironment of the tumour. Most of the current research in CGT is aimed at its development as a novel form of targeted therapy that can be combined with other treatment modalities such as radiotherapy and chemotherapy. CGT may be integrated into radical chemoradiotherapy regimens, with the rationale of optimising the therapeutic index, through selective enhancement of radiosensitivity and cytotoxicity in tumour compared to normal tissues. CGT strategies have been developed that are aimed at enhancing the radiosensitivity of tissues by targeting angiogenesis, silencing abnormal cellular signalling, restoration of apoptosis, and promotion of immune detection and destruction of tumour cells. In addition, cytotoxic approaches such as virus directed enzyme prodrug therapy (VDEPT), genetic radionuclide therapy (GRANT) and oncolytic viral therapy have been combined with radiation to augment the cumulative tumour cell kill and overall therapeutic effect. In this article, we discuss various CGT strategies that have been investigated in combination with radiation. All the available preclinical and clinical evidence is reviewed with special emphasis on strategies that have already found their way into the clinic, or those with significant translational potential for the future.     

Targeting P-glycoprotein for effective oral anti-cancer chemotherapeutics

Oral anticancer drug treatment represents a significant change to current oncology practice. Support for oral anticancer treatment is driven by issues of pharmacoeconomics, accommodating the need for protracted drug administration for many emerging cytostatic therapies, response to patient preference and in improving patient quality of life. Much focus has concentrated on defining the cellular mechanisms underlying the pharmacokinetic limitations associated with the oral route of administration. However, the potential effects of oral anticancer drugs on gut associated host mediated immunity have been overlooked. Given that the immune system is central for tumour rejection, an assessment of the potential effects oral anticancer drugs may have at this level, and the impact of this on the treatment of gastrointestinal malignancy is of significant clinical importance. P-glycoprotein is a multidrug transporter that contributes to the reduced bioavailability of many orally administered medications. P-glycoprotein achieves this by virtue of its drug efflux capacity at the level of the gut epithelia. P-glycoprotein is also notorious for contributing to the multidrug resistance phenotype observed in many drug refractory human cancers. Likewise, this drug transporter serves a role in the cells of the immune system; particularly in dendritic cell maturation and function. This multifaceted involvement in drug disposition, cancer drug resistance and regulation of the immune response makes P-glycoprotein an attractive target for the optimization of oral anticancer drug treatment strategies. This review introduces and discusses for the first time the potential impact that oral anticancer drugs may have on P-glycoprotein expression and function and the potential consequences of this on dendritic cell function in relation to human cancer. This review also aims to foster a better understanding of the host mediated immunological mechanisms which may be potentially manipulated in cancer patients undergoing oral chemotherapy.     

基于单克隆抗体的肿瘤免疫治疗

近年来,肿瘤免疫治疗已成为肿瘤免疫学基础和应用研究的一个重要领域。肿瘤免疫治疗主要有癌症疫苗、溶瘤病毒治疗、嵌合抗原受体T细胞(chimeric antigen receptor T cells, CAR-T cells)、免疫检查点阻滞和单克隆抗体等策略。其中,基于单克隆抗体的肿瘤免疫治疗发展最快。在过去20多年中,单克隆抗体已成为针对人类恶性肿瘤疗效显著且类型新颖的药物之一,特别是靶向免疫检查点的单克隆抗体药物在肿瘤免疫治疗中发挥重要作用。本文将综述基于单克隆抗体的肿瘤免疫治疗的现状、潜在的免疫调节机制、抗体作用靶分子和免疫治疗剂,探讨抗体类免疫治疗药物的发展趋势。     

Cell adhesion and cancer: is there a potential for therapeutic intervention?

Carcinogenesis involves a disruption in adhesion molecule expression and tissue architecture, and tumour invasion requires adhesion-dependent migration into surrounding tissues. Therefore, a variety of peptide and antibody-based reagents that block integrins, cadherins, immunoglobulin superfamily and selectin adhesion molecules have been developed to treat cancers. Therapeutics directed at adhesion molecules can block interactions between tumour cells, endothelial cells and immune cells to prevent tumour cell invasiveness and metastasis. Blocking the adhesion molecules that facilitate the invasion of tumours by endothelial cells and immune cells can prevent tumour-associated angiogenesis and the recruitment of immune-mediated growth factors which are required for tumour growth and spread. In addition, targeted therapies using anticancer agents attached to antibodies or peptides directed as tumour-specific adhesion molecules are being developed.     

Interleukin 21: combination strategies for cancer therapy

In the past 20 years researchers have attempted to activate the host immune defence system to kill tumour cells and eradicate cancer. In some cases, the response of patients to immunotherapy has been extremely successful; however, other trials have shown disappointing results, and so there is a clear need for more effective therapies that can effectively adjunct conventional approaches. Interleukin 21 (IL21) is a new immune-stimulating cytokine that has demonstrated antitumour activity in several preclinical models, and has recently undergone Phase I trials in metastatic melanoma and renal cell carcinoma. Here, we provide an overview of the antitumour effects of IL21 and describe strategies to combine IL21 with other drugs for future cancer therapies.     

Cell adhesion and cancer: is there a potential for therapeutic intervention?

Carcinogenesis involves a disruption in adhesion molecule expression and tissue architecture, and tumour invasion requires adhesion-dependent migration into surrounding tissues. Therefore, a variety of peptide and antibody-based reagents that block integrins, cadherins, immunoglobulin superfamily and selectin adhesion molecules have been developed to treat cancers. Therapeutics directed at adhesion molecules can block interactions between tumour cells, endothelial cells and immune cells to prevent tumour cell invasiveness and metastasis. Blocking the adhesion molecules that facilitate the invasion of tumours by endothelial cells and immune cells can prevent tumour-associated angiogenesis and the recruitment of immune-mediated growth factors which are required for tumour growth and spread. In addition, targeted therapies using anticancer agents attached to antibodies or peptides directed as tumour-specific adhesion molecules are being developed.     

Interaction of current cancer treatments and the immune system: implications for breast cancer therapeutics

Early diagnosis and treatment of breast cancer may account for the current improvement in the mortality of breast cancer. However, achieving a complete 'cure' is the holy grail of cancer medicine and, in many cases, cancer patients still succumb to their ultimate fate. There is therefore a need to devise innovative therapies to overcome this problem. To this end, many emerging therapies utilizing the immune system to eradicate the residues of disease have been described in the preclinical and clinical arenas. However, there is very little work examining the impact of immunotherapy on the existing natural immunity. The relationship between antitumor immunity, in the form of immunotherapy (either passive or active), and current strategies of treatment also needs to be explored. If we are to improve the success of cancer treatment, we must understand how current therapies interact with the immune system and with the emerging immunotherapies. For breast-cancer treatment to be successful, therapeutics should be tailored towards antitumor immunity; they should also avoid tumor-specific tolerance. The sources of information used to prepare this paper were obtained through published work on Pubmed/Medline and materials published on the US/UK governmental agencies' websites.     

Interaction of current cancer treatments and the immune system: implications for breast cancer therapeutics

Early diagnosis and treatment of breast cancer may account for the current improvement in the mortality of breast cancer. However, achieving a complete ‘cure’ is the holy grail of cancer medicine and, in many cases, cancer patients still succumb to their ultimate fate. There is therefore a need to devise innovative therapies to overcome this problem. To this end, many emerging therapies utilizing the immune system to eradicate the residues of disease have been described in the preclinical and clinical arenas. However, there is very little work examining the impact of immunotherapy on the existing natural immunity. The relationship between antitumor immunity, in the form of immunotherapy (either passive or active), and current strategies of treatment also needs to be explored. If we are to improve the success of cancer treatment, we must understand how current therapies interact with the immune system and with the emerging immunotherapies. For breast-cancer treatment to be successful, therapeutics should be tailored towards antitumor immunity; they should also avoid tumor-specific tolerance. The sources of information used to prepare this paper were obtained through published work on Pubmed/Medline and materials published on the US/UK governmental agencies' websites.