Maximizing dendritic cell migration in cancer immunotherapy

Background: The success of dendritic cell (DC)-based immunotherapy in inducing cellular immunity against tumors is highly dependent on accurate delivery and trafficking of the DC to T-cell-rich areas of secondary lymphoid tissues. Objective: To provide an overview of DC migration in vivo and how migration to peripheral lymph nodes might be improved to optimize DC therapy. Methods: We focused on DC migration in preclinical models and human skin explants and on clinical vaccination trials studying migration of in vitro-generated DC. Results/conclusions: DC migration requires an intricate interplay between the cell and its environment. To maximize migration for cellular therapy, it is important to optimize the generation of migratory DC as well as treatment strategies.     

Natural killer–dendritic cell cross-talk in cancer immunotherapy

ABSTRACT

Introduction: Rheumatoid arthritis (RA) treatment has been revolutionized by the development of highly efficacious biotherapeutics. However, a significant subset of RA patients has persistently active disease and ongoing erosive joint damage despite the available therapies. Sarilumab targets interleukin-6, one of the main cytokines mediating inflammation in RA. Positive results with sarilumab in RA clinical trials support the licensing application currently under review with the US Food and Drug Administration.

Areas covered: The rationale for IL-6 targeting in RA, the pharmacologic properties of sarilumab, and the clinical trial results are reviewed focusing on the pending application for the RA indication. Comparisons with other IL-6 targeting biologics as well as additional potential therapeutic directions are discussed.

Expert opinion: Sarilumab is a highly active therapeutic in patients with RA. While pharmacologic data demonstrate that sarilumab has a higher affinity than tocilizumab for the target receptor, available clinical results suggest that efficacy and adverse event profiles are similar to this other IL-6 blocker, which is currently approved for the treatment of RA. Whether there are other distinct differences or advantages of sarilumab that will support the approval and successful marketing of this drug, over existing therapies, remains to be determined.     

Optimization of dendritic cell loading with tumor cell lysates for cancer immunotherapy

The immune response to cancer is critically determined by the way in which tumor cells die. As necrotic, stress-associated death can be associated with activation of antitumor immunity, whole tumor cell antigen loading strategies for dendritic cell (DC)-based vaccination have commonly used freeze-thaw "necrotic" lysates as an immunogenic source of tumor-associated antigens. In this study, the effect of such lysates on the ability of DCs to mature in response to well-established maturation stimuli was examined, and methods to enhance lysate-induced DC activation explored. Freeze-thaw lysates were prepared from murine tumor cell lines and their effects on bone marrow-derived DC maturation and function examined. Unmodified freeze-thaw tumor cell lysates inhibited the toll-like receptor-induced maturation and function of bone marrow-derived DCs, preventing up-regulation of CD40, CD86, and major histocompatibility complex class II, and reducing secretion of inflammatory cytokines [interleukin (IL)-12 p70, tumor necrosis factor-alpha, and IL-6]. Although IL-10 secretion was increased by lysate-pulsed DCs, this was not responsible for the observed suppression of IL-12. Although activation of the nuclear factor-kappaB pathway remained intact, the kinase activity of phosphorylated p38 mitogen-activated protein kinase was inhibited in lysate-pulsed DCs. Lysate-induced DC suppression was partially reversed in vitro by induction of tumor cell stress before lysis, and only DCs loaded with stressed lysates afforded protection against tumor challenge in vivo. These data suggest that ex vivo freeze-thaw of tumor cells does not effectively mimic in vivo immunogenic necrosis, and advocates careful characterization and optimization of tumor cell-derived vaccine sources for cancer immunotherapy.     

Quality issues in stem cell and immunotherapy laboratories

The advent of the Code of Practice for Tissue Banks has led to the requirement for quality systems to be established in all laboratories involved in the production or processing of all cellular tissues to be used therapeutically. The quality system is all-encompassing from process validations and quality assurance to the standard of facilities and staff training. This seems self-evident to those working within the transfusion field but is a relatively novel concept to many hospital laboratories preparing transplant products such as bone marrow or peripheral blood derived haematopoietic stem cells. This review places the current guidelines in an historical context and explains many of the central tenets and requirements of the Code of Practice while outlining a process to facilitate preparation for accreditation.     

肺癌免疫治疗现状分析

肺癌发病率和死亡率已居各种癌症之首位．需要探索新的治疗模式,免疫治疗以其低毒,高特异性等优点有望成为肺癌治疗的重要辅助治疗方式。本文综述了肺癌的过继免疫治疗、单克隆抗体疗法、基因治疗、肿瘤疫苗、细胞因子治疗、生物反应调节剂六个方面现状及最新进展。     

Targeting Toll-like receptor 3 in dendritic cells for cancer immunotherapy

ABSTRACT

Introduction

Activation of innate immune system is a key step to develop anti-tumor immunity. Antigen-presenting dendritic cells (DCs) cross-present tumor-associated antigens to cytotoxic CD8⁺ T cells (CTLs). Signaling from pattern-recognition receptors (PRRs) in DCs is required to induce tumor-specific CTLs.     

树突细胞应用于荷白血病小鼠免疫治疗的实验研究

目的探讨白血病抗原活化的树突细胞(DC)应用于荷白血病小鼠异基因骨髓移植 (allo-BMT)后免疫治疗的可行性及有效性。方法应用mGM-CSF及mIl-4从小鼠骨髓细胞扩增出成熟DC,使其负载经冻融法制备的L7212白血病细胞相关抗原。将进行allo-BMT后的荷白血病小鼠分 A(对照组)、B(T细胞组)、C(DC T细胞组)三组进行免疫治疗,观察小鼠生存率、生存期、移植物抗宿主病(GVHD)发生等情况及血清细胞因子水平和脾细胞细胞毒活力变化。对各组长期生存小鼠行二次攻击,以观察其体内抗白血病免疫能力。结果小鼠骨髓单个核细胞经mGM-CSF、mIL-4联合作用7 d可生成大量成熟DC。B、C二组复发率分别为30％及0％,移植后长期生存率分别为30％及 70％,两组差异均有统计学意义(P<0．05),而GVHD发生率差异无统计学意义。两组平均生存时间分别为(32．95±13．29)d、(41．15±13．88)d,差异有统计学意义(P<0．01)。MYT法检测发现C组小鼠脾细胞对L7212细胞产生特异性杀伤作用;EIJSA法检测显示血清中Th1类因子IL-2水平为 (419．75±26．66)pg／ml,明显高于其他两组(P<0．01)。二次攻击后B、C二组生存率分别为33．3％及85．7％,差异有统计学意义(P<0．05)。结论肿瘤抗原负载的DC联合供者淋巴细胞输注是增强 allo-BMT后移植物抗白血病效应、减少白血病复发的有效手段。     

树突状细胞瘤苗抗肿瘤临床应用进展

树突状细胞(DC)是目前功能最强的抗原提呈细胞,在机体抗肿瘤免疫中发挥重要作用。近年来,DC瘤苗抗肿瘤临床应用取得较大进展,现对DC瘤苗的制备及其在肿瘤免疫治疗中的临床应用以及存在问题作一综述。     

Recent developments in renal cell cancer immunotherapy

Various immunotherapeutic approaches for the treatment of renal cell carcinoma (RCC) have been developed for > 90 years. Existing immunotherapeutic strategies against RCC include: systemic administration of cytokines; therapeutic vaccines based on tumor cells or dendritic cells; monoclonal antibodies; and adoptive immunotherapy (T cell transfer or allogeneic hematopoietic cell transplantation). However, the overall efficacy of immunotherapy for advanced RCC remains moderate. With the advent of molecularly targeted biological therapies that turned out to be significantly effective in the treatment of metastatic RCC, to many oncologists immunotherapy may seem to be moving into the periphery of RCC treatment strategies. However, for the last 2 years there has been significant progress made in immunotherapeutic approaches for the treatment of RCC. Immunotherapy still remains the only systemic therapeutic strategy that is believed to potentially cure RCC patients. The development of active and passive specific immunotherapeutic approaches, along with the possibility to ‘switch off’ particular immunosuppressive mechanisms (e.g., elimination of regulatory T cells, blockage of cytotoxic T lymphocyte antigen-4 signaling), have paved the way for future trials of new immunotherapies of RCC. However, the new studies will have to enroll optimally selected patients (nephrectomized, with non-massive metastases and good performance status) and will use tumor response criteria that are specifically optimized for clinical trials of immunotherapy.     

Natural killer-dendritic cell cross-talk in cancer immunotherapy

Natural killer (NK) cells and dendritic cells (DCs), two important components of the immune system, can exchange bidirectional activating signals in a positive feedback. Myeloid DCs, the cell type specialised in the presentation of antigen and initiation of antigen-specific immune responses, have recently been documented to be involved in supporting innate immunity, promoting the production of cytokines and cytotoxicity of NK cells, and enhancing their tumouricidal activity. Natural interferon-producing cells/plasmacytoid DCs (IPCs/PDCs) play an additional role in NK cell activation. Reciprocally, NK cells, traditionally considered to be major innate effector cells, have also recently been shown to play immunoregulatory 'helper' functions, being able to activate DCs and to enhance their ability to produce pro-inflammatory cytokines, and to stimulate T helper (Th) 1 and cytotoxic T lymphocyte (CTL) responses of tumour-specific CD4+ and CD8+ T cells. Activated NK cells induce the maturation of myeloid DCs into stable type-1 polarised DCs (DC1), characterised by up to a 100-fold enhanced ability to produce IL-12p70 in response to subsequent interaction with Th cells. In addition, the ability of NK cells to kill tumour cells may facilitate the generation of tumour-related antigenic material, further accelerating the induction of tumour-specific immunity. DC1, induced by NK cells or by NK cell-related soluble factors, are stable, resistant to tumour-related suppressive factors, and demonstrate a strongly enhanced ability to induce Th1 and CTL responses in human in vitro and mouse in vivo models. Compared with the standard mature DCs that are used in clinical trials at present, human NK cell-induced DC1s act as superior inducers of anticancer CTL responses during in vitro sensitisation. This provides a strong rationale for the combined use of NK cells and DCs in the immunotherapy of patients with cancer and patients with chronic infections that are resistant to standard forms of treatment. Stage I/II clinical trials that are being implemented at present should allow evaluation of the immunological and clinical efficacy of combined NK-DC therapy of melanoma and other cancers.     

Recent developments in renal cell cancer immunotherapy

Various immunotherapeutic approaches for the treatment of renal cell carcinoma (RCC) have been developed for > 90 years. Existing immunotherapeutic strategies against RCC include: systemic administration of cytokines; therapeutic vaccines based on tumor cells or dendritic cells; monoclonal antibodies; and adoptive immunotherapy (T cell transfer or allogeneic hematopoietic cell transplantation). However, the overall efficacy of immunotherapy for advanced RCC remains moderate. With the advent of molecularly targeted biological therapies that turned out to be significantly effective in the treatment of metastatic RCC, to many oncologists immunotherapy may seem to be moving into the periphery of RCC treatment strategies. However, for the last 2 years there has been significant progress made in immunotherapeutic approaches for the treatment of RCC. Immunotherapy still remains the only systemic therapeutic strategy that is believed to potentially cure RCC patients. The development of active and passive specific immunotherapeutic approaches, along with the possibility to 'switch off' particular immunosuppressive mechanisms (e.g., elimination of regulatory T cells, blockage of cytotoxic T lymphocyte antigen-4 signaling), have paved the way for future trials of new immunotherapies of RCC. However, the new studies will have to enroll optimally selected patients (nephrectomized, with non-massive metastases and good performance status) and will use tumor response criteria that are specifically optimized for clinical trials of immunotherapy.     

Recent clinical development of dendritic cell-based immunotherapy for prostate cancer

Dendritic cells (DCs) are the most powerful immune cells that present antigens to T cells, resulting in a T cell response. Therapeutic strategies involving DCs have been explored in many malignancies, including prostate cancer. These strategies are designed to stimulate DC proliferation, promote antigen uptake and processing by DCs, or to directly provide antigen-loaded DCs. All approaches are designed to stimulate an antitumour T cell response leading to clinical benefit. Many approaches in prostate cancer have demonstrated successful induction of the desired immune response. Clinical effect has also been observed, prompting larger definitive trials.     

Recent clinical development of dendritic cell-based immunotherapy for prostate cancer

Dendritic cells (DCs) are the most powerful immune cells that present antigens to T cells, resulting in a T cell response. Therapeutic strategies involving DCs have been explored in many malignancies, including prostate cancer. These strategies are designed to stimulate DC proliferation, promote antigen uptake and processing by DCs, or to directly provide antigen-loaded DCs. All approaches are designed to stimulate an antitumour T cell response leading to clinical benefit. Many approaches in prostate cancer have demonstrated successful induction of the desired immune response. Clinical effect has also been observed, prompting larger definitive trials.     

Dendritic cell immunotherapy for breast cancer

Novel adjuvant therapies are urgently needed to complement the existing treatment options for breast cancer. The advent of the use of dendritic cells (DCs) for cancer immunotherapy provides a unique opportunity to overcome the relative non-immunogenic property of breast tumours and address the underlying immunodeficiency. To date, the success of this approach has been limited, possibly due to the targeting of specific tumour antigens that rapidly mutate and, thus, become undetectable to the immune system. A more efficient approach would include preparations encompassing multiple antigens, such as those provided by loading of whole tumour cells or tumour RNA. It is proposed that targeting mammary stem cells responsible for resistance to chemo/immunotherapy, through the expression of a broad array of wild-type and mutated tumour antigens in the context of DCs, will become a mainstay for immunotherapy of breast cancer.