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.     

Targeted immunotherapy of cancer: development of antibody-induced cellular immunity

Although immunotherapy of cancer encompasses a large variety of distinct protocols, virtually all therapeutic strategies require the enabling/training of the immune system to distinguish tumour tissue from healthy tissue. In the case of antibody-based therapies, specificity obviously arises from the selectivity of the antibodies for tumour antigens, and tumour cell death derives from either direct cytotoxicity of the antibody or antibody-dependent cellular cytotoxicity. However, even when both of the above killing mechanisms are simultaneously active, we suggest that antibody-based immunotherapies may fall far short of their full potential. In this editorial, we first summarize the mechanisms by which current antibody-based therapies mediate cancer cell removal, and then propose two strategies by which this class of immunotherapies might be further improved. These suggested improvements involve the decoration of tumour cell surfaces with foreign haptens against which an endogenous humoral immune response can be mounted and the recruitment of the cellular arm of the immune system in an antibody-dependent process.     

American Association for Cancer Research: dendritic cells: strategies and vaccines. April 1-5, 2000, San Francisco, CA, USA

Several major sessions on dendritic cells (DCs) reflected the importance of these members of the immune system within cancer research. Technical hurdles to their routine propagation were largely overcome within the past decade, so the study of precursors, as well as the numerous types of dendritic cells, is the focus of intense research. In vitro studies were presented that described further refinements in dendritic cells are collected and culture. Cytokines and other growth factors have been analysed to assess their contribution to the ability of dendritic cells to intake, process and present antigen. In some instances, the dendritic cells themselves are genetically altered to improve their natural biological activity. Many studies have advanced from in vitro work and demonstrated utility in various animal models. Ultimately, there is the hopeful, steady progress into the increasing numbers of experimental immunotherapies against human cancer.     

Use of cytokines in cancer vaccines/immunotherapy: recent developments improve survival rates for patients with metastatic malignancy

Historically, patients with disseminated cancer have had poor prognoses and chemotherapy has been of little benefit. However, several different avenues of clinical research are providing reasons for hope. The advent of cytokine immunotherapy, particularly in combination with chemotherapy (biochemotherapy) has seen significantly improved outcomes for metastatic disease. Early biochemotherapy trials often revealed more than 20% complete responses. Unfortunately, Phase III trials have not confirmed earlier expectations for reasons that are not clear, but may reflect the inclusion of patients with refractory brain or other metastases in later trials. More recently, cancer vaccine therapies have provided significantly improved patient survival rates. It is not uncommon for 5-year survival rates of post-surgical patients recovering from metastatic malignancy who receive cancer vaccine therapy to reach more than 50%. Cytokines have become an integral part of cancer therapy and are also under trial together with cancer vaccines as post-surgical adjuvant therapies providing significant gains in long term survival rates. New insights from several different areas of research into the properties of tumour cells and their significance for immunosurveillance point to the importance of the tumour cells themselves as antigen presenting cells. Recent developments with genetically deficient animals and cancer cells have provided greater understanding at the molecular level of the importance of a functioning antigen presenting system operating inside tumour cells. This new knowledge offers support for further enhancing patient survival by combining previous therapies such as use of cytokines in biochemotherapy together with immunization using cytokine activated whole cell cancer vaccines in the future.     

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.     

CAR-T cells: Early successes in blood cancer and challenges in solid tumors

New approaches to cancer immunotherapy have been developed, showing the ability to harness the immune system to treat and eliminate cancer. For many solid tumors, therapy with checkpoint inhibitors has shown promise. For hematologic malignancies, adoptive and engineered cell therapies are being widely developed, using cells such as T lymphocytes, as well as natural killer (NK) cells, dendritic cells, and potentially others. Among these adoptive cell therapies, the most active and advanced therapy involves chimeric antigen receptor (CAR)-T cells, which are T cells in which a chimeric antigen receptor is used to redirect specificity and allow T cell recognition, activation and killing of cancers, such as leukemia and lymphoma. Two autologous CAR-T products have been approved by several health authorities, starting with the U.S. Food and Drug Administration (FDA) in 2017. These products have shown powerful, inducing, long-lasting effects against B cell cancers in many cases. In distinction to the results seen in hematologic malignancies, the field of using CAR-T products against solid tumors is in its infancy. Targeting solid tumors and trafficking CAR-T cells into an immunosuppressive microenvironment are both significant challenges. The goal of this review is to summarize some of the most recent aspects of CAR-T cell design and manufacturing that have led to successes in hematological malignancies, allowing the reader to appreciate the barriers that must be overcome to extend CAR-T therapies to solid tumors successfully.KEY WORDS: Immunotherapy, T cell therapy, Chimeric antigen receptor (CAR), Genetic engineering     

Immunotherapeutic applications of CpG oligodeoxynucleotide TLR9 agonists

Toll-like receptor 9 (TLR9) agonists have demonstrated substantial potential as vaccine adjuvants, and as mono- or combination therapies for the treatment of cancer and infectious and allergic diseases. Commonly referred to as CpG oligodeoxynucleotides (ODN), TLR9 agonists directly induce the activation and maturation of plasmacytoid dendritic cells and enhance differentiation of B cells into antibody-secreting plasma cells. Preclinical and early clinical data support the use of TLR9 agonists as vaccine adjuvants, where they can enhance both the humoral and cellular responses to diverse antigens. In mouse tumor models TLR9 agonists have shown activity not only as monotherapy, but also in combination with multiple other therapies including vaccines, antibodies, cellular therapies, other immunotherapies, antiangiogenic agents, radiotherapy, cryotherapy, and some chemotherapies. Phase I and II clinical trials have indicated that these agents have antitumor activity as single agents and enhance the development of antitumor T-cell responses when used as therapeutic vaccine adjuvants. CpG ODN have shown benefit in multiple rodent and primate models of asthma and other allergic diseases, with encouraging results in some early human clinical trials. Although their potential clinical contributions are enormous, the safety and efficacy of these TLR9 agonists in humans remain to be determined.     

肿瘤干细胞的研究进展

随着对肿瘤研究的不断深入,以及对干细胞了解的日益加深,越来越多的证据提示肿瘤中某些细胞具有干细胞特性,并提出了肿瘤干细胞的学说,认为肿瘤的生长、转移以及耐药等均于肿瘤干细胞的关系密切.该文综述了肿瘤干细胞的发现、特点,以及在肿瘤的诊断、治疗和预后判断中的作用.     

American Association for Cancer Research

Several major sessions on dendritic cells (DCs) reflected the importance of these members of the immune system within cancer research. Technical hurdles to their routine propagation were largely overcome within the past decade, so the study of precursors, as well as the numerous types of dendritic cells, is the focus of intense research. In vitro studies were presented that described further refinements in dendritic cells are collected and culture. Cytokines and other growth factors have been analysed to assess their contribution to the ability of dendritic cells to intake, process and present antigen. In some instances, the dendritic cells themselves are genetically altered to improve their natural biological activity. Many studies have advanced from in vitro work and demonstrated utility in various animal models. Ultimately, there is the hopeful, steady progress into the increasing numbers of experimental immunotherapies against human cancer.     

Folate receptor-targeted immunotherapy of cancer: mechanism and therapeutic potential

The vitamin, folic acid, has become a useful ligand for targeted cancer therapies because it binds to a tumor-associated antigen known as the folate receptor (FR). By linking folic acid to therapeutic agents, folate-targeted cancer therapies can deliver therapeutic drugs specifically to FR-positive tumor cells. This chapter provides a summary of a specific application of folate-targeted therapies whereby folic acid is exploited to carry an attached hapten (a highly antigenic molecule) to the surfaces of tumor cells for the purpose of rendering the tumors more immunogenic. The basic strategy is to (i) saturate (label) the surface of FR-positive tumor cells with a folate-hapten conjugate against which the cancer-bearing host already has a pre-existing or induced immunity, (ii) allow the surface bound haptens to attract anti-hapten antibodies to the tumor cell surface, and (iii) stimulate Fc receptor-bearing immune cells to mount an antitumor response against the anti-hapten antibody opsonized tumor cells. In immune competent murine tumor models, hapten-marked cancer cells have been shown to be quickly recognized by antibodies and the associated Fc receptor-expressing immune cells dedicated to eliminating antibody-coated target cells. Given the need for cancer cells to escape immune surveillance in order to proliferate and survive in vivo, folate-targeted immunotherapies that mark an otherwise immunologically "invisible" cancer cell as distinctively "non-self" may provide a key strategy for combating malignant disease.     

mRNA delivery in cancer immunotherapy

Messenger RNA (mRNA) has drawn much attention in the medical field. Through various treatment approaches including protein replacement therapies, gene editing, and cell engineering, mRNA is becoming a potential therapeutic strategy for cancers. However, delivery of mRNA into targeted organs and cells can be challenging due to the unstable nature of its naked form and the low cellular uptake. Therefore, in addition to mRNA modification, efforts have been devoted to developing nanoparticles for mRNA delivery. In this review, we introduce four categories of nanoparticle platform systems: lipid, polymer, lipid-polymer hybrid, and protein/peptide-mediated nanoparticles, together with their roles in facilitating mRNA-based cancer immunotherapies. We also highlight promising treatment regimens and their clinical translation.     

Apoptosis and cancer stem cells: Implications for apoptosis targeted therapy

Evidence is accumulating showing that cancer stem cells or tumor-initiating cells are key drivers of tumor formation and progression. Successful therapy must therefore eliminate these cells, which is hampered by their high resistance to commonly used treatment modalities. Thus far, only a limited number of studies have addressed the cancer stem cell killing potential of apoptosis targeted therapies and mechanisms of apoptosis resistance in these cells. Apoptosis resistance may involve inherent cellular mechanisms that may change depending on the differentiations status of stem cells and, on the other hand, extrinsic factors provided by the microenvironment such as secreted survival factors, adhesion-mediated apoptosis resistance and hypoxic conditions. In order to metastasize, cancer stem cells from solid tumors have to break free from their primary epithelial sites and resist cell death activation after detachment (anoikis). The induction of an embryonic genetic program causing the transition from an epithelial to a mesenchymal state (EMT) has been implicated in enhanced migration and metastatic spread of tumor cells and may contribute to apoptosis and anoikis resistance. Considering the plasticity of cancer stem cells the question arises whether a particular apoptosis-inducing strategy will be sufficient for eliminating all the cellular appearances of these cells, also taking into account a varying microenvironment. Here, the different mechanisms of apoptosis resistance that may be encountered in the context of cancer stem cell plasticity described thus far are discussed in relation to the efficacy of apoptosis therapies, such as TRAIL, BCL-2 family and XIAP targeted therapies.     

Current status of immunotherapy in B cell malignancies

Conventional treatment of hematologic malignancies mainly consists of chemotherapeutic agents or a combination of both, chemotherapy and monoclonal antibodies. Despite recent advances, chemotherapeutic treatments often remain unsatisfying due to severe side effects and incomplete long-term remission. Therefore the evaluation of novel therapeutic options is of great interest. B cell malignancies, in particularly follicular lymphomas, chronic lymphocytic leukemia and multiple myeloma, represent the most immune-responsive types of all human cancer. Several immunotherapeutic strategies are presently employed to combat these B-cell malignancies. Active immunotherapies include vaccination strategies with dendritic cells (DCs) and genetically-modified tumor cell preparations as well as DNA and protein vaccination. Most of these vaccines target the tumor-specific immunoglobulin idiotype and have already demonstrated some anti-lymphoma activity in early phase clinical trials while their definitive impact is evaluated in ongoing phase III randomized trials. In contrast to these active immunizations, T cells transduced with chimeric antigen receptors and donor leukocyte infusions (DLI) represent adoptive (passive) immunotherapies. Recent advances of gene transduction technologies enabled improvement of immunotherapeutic strategies based on genetic modification of malignant cells or adoptive T cells. Current early phase clinical trials are investigating the potential of these innovative approaches. At the moment it remains unclear if the novel immunotherapeutic strategies will be able to play a similar role in the treatment of B cell malignancies than the already established antibody-based immunotherapy.     

Developing dendritic cell-based therapies to condition immune responses to novel oncogenic proteins and stem cells

Cancer vaccines have been disappointing when utilized as stand-alone therapy, especially in late disease settings. However, recent clinical studies in prostate cancer have suggested that dendritic cellular (DC) vaccines may impact patient survival, reviving the notion that cancer vaccines can impact established cancer. In this review we will highlight the advances that have been made in the development of DC-based therapies activated by Toll-like receptor agonists with the capacity to condition toward strong Th1 cellular responses, through the production of cytokines and chemokines, and a capacity to induce apoptosis of tumor cells. Used in early cancer settings, these DCs induce clinically effective immune responses, thus shifting the emphasis toward using these cells earlier in the disease process. We will also discuss targeting novel molecules and cancer stem cells that can eliminate cells with high metastatic potential, moving DC-based therapies into mainstream cancer therapy.     

Developing dendritic cell-based therapies to condition immune responses to novel oncogenic proteins and stem cells

Cancer vaccines have been disappointing when utilized as stand-alone therapy, especially in late disease settings. However, recent clinical studies in prostate cancer have suggested that dendritic cellular (DC) vaccines may impact patient survival, reviving the notion that cancer vaccines can impact established cancer. In this review we will highlight the advances that have been made in the development of DC-based therapies activated by Toll-like receptor agonists with the capacity to condition toward strong Th1 cellular responses, through the production of cytokines and chemokines, and a capacity to induce apoptosis of tumor cells. Used in early cancer settings, these DCs induce clinically effective immune responses, thus shifting the emphasis toward using these cells earlier in the disease process. We will also discuss targeting novel molecules and cancer stem cells that can eliminate cells with high metastatic potential, moving DC-based therapies into mainstream cancer therapy.     

Cancer immunotherapy using recombinant Listeria monocytogenes: transition from bench to clinic

Cancer immunotherapy has developed into a field of intense study as aspects of the immune system involved in the eradication of cancer have become delineated. Listeria monocytogenes is a gram-positive, facultative intracellular bacterium which infects antigen presenting cells (APC), and is being used as a cancer vaccine to deliver tumor antigens directly to the APC. This results in the generation of a strong immune response towards the tumor associated antigen and direct targeting of the tumor by the immune system. Advances in this field have led to the development of a series of L. monocytogenes-based cancer vaccines, which are currently in clinical trials. A phase I study has shown these vaccines can be safely administered and well-tolerated in terminal stage cancer patients and an efficacy signal was observed in patients who did not respond to other therapies. Additional data on the efficacy of these vaccines is expected in the near-term.     

Recent advances in targeting regulators of apoptosis in cancer cells for therapeutic gain

Apoptosis is a fundamental cellular death process that is essential for normal tissue homeostasis, whose deregulation is associated with several human disease states, including cancer. Increased understanding of cancer biology has led to the hypothesis that although cancer cells are inherently resistant to the engagement of apoptosis due to the deregulation of molecular components of core apoptotic machinery or of survival signalling cascades, they are primed to die as a result of microenvironmental and oncogenic proapoptotic stress. Recently, deeper insight into the molecular regulation of apoptosis and, specifically, into its deregulation in cancer has led to the development of promising therapies to restore apoptosis and enable selective tumour cell kill. It is hoped that these mechanism-based therapies will exhibit less problematic toxicity profiles than those of conventional agents. Moreover, the development of tailored therapies directed at malignancies bearing specific alterations in apoptotic or survival signalling components may be used in combination approaches to overcome the resistance to other forms of treatment.     

Recent advances in targeting regulators of apoptosis in cancer cells for therapeutic gain

Apoptosis is a fundamental cellular death process that is essential for normal tissue homeostasis, whose deregulation is associated with several human disease states, including cancer. Increased understanding of cancer biology has led to the hypothesis that although cancer cells are inherently resistant to the engagement of apoptosis due to the deregulation of molecular components of core apoptotic machinery or of survival signalling cascades, they are primed to die as a result of microenvironmental and oncogenic proapoptotic stress. Recently, deeper insight into the molecular regulation of apoptosis and, specifically, into its deregulation in cancer has led to the development of promising therapies to restore apoptosis and enable selective tumour cell kill. It is hoped that these mechanism-based therapies will exhibit less problematic toxicity profiles than those of conventional agents. Moreover, the development of tailored therapies directed at malignancies bearing specific alterations in apoptotic or survival signalling components may be used in combination approaches to overcome the resistance to other forms of treatment.     

Receptor-mediated delivery of antigens to dendritic cells: anticancer applications

Recently, there has been a surge of interest in the use of ex vivo antigen-pulsed dendritic cells (DCs) in the immunotherapy for cancer. DCs are powerful adjuvants with the ability to prime naive CD4+ and CD8+ T cells. As antigen sources, various preparations, including peptides, proteins, crude tumor lysates, and DCs transfected or transformed with various viruses, have been used. These procedures that involve the isolation of patient DCs and reintroduction after in vitro manipulation are time-consuming and expensive. The DC populations used frequently in ex vivo clinical studies are IL-4 and GM-CSF cultured DCs that may not represent the in vivo DC populations. An attractive method of targeting in vivo DCs is to utilize various ligands or antibodies that bind discrete populations of DCs. These cell surface receptors will direct the antigen to different antigen processing pathways depending on the targeted receptor to induce cytotoxic T cell or T helper responses. This review will discuss the various approaches and receptors that have been used for antigen targeting that may eventually be translated to alternative DC-based immunotherapies.