The sweet side of tumor immunotherapy

Carbohydrate signatures on tumor cells have functional implications in tumor growth and metastasis and constitute valuable tools in cancer diagnosis and immunotherapy. Increasing data regarding the mechanisms by which they are recognized by the immune system are facilitating the design of more efficient immunotherapeutic protocols based on cancer-associated glycan structures. Recent molecular and proteomic studies revealed that carbohydrates are recognized, not only by B cells and antibodies, but also by cells from the innate arm of immunity, as well as by T cells, and are able to induce specific T-cell immunity and cytotoxicity. In this review, we discuss and update the different strategies targeting tumor-associated carbohydrate antigens that are being evaluated for antitumor immunotherapy, an approach that will be highly relevant, especially when combined with other strategies, in the future fight against cancer.     

Immunity and immune suppression in human ovarian cancer

Clinical outcomes in ovarian cancer are heterogeneous, independent of common features such as stage, response to therapy and grade. This disparity in outcomes warrants further exploration into tumor and host characteristics. One compelling issue is the response of the patient's immune system to her ovarian cancer. Several studies have confirmed a prominent role for the immune system in modifying disease course. This has led to the identification and evaluation of novel immune-modulating therapeutic approaches such as vaccination and antibody therapy. Antitumor immunity, however, is often negated by immune suppression mechanisms present in the tumor microenvironment. Thus, in the future, research into immunotherapy targeting ovarian cancer will probably become increasingly focused on combination approaches that simultaneously augment immunity while preventing local immune suppression. In this article, we summarize important immunological issues that could influence ovarian cancer outcome, including tumor antigens, endogenous immune responses, immune escape and new and developing immunotherapeutic strategies.     

Manipulating dendritic cell biology for the active immunotherapy of cancer

Dendritic cells (DCs) are specialized antigen-presenting cells (APCs) that have an unequaled capacity to initiate primary immune responses, including tolerogenic responses. Because of the importance of DCs in the induction and control of immunity, an understanding of their biology is central to the development of potent immunotherapies for cancer, chronic infections, autoimmune disease, and induction of transplantation tolerance. This review discusses recent advances in DC research and the application of this knowledge toward new strategies for the clinical manipulation of DCs for cancer immunotherapy.     

Dendritic cell engineering for tumor immunotherapy: from biology to clinical translation

Dendritic cells (DCs) are the most potent APCs, with the ability to orchestrate a repertoire of immune responses. DCs play a pivotal role in the initiation, programming and regulation of tumor-specific immune responses, as they are poised to take up, process and present tumor antigens to naive or effector T lymphocytes. Although, to an extent, DC-based immunotherapeutic strategies have successfully induced specific anti-tumor responses in animal models, their clinical efficacy has rarely been translated into the clinic. This article attempts to present a complete picture of recent developments of DC-based therapeutic strategies addressing multiple components of tumor immunoenvironment. It also showcases certain practical intricacies in order to explore novel strategies for providing new impetus to DC-based cancer vaccination.     

Immunity for tumors and microbes after autotransplantation: if you build it, they will (not) come

Relapses after autologous stem cell transplants for hematopoietic malignancies are frequent and post-transplant infections continue to cause significant post-transplant morbidity and even mortality. The post-transplant period is typically characterized by low lymphocyte counts and impaired immune cell function. Early restoration of immune function may contribute to better disease control and enhance protection from infections. Indeed the attainment of a 'minimal residual disease' status following high-dose therapy makes the early post-transplant period ideal for the introduction of antitumor immunotherapy. Attempts to generate immunity against tumor and microbial antigens after autotransplantation have included vaccinations, T cell infusions (both resting and activated) and combinations of vaccinations and adoptive T cell infusions. One successful strategy for generating robust immune responses against microbial antigens was the combination of pre and post-transplant immunizations along with an early (post-transplant) infusion of in vivo vaccine-primed and ex vivo co-stimulated autologous T cells. Whether this or similar strategies will lead to the generation of effective antitumor immunity is unknown. The lessons gained from efforts to rebuild immune system function in the setting of autotransplantation may also be applicable to the problem of restoring immunity in other immunodeficient groups such as patients with cancer or HIV disease and the elderly.     

The Effect of Herpes Simplex Virus-Type-1 (HSV-1) Oncolytic Immunotherapy on the Tumor Microenvironment

The development of cancer causes disruption of anti-tumor immunity required for surveillance and elimination of tumor cells. Immunotherapeutic strategies aim for the restoration or establishment of these anti-tumor immune responses. Cancer immunotherapies include immune checkpoint inhibitors (ICIs), adoptive cellular therapy (ACT), cancer vaccines, and oncolytic virotherapy (OVT). The clinical success of some of these immunotherapeutic modalities, including herpes simplex virus type-1 derived OVT, resulted in Food and Drug Administration (FDA) approval for use in treatment of human cancers. However, a significant proportion of patients do not respond or benefit equally from these immunotherapies. The creation of an immunosuppressive tumor microenvironment (TME) represents an important barrier preventing success of many immunotherapeutic approaches. Mechanisms of immunosuppression in the TME are a major area of current research. In this review, we discuss how oncolytic HSV affects the tumor microenvironment to promote anti-tumor immune responses. Where possible we focus on oncolytic HSV strains for which clinical data is available, and discuss how these viruses alter the vasculature, extracellular matrix and immune responses in the tumor microenvironment.     

Idiotypic Immune Targeting of Multiple Myeloma

Immunotherapy of malignant diseases remains a major therapeutic challenge. In multiple myeloma, interests have been focussed primarily on the targeting of the idiotypic protein since it represents one of the few tumor specific antigens. Various vaccination strategies have been employed, including the use of naked protein, protein conjugated to Keyhole Limpet Hemocyanin and, most recently, vaccine delivered via dendritic cells. Studies so far indicate the feasibility of inducing potentially beneficial idiotype-specific immune responses in the autologous hosts. However, the antitumor responses produced by the vaccines have been generally modest and sup-optimal. Further work is therefore ongoing to optimize the antitumor responses by including cytokines in the vaccination schedule. In addition, the development of a polyvalent vaccine is also being explored. The next few years should prove interesting and crucial in bringing effective and reliable immunotherapeutic strategies to the clinics.     

Immune therapy for hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Currently, there are no treatment options available for a large number of these patients. One of the mechanisms that may contribute to tumor growth is the lack of an effective immune response toward viral antigens or other tumor-associated antigens (TAAs). Immunotherapy has been tested as a potential therapeutic option for these patients. Several methods of immune modulation for augmenting antitumor immunity are being explored and have been shown to be effective in suppressing HCC growth in animal models. Activation of HCC-specific response can be accomplished by targeting hepatitis B or C viral antigens, alpha-fetoprotein, or other TAAs. This review summarizes part of the recent data on the use of adoptive transfer of immunity against viral antigens, oral immune modulation against TAAs, and the use of pulsed innate immune cells and gut adjuvants for the suppression of HCC; it reviews some additional new immunotherapeutic approaches.     

Malignancy: Idiotypic Immune Targeting of Multiple Myeloma

Immunotherapy of malignant diseases remains a major therapeutic challenge. In multiple myeloma, interests have been focussed primarily on the targeting of the idiotypic protein since it represents one of the few tumor specific antigens. Various vaccination strategies have been employed, including the use of naked protein, protein conjugated to Keyhole Limpet Hemocyanin and, most recently, vaccine delivered via dendritic cells. Studies so far indicate the feasibility of inducing potentially beneficial idiotype-specific immune responses in the autologous hosts. However, the antitumor responses produced by the vaccines have been generally modest and sup-optimal. Further work is therefore ongoing to optimize the antitumor responses by including cytokines in the vaccination schedule. In addition, the development of a polyvalent vaccine is also being explored. The next few years should prove interesting and crucial in bringing effective and reliable immunotherapeutic strategies to the clinics.     

Immune checkpoint molecules in acute myeloid leukaemia: managing the double‐edged sword

New immunotherapeutic interventions have revolutionized cancer treatment. The immune responsiveness of acute myeloid leukaemia (AML) was first demonstrated by allogeneic stem cell transplantation. In addition, milder immunotherapeutic approaches are exploited. However, the long‐term efficacy of these therapies is hampered by various immune resistance and editing mechanisms. In this regard, co‐inhibitory signalling pathways have been shown to play a crucial role. Via up‐regulation of inhibitory checkpoints, tumour‐reactive T cell and Natural Killer cell responses can be strongly impeded. Accordingly, the introduction of checkpoint inhibitors targeting CTLA‐4 (CTLA4) and PD‐1 (PDCD1, CD279)/PD‐L1 (CD274, PDCD1LG1) accomplished a breakthrough in cancer treatment, with impressive clinical responses. Numerous new co‐inhibitory players and novel combination therapies are currently investigated for their potential to boost anti‐tumour immunity and improve survival of cancer patients. Although the challenge here remains to avoid severe systemic toxicity. This review addresses the involvement of co‐inhibitory signalling in AML immune evasion and discusses the opportunities for checkpoint blockers in AML treatment.     

Role of myeloid-derived suppressor cells in tumor immunotherapy

Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells that infiltrate human and experimental tumors and strongly inhibit anticancer immune response directly or by inducing regulatory T-lymphocyte activity. Consequently, MDSCs are important actors of cancer-induced immune tolerance and a major obstacle to efficiency of cancer immunotherapy. Several means of preventing MDSCs accumulation or inhibiting their immunosuppressive effect were recently discovered in cancer-bearing hosts, contributing to restoring antitumor immunity and consequently to control of tumor growth. In experimental tumor models, targeting MDSCs can enhance the effects of active or passive immunotherapy. While similar effects have not yet been noted in cancer-bearing patients, recent preclinical findings demonstrating that the selective toxicity of conventional chemotherapies such as gemcitabine and 5-fluorouracil on MDSCs might contribute to their anticancer effect provide impetus to pursue investigations to unravel novel therapeutics that target MDSCs in humans.     

Role of Myeloid Cells in Oncolytic Reovirus-Based Cancer Therapy

Oncolytic reovirus preferentially targets and kills cancer cells via the process of oncolysis, and additionally drives clinically favorable antitumor T cell responses that form protective immunological memory against cancer relapse. This two-prong attack by reovirus on cancers constitutes the foundation of its use as an anticancer oncolytic agent. Unfortunately, the efficacy of these reovirus-driven antitumor effects is influenced by the highly suppressive tumor microenvironment (TME). In particular, the myeloid cell populations (e.g., myeloid-derived suppressive cells and tumor-associated macrophages) of highly immunosuppressive capacities within the TME not only affect oncolysis but also actively impair the functioning of reovirus-driven antitumor T cell immunity. Thus, myeloid cells within the TME play a critical role during the virotherapy, which, if properly understood, can identify novel therapeutic combination strategies potentiating the therapeutic efficacy of reovirus-based cancer therapy.     

GENiusVac, a novel antitumor vaccine strategy based on allogeneic plasmacytoid dendritic cells

The development of effective vaccines against cancer and viruses still remains a challenge. Many immunotherapeutic strategies have been developed but without sufficient therapeutic success. Plasmacytoid dendritic cells (pDC) play a crucial role in antitumor and antiviral responses. Despite their outstanding functional properties, their therapeutic potential has not yet been worked out. We propose a new immunotherapeutic strategy based on a pDC cell line irradiated and pulsed with tumor or viral antigens. GENiusVac allows the induction of multispecific and highly functional cytotoxic cell responses directed against viral or tumor targets. We demonstrated the potential of this strategy in vitro, its therapeutic efficacy in vivo in a humanized mouse model, and its clinical relevance ex vivo from melanoma patients’ cells. GENiusVac highlights pDCs as potent vector of immunotherapy and provide a way to exploit them in cell therapy to fight cancer or chronic viral infections.     

Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination

Active suppression of tumor-specific T lymphocytes can limit the immune-mediated destruction of cancer cells. Of the various strategies used by tumors to counteract immune attacks, myeloid suppressors recruited by growing cancers are particularly efficient, often resulting in the induction of systemic T lymphocyte dysfunction. We have previously shown that the mechanism by which myeloid cells from tumor-bearing hosts block immune defense strategies involves two enzymes that metabolize L-arginine: arginase and nitric oxide (NO) synthase. NO-releasing aspirin is a classic aspirin molecule covalently linked to a NO donor group. NO aspirin does not possess direct antitumor activity. However, by interfering with the inhibitory enzymatic activities of myeloid cells, orally administered NO aspirin normalized the immune status of tumor-bearing hosts, increased the number and function of tumor-antigen-specific T lymphocytes, and enhanced the preventive and therapeutic effectiveness of the antitumor immunity elicited by cancer vaccination. Because cancer vaccines and NO aspirin are currently being investigated in independent phase I/II clinical trials, these findings offer a rationale to combine these treatments in subjects with advanced neoplastic diseases.     

Role of Damage-Associated Molecular Pattern/Cell Death Pathways in Vaccine-Induced Immunity

Immune responses induced by natural infection and vaccination are known to be initiated by the recognition of microbial patterns by cognate receptors, since microbes and most vaccine components contain pathogen-associated molecular patterns. Recent discoveries on the roles of damage-associated molecular patterns (DAMPs) and cell death in immunogenicity have improved our understanding of the mechanism underlying vaccine-induced immunity. DAMPs are usually immunologically inert, but can transform into alarming signals to activate the resting immune system in response to pathogenic infection, cellular stress and death, or tissue damage. The activation of DAMPs and cell death pathways can trigger local inflammation, occasionally mediating adaptive immunity, including antibody- and cell-mediated immune responses. Emerging evidence indicates that the components of vaccines and adjuvants induce immunogenicity via the stimulation of DAMP/cell death pathways. Furthermore, strategies for targeting this pathway to enhance immunogenicity are being investigated actively. In this review, we describe various DAMPs and focus on the roles of DAMP/cell death pathways in the context of vaccines for infectious diseases and cancer.     

血吸虫及其相关产物在宿主免疫调节中的作用

血吸虫可通过合成、分泌或者排泄多种具有免疫调节功能的分子影响宿主的免疫系统,主要表现为促进Th2免疫效应,抑制Th1/Th17免疫效应.血吸虫感染过程中,其免疫调节效应可以调控宿主固有免疫和适应性免疫,使其能够逃避宿主的免疫攻击,而在人体内长期存活.研究显示血吸虫感染对于过敏性疾病、自身免疫性疾病以及同种异体免疫反应等...     

T cell-mediated immune responses in melanoma: implications for immunotherapy

In the last few years, a great deal of efforts have been directed towards understanding the molecular basis of T cell-mediated anti-tumor immunity and elucidating the molecular nature of tumor antigens recognized by T cells. Identification of a number of major histocompatibility complex (MHC) class I-restricted melanoma antigens has led to clinical trials aimed at developing effective cancer vaccines. These studies showed some evidence of therapeutic effect on the treatment of cancer, but the exclusive use of CD8+ T cells may not be effective in eradicating tumor. This rekindles interest in the role of CD4+ T cells in antitumor immunity, which play a central role in orchestrating the host immune response against cancer. Thus, we have attempted to identify MHC class II-restricted tumor antigens recognized by tumor-specific CD4+ T cells. The identification of tumor rejection antigens provides new opportunities for the development of therapeutic strategies against cancer. This review will summarize the current status of MHC class I and class II-restricted human tumor antigens, and their potential application to cancer treatment.     

Coinhibitory molecules in hematologic malignancies: targets for therapeutic intervention

The adaptive immune system can be a potent defense mechanism against cancer; however, it is often hampered by immune suppressive mechanisms in the tumor microenvironment. Coinhibitory molecules expressed by tumor cells, immune cells, and stromal cells in the tumor milieu can dominantly attenuate T-cell responses against cancer cells. Today, a variety of coinhibitory molecules, including cytotoxic T lymphocyte-associated antigen-4, programmed death-1, B and T lymphocyte attenuator, LAG3, T-cell immunoglobulin and mucin domain 3, and CD200 receptor, have been implicated in immune escape of cancer cells. Sustained signaling via these coinhibitory molecules results in functional exhaustion of T cells, during which the ability to proliferate, secrete cytokines, and mediate lysis of tumor cells is sequentially lost. In this review, we discuss the influence of coinhibitory pathways in suppressing autologous and allogeneic T cell-mediated immunity against hematologic malignancies. In addition, promising preclinical and clinical data of immunotherapeutic approaches interfering with negative cosignaling, either as monotherapy or in conjunction with vaccination strategies, are reviewed. Numerous studies indicate that coinhibitory signaling hampers the clinical benefit of current immunotherapies. Therefore, manipulation of coinhibitory networks is an attractive adjuvant immunotherapeutic intervention for hematologic cancers after standard treatment with chemotherapy and hematopoietic stem cell transplantation.     

Recent Insights into the Pathobiology of Innate Immune Deficiencies

Primary immunodeficiencies are a heterogeneous group of genetically inherited diseases affecting the innate and adaptive immune systems that confer susceptibility to infection, autoimmunity, and cancer. Innate immunity includes neutrophils, macrophages, dendritic cells, natural killer cells, and natural killer T cells in conjunction with natural barriers (mostly skin and gastrointestinal and respiratory mucosa), as well as antimicrobial agents, opsonins (e.g., complement), and cytokines. Although somewhat primitive, innate immune cells can orchestrate discrete immune responses through the recognition of diverse pathogens by different pattern-recognition receptors. In this review, we discuss the most recent discoveries as well as the already established pathophysiologic mechanisms underlying innate immunity defects associated with primary immunodeficiencies.     

The immune system as a foundation for immunologic therapy and hematologic malignancies: a historical perspective

In this review we aim to provide a historical overview of the immunotherapeutic approaches which have been developed for the treatment of hematological malignancies. After briefly summarizing the development of the theory of cancer immune surveillance, we describe how initial studies discovering the efficacy of the immune-mediated graft-versus-tumor effects after allogeneic hematopoietic cell transplantation led to new transplantation approaches (termed non-myeloablative transplantation) relying almost exclusively on graft-versus-tumor effects for tumor eradication. We then summarize important steps in the development of tumor vaccines and autologous adoptive immunotherapy in patients with hematological malignancies. Finally, we describe historical discoveries leading to the recent success with monoclonal antibodies as treatment for lymphomas, chronic lymphocytic leukemia, and acute myeloid leukemia.