乳腺癌免疫治疗研究进展

肿瘤的免疫治疗是指通过给予某些生物物质或刺激宿主产生免疫防御应答以取得抗肿瘤效应的治疗方法的总称。随着免疫学和分子生物学的研究,乳腺癌的免疫治疗取得了一定的进步。本文对乳腺癌的免疫治疗研究进展作一综述。     

BILITE: A Bayesian randomized phase II design for immunotherapy by jointly modeling the longitudinal immune response and time-to-event efficacy

Immunotherapy—treatments that target a patient's immune system—has attracted considerable attention in cancer research. Its recent success has led to generation of novel immunotherapeutic agents that need to be evaluated in clinical trials. Two unique features of immunotherapy are the immune response and the fact that some patients may achieve long-term durable response. In this article, we propose a two-arm Bayesian adaptive randomized phase II clinical trial design for immunotherapy that jointly models the longitudinal immune response and time-to-event efficacy (BILITE), with a fraction of patients assumed to be cured by the treatment. The longitudinal immune response is modeled using hierarchical nonlinear mixed-effects models with possibly different trajectory patterns for the cured and susceptible groups. Conditional on the immune response trajectory, the time-to-event efficacy data for patients in the susceptible group is modeled via a time-dependent Cox-type regression model. We quantify the desirability of the treatment using a utility function and propose a two-stage design to adaptively randomize patients to treatments and make treatment recommendations at the end of the trial. Simulation studies show that compared with a conventional design that ignores the immune response, BILITE yields superior operating characteristics in terms of the ability to identify promising agents and terminate the trial early for futility.     

A BCG success story: From prevention of tuberculosis to optimal bladder cancer treatment

BCG remains the most important vaccine for tuberculosis 100 years after its first use, and over the past 4 decades it has become the most widely accepted, effective drug used in the treatment of aggressive localized bladder cancer. This review chronicles the narrow path that led to approval and world-wide acceptance of BCG immunotherapy for bladder cancer while immunotherapy trials in other malignancies were abandoned. Six intravesical instillations of 5x10^8 CFU of BCG weekly after bladder tumor resection, first reported in 1976, is superior to resection alone and resection plus intravesical chemotherapy. Maintenance of effective immune stimulation is surprisingly difficult, but 3 weekly treatments 3, 6, and 12, 18, 24, 30 and 36 months after induction produces further significant reduction in tumor recurrence. This 3 week BCG maintenance schedule alone has reduced disease progression and mortality in multicenter randomized clinical trials. In the new age of immuno-oncology patients with many types of cancer now benefit from immunotherapy, but currently these modern agents are prohibitively expensive for most of the world. In contrast, the low cost and therefore low profitability of BCG has resulted in recurrent shortages that threaten both bladder cancer patients and children at risk for tuberculosis and other serious infections. Humanity has greatly benefited from early 20th century science that developed BCG and the benevolence of doctors Calmette and Guerin who put people over profit and widely shared cultures of the vaccine. The 21st century is bringing new immunotherapies and greatly expanding the types of malignancies that can be treated. Recombinant technology is expected to improve both the efficacy and production of BCG, hopefully expanding the availability of BCG and relieving the recurring supply shortage for both vaccination and cancer therapy.     

Designing therapeutic cancer vaccine trials with delayed treatment effect

Arming the immune system against cancer has emerged as a powerful tool in oncology during recent years. Instead of poisoning a tumor or destroying it with radiation, therapeutic cancer vaccine, a type of cancer immunotherapy, unleashes the immune system to combat cancer. This indirect mechanism‐of‐action of vaccines poses the possibility of a delayed onset of clinical effect, which results in a delayed separation of survival curves between the experimental and control groups in therapeutic cancer vaccine trials with time‐to‐event endpoints. This violates the proportional hazard assumption. As a result, the conventional study design based on the regular log‐rank test ignoring the delayed effect would lead to a loss of power. In this paper, we propose two innovative approaches for sample size and power calculation using the piecewise weighted log‐rank test to properly and efficiently incorporate the delayed effect into the study design. Both theoretical derivations and empirical studies demonstrate that the proposed methods, accounting for the delayed effect, can reduce sample size dramatically while achieving the target power relative to a standard practice. Copyright © 2016 John Wiley & Sons, Ltd.     

中国国家出生队列母婴肠道微生物亚队列研究

肠道微生物对人类健康的重要性逐渐被人们关注。动物模型揭示了孕期母体微生物通过对子代微生物、代谢和免疫发育的作用影响了子代健康结局。然而,人体生理机制更为复杂,并受到多种暴露因素的交互影响,在动物模型中得到的研究结果往往与人群研究不一致。目前,孕期母体肠道微生物对子代微生物定植和健康的影响尚不明确。在大型前瞻性出生队列的...     

CD4+ T-cell activation for immunotherapy of malignancies using Ii-Key/MHC class II epitope hybrid vaccines

Active immunotherapy is becoming a reality in the treatment of malignancies. Peptide-based vaccines represent a simple, safe, and economic basis for cancer immunotherapeutics development. However, therapeutic efficacy has been disappointing. Some of the reasons for this, such as selection of patients with advanced disease and ignorance of the delayed activity of many immunotherapeutic vaccines, have hampered the entire field of cancer immunotherapy over the last decade. Another reason for this may be that most peptide regimens historically have focused on activation of CD8+ cytotoxic T lymphocytes, having little or only indirect CD4+ T helper (Th) cell activation. We review here evidence for the importance of specific CD4+ Th activation in cancer immunotherapy and the use of Ii-Key technology to accomplish this. Ii-Key (LRMK), a portion of the MHC class II-associated invariant chain (Ii protein), facilitates the direct charging of peptide epitopes onto MHC class II molecules. Directly linking Ii-Key to MHC class II peptide epitopes greatly enhances their potency in activating CD4+ T-cells. The Ii-Key hybrid AE37, generated by linking LRMK to the known HER2 MHC class II epitope HER2 (aa 776-790), has been shown to generate robust, long lasting HER2-specific immune responses both in patients with breast and prostate cancer. Interim data from a phase II study of AE37 in breast cancer patients suggest a possible improvement in clinical outcome. The Ii-Key hybrid technology is compared to other methods for enhancing the potency of peptide immunotherapy for cancer.     

Virus-associated immunopathology: animal models and implications for human disease. 2. Cell-mediated immunity, autoimmune diseases, genetics, and implications for clinical research

Part 2 of this memorandum describes further mechanisms whereby the interaction of a virus with the host''s immune system may lead to tissue damage. Cell-mediated immunity plays a vital role in promoting recovery from virus infections, but under some circumstances tissue damage may be caused by the reaction of immune cells with viral antigens. When mice are infected with lymphocytic choriomeningitis virus neonatally or as adults while receiving immunosuppressive drugs, widespread invasion of cells is seen but there is little overt disease. If, however, normal adults are infected or if immune cells are transfused into tolerant mice, cell injury and death follow. Viruses have long been suspected of contributing to the pathogenesis of autoimmune diseases. Antibodies directed against normal cell constituents have been reported in several virus infections. Viruses may conceivably unmask or release host antigens, alter host antigens and act as “helper determinants”, or perhaps in other ways provoke immune responses against normal body constituents. The immunopathological manifestations caused by viruses may also be influenced by the host''s genetic makeup. Certain observations indicate that, in addition to controlling susceptibility to virus infection, genetic factors partly determine the effectiveness of the immune response. The memorandum calls attention to the possible implications of these concepts and findings for clinical research. Some of the diseases of animals and man that serve as models for studies of virus-associated immunopathology are briefly described.     

肝细胞癌免疫治疗的研究进展

肝细胞癌(HCC)是最常见的消化道恶性肿瘤之一,严重威胁人类健康和寿命。HCC致病因素较多,目前主要治疗方法包括手术切除、动脉化疗栓塞等。但由于发病早期临床表现不典型,临床症状不明显,且影像学检查不易发现,易造成病情延误,确诊时病情多为中晚期,错过手术治疗的最佳时机,只能接受姑息治疗,治疗后复发率及转移率高,导致患者的临床预后不良。近年来随着对肿瘤免疫治疗研究的不断深入,肿瘤免疫治疗受到越来越多的关注,其通过调节人体特异性免疫应答反应,提高免疫系统的自我调节能力,进而实现提高肿瘤治愈率,延长患者生存期的目的。本文主要就免疫检查点抑制剂治疗、过继免疫细胞治疗和肿瘤疫苗等对HCC的免疫疗法研究进展进行综述。     

Immunology of Chagas' disease

After reviewing present knowledge of the morphology, multiplication, and transmission of Trypanosoma cruzi, this Memorandum discusses the animal models that may be of value in understanding the immune mechanisms operating in Chagas'' disease. The role of both circulating antibody and cell-mediated immunity in protection against the parasite is discussed, together with the possibility that immunopathological mechanisms may be responsible for some of the lesions found in patients with Chagas'' disease. The immunodiagnostic methods at present available are also reviewed, and the possibility of producing a vaccine for human use is considered in the light of recent findings in experimental animals. A series of recommendations for further research is included.     

Immunotherapy for advanced gastric cancer

Gastric cancer (GC) is believed to be the fifth most common cancer and the third most common cause of death worldwide. Treatment techniques include radiation, chemotherapy, gastrectomy, and targeted treatments are often employed. Some hopeful results from the development of GC immunotherapy have already changed treatment approaches. Along with previous combination medicines, new immunotherapies have been developed that target distinct molecules. Despite ongoing studies into the current therapeutic options and significant improvements in this field, the prognosis for the ailment is poor. Since there are few treatment options and a delay in detection, the illness actually advances, spreads, and metastasizes. The bulk of immunotherapies in use today rely on cytotoxic immune cells, monoclonal antibodies, and gene-transferred vaccines. Immune checkpoint inhibitors have become more popular. In this review, we sought to examine the viewpoint and development of several immunotherapy treatment modalities for advanced GC, as well as the clinical results thus far reported. Additionally, we outlined tumor immune escape and tumor immunosurveillance.     

Creatine in T Cell Antitumor Immunity and Cancer Immunotherapy

Creatine is a broadly used dietary supplement that has been extensively studied for its benefit on the musculoskeletal system. Yet, there is limited knowledge regarding the metabolic regulation of creatine in cells beyond the muscle. New insights concerning various regulatory functions for creatine in other physiological systems are developing. Here, we highlight the latest advances in understanding creatine regulation of T cell antitumor immunity, a topic that has previously gained little attention in the creatine research field. Creatine has been identified as an important metabolic regulator conserving bioenergy to power CD8 T cell antitumor reactivity in a tumor microenvironment; creatine supplementation has been shown to enhance antitumor T cell immunity in multiple preclinical mouse tumor models and, importantly, to synergize with other cancer immunotherapy modalities, such as the PD-1/PD-L1 blockade therapy, to improve antitumor efficacy. The potential application of creatine supplementation for cancer immunotherapy and the relevant considerations are discussed.     

Gut Microbiota Modulation in the Context of Immune-Related Aspects of Lactobacillus spp. and Bifidobacterium spp. in Gastrointestinal Cancers

Accumulating evidence has revealed the critical roles of commensal microbes in cancer progression and recently several investigators have evaluated the therapeutic effectiveness of targeting the microbiota. This gut microbiota-related approach is especially attractive in the treatment of gastrointestinal cancers. Probiotics supplementation is a microbiota-targeted strategy that appears to improve treatment efficacy; Lactobacillus spp. and Bifidobacterium spp. are among the most commonly used probiotic agents. These bacteria seem to exert immunomodulatory effects, impacting on the immune system both locally and systemically. The gut microbiota are able to affect the efficiency of immunotherapy, mainly acting as inhibitors at immune checkpoints. The effects of immunotherapy may be modulated using traditional probiotic strains and/or next generation probiotics, such as Akkermansia municiphila. It is possible that probiotics might enhance the efficiency of immunotherapy based on PD-1/PD-L1 and CTLA-4 but more data are needed to confirm this speculation. Indeed, although there is experimental evidence for the efficacy of several strains, the health-promoting effects of numerous probiotics have not been demonstrated in human patients and furthermore the potential risks of these products, particularly in oncologic patients, are rarely mentioned.     

An areawide cancer reporting network.

A cancer Surveillance Program was formed in 1970 to provide a mechanism for the early identification of some 22,000 cancer cases that are diagnosed annually among the large and varied population of Los Angeles County. The program''s rapid reporting procedures facilitate early access to patients for interviewing and specimen collection. Routine review of all reports of microscopically diagnosed malignancies in hospitals throughout the county and screening of all of the county''s death certificates provide virtually complete data on cancer incidence in the county. Case reports include information on age, ethnic group, birthplace, residence, religion, marital status, occupation, and industry. Continuing analysis of this information has led to the development of epidemiologic studies of several factors which may have an etiological relationship to human cancer. Among these factors are genetic susceptibility, exposure to air pollutants and industrial carcinogens and possible viral transmission.     

Development of sipuleucel-T: autologous cellular immunotherapy for the treatment of metastatic castrate resistant prostate cancer

Sipuleucel-T, the first autologous cellular immunotherapy approved by the United States Food and Drug Administration, is designed to stimulate an immune response to prostate cancer. Sipuleucel-T is manufactured by culturing a patient's peripheral blood mononuclear cells, including autologous antigen presenting cells (APCs), with a recombinant protein comprising a tumor-associated antigen (prostatic acid phosphatase [PAP]) and granulocyte colony-macrophage stimulating factor (GM-CSF). A full course of treatment comprises 3 infusions of sipuleucel-T, given at approximately 2-week intervals. The pattern of APC activation is consistent with priming by the first infusion, and boosting by the second and third infusions. Preclinical and clinical studies have demonstrated evidence of a robust antigen-specific immune response that includes a progressive and persistent increase in antigen-specific cellular and humoral immune responses. Treatment with sipuleucel-T has demonstrated a survival benefit in Phase 3 studies of subjects with metastatic castrate resistant (hormone refractory) prostate cancer (mCRPC). Adverse events with sipuleucel-T were generally mild to moderate and resolved within 2 days. Serious adverse events, autoimmune events, and cerebrovascular events occurred at a similar rate to control subjects. As the first autologous cellular immunotherapy to demonstrate an improvement in overall survival in asymptomatic or minimally symptomatic mCRPC patients, sipuleucel-T represents a new treatment paradigm in oncology.     

宫颈癌的免疫治疗进展

随着免疫学与分子生物学的发展 ,宫颈癌的免疫治疗研究也迅速进展 ,免疫治疗从多个方面进行 ,包括人乳头瘤病毒疫苗 ,树突状细胞免疫治疗 ,表面CD的单克隆抗体治疗等 ,该文就此作一简要综述     

Antibody response and plasma Aβ1-40 levels in young Microcebus murinus primates immunized with Aβ1-42 and its derivatives

We have been developing Aβ derivative vaccines with the objective to improve the safety of Aβ targeting immunotherapy. Our Aβ homologs are designed to have less direct toxicity and to produce a modified immune response compared to Aβ. In extensive mouse studies, all our vaccines have improved cognition in transgenic mice while eliciting different immune responses and reducing brain amyloid burden to a variable degree. While we are continuing to characterize these vaccines in mice, in preparation for studies in old primates and for human trials we assessed their effect in young lemur primates (n = 25) that with age develop Aβ plaques and tau aggregates as seen in Alzheimer's disease.     

Bone marrow vaccination: a novel approach to enhance antigen specific antitumor immunity

Bone marrow (BM) serves as a reservoir for a unique population of memory T cells with strong effector properties that make them ideal targets for cancer immunotherapy strategies. However, direct vaccination and priming of T cells within the BM of the host has never been investigated. This study evaluates the specific immune response induced via a new method of direct intra-bone marrow (IBM) vaccination in an animal model of human papillomavirus-associated cancer. We found that IBM vaccinations with the class I HPV-16 E7 epitope induce large numbers of activated, IFN-γ-producing E7-specific lymphocytes in the BM. In prophylactic tumor challenge experiments, direct intra-BM vaccination was found to be protective against tumor formation for 80% of the mice. In the therapeutic setting, IBM vaccination induced tumor regression in 3 of 10 vaccinated mice and delayed tumor growth in the remaining animals. Finally, adoptive transfer of BM cells from IBM vaccinated mice to naïve animals conferred complete protection against tumor growth. These data demonstrate the capacity of direct IBM vaccination to induce potent antigen-specific immunity resulting in protection from tumor growth in an animal model. Specifically targeting BM T cells with vaccines may improve responses to cancer immunotherapy and offer important clinical advantages, especially in the setting of bone marrow malignancies.     

HLA class I antigen loss,tumor immune escape and immune selection

Poor clinical response rates have been observed in the majority of the T cell-based immunotherapy clinical trials conducted to date. One reason might be the presence of abnormalities in HLA class I antigen presentation in malignant lesions. An increased frequency of HLA class I abnormalities has been observed in malignant lesions from patients treated with T cell-based immunotherapy and in lesions which have recurred in patients who had experienced clinical responses following T cell-based immunotherapy. These observations are compatible with the possibility that the outgrowth of a patient's tumor reflects immune selection of tumor cells which have acquired escape mechanisms from immune recognition.     

树突状细胞疫苗在宫颈癌治疗中的研究进展

树突状细胞是至今发现的功能最强的专职抗原提呈细胞 ,人们能通过各种刺激提高其抗原提呈能力和诱导T细胞应答能力 ,本文简单介绍了树突状细胞疫苗在宫颈癌的免疫治疗方面的新进展。