多发性骨髓瘤的嵌合抗原受体T细胞治疗研究进展

多发性骨髓瘤(MM)是一种浆细胞恶性肿瘤,目前仍无法治愈。嵌合抗原受体T细胞(CAR-T)疗法是一种前景乐观的MM治疗方法,其作用机制与标准MM治疗方法完全不同。CAR是一种包含抗原识别域和T细胞信号域的融合蛋白,通过基因改造后表达CAR的T细胞可以特异性识别抗原。理想的CAR靶向抗原要求仅在恶性细胞上表达,而正常细胞缺失或少量表达。目前正在研究的作为CAR靶向的MM抗原包括B细胞成熟抗原、CD138、CD38、淋巴细胞激活信号分子7(SLAMF7)、κ轻链以及CD19等。MM基因和表型的异质性,使得对MM进行有效治疗的CAR-T需要靶向多个抗原;CAR-T联合其他骨髓瘤治疗也是未来研究的一个重要领域。MM的CAR-T疗法尚处于早期发展阶段,但有望改善MM的治疗。     

CAR-T的设计原理及其在卵巢癌治疗中的应用挑战

嵌合型抗原受体T细胞(CAR-T)是通过基因工程方法表达特定靶抗原抗体单链可变区(sc Fv)的T细胞。随着CAR-T在血液系统肿瘤治疗疗效的确定,实体肿瘤的研究者们也开始试用CAR-T治疗。然而,CAR-T在实体肿瘤中的治疗疗效远远低于预期。本文对CAR-T的设计原理做了简单的总结并讨论各种形式CAR-T及其优缺点。在此基础上,我们也讨论了CAR-T在实体肿瘤中疗效低的原因。最后,我们以卵巢癌为例对CAR-T研究存在的挑战做了前瞻性的预测。     

靶向B7-H3的CAR-T细胞在实体瘤免疫治疗的研究进展北大核心CSCD

近年,以嵌合抗原受体修饰T细胞(CAR-T)为代表的过继细胞免疫疗法在血液系统肿瘤中的治疗取得了突破性进展。然而对于实体瘤的治疗,CAR-T疗法仍面临着一系列挑战。肿瘤异质性、T细胞归巢效率低下、肿瘤免疫抑制性微环境和特异性抗原的缺乏是限制CAR-T在实体瘤中发挥作用的重要因素。B7-H3是B7免疫球蛋白超家族成员,在多种实体瘤中高表达,作为肿瘤免疫治疗的分子靶点受到广泛关注。本文总结了B7-H3的分子特点及其在肿瘤中的功能,并对以B7-H3为靶点的CAR-T疗法在实体瘤中的研究进展做一综述。     

嵌合抗原受体基因修饰的T细胞免疫治疗骨肉瘤的研究进展

骨肉瘤(OS)是一种常见骨恶性肿瘤。常规治疗方式对患者预后生存率有一定改善,但对已转移患者的作用十分有限。靶向骨肉瘤相关抗原的嵌合抗原受体基因修饰的T细胞(CAR-T)疗法是一种很有前景的治疗方式。包括靶向HER-2、IL-11Rα、ROR1和GD2等骨肉瘤相关抗原的特异性CAR-T治疗在一些基础和临床研究中均有报道,且已经表现出了对骨肉瘤良好的治疗效果。     

基于肿瘤微环境的CAR-T 细胞疗法研究现状

通过机体免疫系统发挥抗肿瘤作用是目前新型的癌症治疗方法。嵌合型抗原受体T细胞(CAR-T)疗法作为一种新的免疫疗法在血液系统肿瘤中已经取得良好的治疗效果。然而,由于实体瘤具有复杂的脉管系统和基质屏障,它们会显著影响T细胞迁移和功能。肿瘤微环境(TME)中表达的各种免疫抑制分子阻止T细胞活化,并且肿瘤的高代谢率竞争性地抑制了免疫细胞的代谢。目前,针对实体肿瘤,已经开展许多临床前研究和临床试验,包括优化CAR的结构,增强CAR-T细胞向实体瘤部位的运输,中和TME中的抑制性分子等。随着研究的深入,我们将进一步揭示CAR-T细胞治疗在实体瘤中的作用机理,以充分发挥CAR-T细胞在实体瘤中的作用。     

嵌合抗原受体T细胞与病毒相关的应用进展

嵌合抗原受体T细胞(chimeric antigen receptor T cell, CAR-T)疗法是近年来新兴的细胞免疫疗法，它通过基因工程技术使T细胞表达特异性嵌合抗原受体(chimeric antigen receptor, CAR),以非MHC依赖形式识别并杀伤表达相应抗原的靶细胞。CAR-T疗法在血液系统恶性肿瘤的治疗中取得了令人振奋的结果，但在实体瘤治疗领域仍然存在很多困难。溶瘤病毒可直接裂解实体瘤细胞，逆转肿瘤局部的免疫抑制微环境，与CAR-T疗法联用可以增强抗实体瘤效果。此外，CAR-T疗法也显示出一定的抗病毒作用，主要表现在抗人类免疫缺陷病毒(human immunodeficiency virus, HIV)、HBV等方面。文章从CAR-T与病毒的关系入手，主要就CAR-T疗法抗病毒的研究现状及溶瘤病毒与CAR-T疗法联合抗实体瘤机制等方面展开综述，以期为拓宽CAR-T抗病毒治疗领域以及CAR-T的联合治疗方案制定提供新思路。     

嵌合抗原受体基因修饰的T 细胞治疗实体瘤研究进展

靶向CD19的嵌合抗原受体(CAR)基因修饰的T细胞(CAR-T)在血液肿瘤治疗中取得了巨大成功。然而,迄今为止,由于特异性肿瘤抗原的缺乏、CAR-T细胞难浸润到肿瘤组织内部以及抑制性的肿瘤微环境等因素限制了CAR-T细胞对实体肿瘤的疗效。本文讨论与总结了在CAR-T细胞研究中针对实体瘤的靶点选择、增强免疫细胞向肿瘤迁移、克服肿瘤抑制微环境及联用免疫检查点阻断等新方法、新策略以增加CAR-T细胞对实体肿瘤的疗效,希望对临床前与临床CAR-T细胞治疗实体瘤研究提供新的思路与方向。     

CAR-T细胞疗法新靶点开发专利技术发展状况分析

<正>采用CAR-T细胞治疗,使一位当时年仅6岁险些被晚期白血病置于死地的患儿奇迹般地挣脱了死神的束缚,让更多的研发者看到了希望的曙光,CAR-T细胞治疗研究日趋白热化。CAR-T,即表达嵌合抗原受体(chimeric antigen receptor,CAR)修饰的T细胞。CAR由胞外抗原结合域(scFv)、跨膜结构域和胞内信号传导结构域组成。CAR-T细胞治疗技术,是指通过将上述CAR结构在体外进行基因重组得到     

嵌合抗原受体T(CAR-T)细胞在肿瘤治疗中的研究进展

嵌合抗原受体T(CAR-T)细胞疗法是肿瘤免疫疗法中的一种。该疗法主要原理是将癌症患者的T细胞经基因工程转化为体内表达嵌合肿瘤细胞表面抗原受体的CAR-T细胞,再将其回输到患者体内,使之特异性识别并杀伤肿瘤细胞,从而达到治疗的目的。通过不断且有效的临床试验, CAR-T细胞疗法现已被应用于临床治疗,且在淋巴造血系统恶性肿瘤的治疗中已有显著的成效,但其在实体瘤中的治疗效果并不理想。目前该疗法的难点主要在于如何减少甚至避免治疗过程中出现的包括细胞因子释放综合征和靶位缺失效应等在内的不良反应。对此,近几年业内对该疗法的改进主要集中于改善CAR-T细胞结构、寻找合适的靶点,与具有凋亡调节作用的检查点抑制剂结合使用等方法来提高该疗法的疗效及其安全性。     

实体瘤的嵌合抗原受体T(CAR-T)细胞治疗进展

基于嵌合抗原受体T(CAR-T)细胞的过继治疗成为治疗肿瘤的新策略,CAR-T细胞对肿瘤的杀伤作用无严格的主要组织相容性复合体(MHC)限制性,并且已在血液肿瘤的治疗中,取得了重大的进展。然而针对实体瘤的治疗中,CAR-T细胞疗法具有易脱靶性以及治疗效率低下的问题。合成生物学的迅猛发展极大的提高了CAR-T细胞设计者们的热情,我们围绕CAR-T细胞治疗实体瘤的掣肘现状、合成生物学武装的新型CAR-T细胞的前沿进展进行讨论;并详细介绍目前应用范围较广的几种实体瘤靶点的临床前研究以及临床试验情况。     

Mesothelin-targeted CAR-T cells for adoptive cell therapy of solid tumors

Significant progresses have been made in adoptive cell therapy with CAR-T cells for cancers, especially for hematological malignancies. However, the treatment of solid tumors still poses a tremendous challenge and remains an unmet medical need. Several factors are held responsible for the inadequate responses: tumor heterogeneity, inefficient homing of T cells to tumor tissues, immunosuppressive microenvironment and the shortage of specific antigens shortage. Mesothelin is a cell-surface glycoprotein highly expressed in many types of solid tumors. As such, it has attracted much attention as a molecular target in cancer immunotherapy. Here, we delineate the barriers imposed by solid tumors on CARs, outline the rationale of mesothelin as a target for immunotherapy, summarize the preclinical and clinical results of mesothelin-targeted therapies, and extrapolate the expected results of CAR-T cells directed against mesothelin for solid tumors.     

Cancer immunotherapy harnessing γδ T cells and programmed death-1

Cancer immunotherapy has received increasing attention since the success of CTLA-4 and programmed death-1 (PD-1) immune checkpoint inhibitors and CAR-T cells. One of the most promising next-generation cancer treatments is adoptive transfer of immune effector cells. Developing an efficacious adoptive transfer therapy requires growing large numbers of highly purified immune effector cells in a short period of time. γδ T cells can be effectively expanded using synthetic antigens such as pyrophosphomonoesters and nitrogen-containing bisphosphonates (N-BPs). Pyrophosphomonoester antigens, initially identified in mycobacterial extracts, were used for this purpose in the early years of the development of γδ T cell-based therapy. GMP-grade N-BPs, which are now commercially available, are used in many clinical trials worldwide. In order to develop N-BPs for cancer immunotherapy, N-BP prodrugs have been synthesized; among these, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA) is the most potent compound for stimulating γδ T cells. The activated γδ T cells express high levels of PD-1, suggesting the potential for a combination therapy harnessing γδ T cells and PD-1 immune checkpoint inhibitors. In addition, the functions of γδ T cells can be modified by IL-18. Collectively, the recent findings show that γδ T cells are one of the most promising immune effector subsets for the development of novel cancer immunotherapy.     

Synthesis of pyrophosphate-containing compounds that stimulate Vgamma2Vdelta2 T cells: application to cancer immunotherapy

Human Vgamma2Vdelta2 T cells recognize nonpeptide antigens, such as isoprenoid pyrophosphomonoester intermediates, alkylamine compounds, and bisphosphonate drugs, as well as some tumor cells. Although attempts have been made to derive novel cancer immunotherapies based on the discovery of these unconventional antigens, effective therapies remain to be developed. Here, we synthesized a series of pyrophosphate-containing compounds and examined the chemical requirements for the recognition of pyrophosphomonoester antigens by gammadelta T cells. The structural analysis clearly demonstrated that a proximal methylene moiety plays a crucial role in the stimulatory activity of the antigens. For optimal gammadelta T cell proliferation, we find that the use of human serum albumin was preferred and that pyrophosphomonoesters were superior to nitrogen-containing bisphosphonate compounds. Using these techniques, we have successfully expanded gammadelta T cells from healthy donors as well as from cancer patients using one of the most active compounds, 2-methyl-3-butenyl-1-pyrophosphate (2M3B1PP). The resulting expanded gammadelta T cells exhibited potent, cytotoxic activity against a wide variety of tumor cell lines. Even gammadelta T cells from a patient with advanced liver carcinoma efficiently responded to 2M3B1PP and exhibited strong cytotoxic activity against tumor cells. The pretreatment of tumor cells with nonpeptide antigens was essential for efficient cytotoxicity via TCR-gammadelta. The present study suggests a novel strategy for cancer immunotherapy using synthetic small pyrophosphate-containing compounds and nitrogen-containing bisphosphonates.     

Epitope- and antigen-specific cancer vaccines.

Anti-idiotypic antibodies (Ab2) that functionally mimic epitopes associated with human cancer cells are the most specific cancer vaccines currently available. Ab2 can induce specific humoral anti-tumor immunity in cancer patients. However, the potential of Ab2 for inducing cellular immunity in cancer patients still requires demonstration. Clonotypic antibodies directed against the combining site for tumor Ag on human T-cell clones may provide highly effective reagents for inducing protective T-cell immunity against human cancer. A new generation of cancer vaccines, molecularly cloned tumor-associated antigens (Ag), has recently been developed. Recombinant Ag have been successfully expressed in vectors allowing large scale production of Ag for immunization of cancer patients. Recombinant tumor Ag was shown to induce specific and protective immunity in experimental animals. In contrast to Ab2, which may mimic a single cancer-associated epitope, recombinant Ag express multiple epitopes that are potentially immunogenic. Ag vaccines, therefore, may be more effective in arresting tumor growth than single epitope (Ab2) vaccines because tumor destruction by antibodies is dependent on antibody density on tumor cell surfaces. In light of the important roles that both B and T cells play in the control of tumor growth, the demonstration of induction of specific B and T cell-immunity by recombinant tumor Ag and Ab2 in experimental animals is encouraging. Ultimately, the immunomodulatory role of both types of vaccines has to be compared in cancer patients who are immunologically tolerant to many Ag/epitopes expressed by their growing tumors. The development of both Ab2 and recombinant Ag for single antigenic systems provides the first step towards this goal.     

Human tumor antigens for cancer vaccine development

Summary: The adoptive transfer of tumor-infiltrating lymphocytes (TH.) along with interleukin (H.)-2 into autologous patients with cancer resulted in the objective regression of tumor, indicating that T cells play an important role in tumor regression. In the last few years, efforts have been made towards understanding the molecular basis of T-cell-mediated antitumor immunity and elucidating the molecular nature of tumor antigens recognized by T cells. Tumor antigens identified thus far could be classified into several catagories: tissue-specific differentiation antigens, tumor-specific shared antigens and tumor-specific unique antigens, CD4 T cells play a central role in orchestrating the host immune response against cancer, infections diseases, and autoimmune deseases, and we thus have attempted to identify major histocompatibility complex (MHC) class II-restricted tumor antigens as well. 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.     

Langerhans cell: CD1 antigens and the Birbeck granule

Langerhans cells are characterized by two types of markers: an ultrastructural marker, the Birbeck granule and different membrane markers: HLA-D antigens, T4 antigen, and some of the CD1 antigens. These antigens which are specific for the epidermal Langerhans cells, are not expressed by the other epidermal cells. Three CD1 antigens are biochemically defined on human thymocytes, they display a glycoprotein chain non covalently attached to beta-2-microglobulin. Only two of these glycoproteins: the T6 and M241 molecules have been detected on Langerhans cells. The presence of these CD1 antigens on Langerhans cells enhances their relationships to thymocytes, in contrast, Langerhans cells cannot be any more easily associated with the macrophage-monocyte lineage. The physiology of the ultrastructural marker is not well known. Its membrane origin has been experimentally proved since T6 antigen has been found closely associated to newly formed Birbeck granules.     

Early cancer detection by microsatellite marker analysis.

A major goal of tumor biology has been the development of tumor markers that are useful for the diagnosis and management of cancer. A drawback associated with many of these markers is that they are not unique to tumor cells, but rather are normal or developmental antigens which are overexpressed in tumor tissue Therefore, determination of possible malignancy is based on a designated expression level rather than a clear-cut difference. Studies have shown that DNA from tumor cells has a pattern of chromosomal deletion clearly distinguishable from normal cell DNA, and more importantly, DNA from tumor cells can be detected in the serum of cancer patients. Particular chromosomal deletion patterns are associated with specific tumor types. It is hypothesized that individuals at risk for certain genetically well-characterized cancers, could be successfully screened for those cancers by a PCR-based blood test. In this way, neoplasia could be detected at earlier, more treatable stages of development.     

Anti-tumor antibodies in ovarian cancer

Anti-tumor antibodies have potential as cancer biomarkers. There is relatively limited identification of anti-tumor antibodies in response to ovarian cancer, compared with studies for other cancers. There is also very limited information on the prevalence of anti-tumor antibodies among ovarian cancer patients. Although most anti-tumor antibodies react with antigens common to both tumor and normal tissue, the anti-tumor response tends to be confined to individuals with ovarian cancer, similar to other cancers. Antibodies to HOXA7, a differentiation antigen, have the highest reported prevalence in ovarian cancer (67%). Antibodies to other ubiquitous antigens including NY-ESO-1, Ep-CAM (epithelial cell adhesion molecule), HSP-90 (heat shock protein 90), and mutated p53 have been identified in ovarian cancer. Anti-tumor antibody specificity reflects the heterogeneity of antigen expression in tumors. Tests based on panels of a combination of anti-tumor antibodies may be more predictive for ovarian cancer, as no single specificity accounts for ovarian tumors. In addition to characterization of anti-tumor antibodies as diagnostic markers, study of anti-tumor antibodies is likely to provide insights into mechanisms of tumor development. There is evidence of antibodies to tumor antigens and of activated T cells, suggesting immune recognition of tumor antigens occurred. Nonetheless, as tumors are not 'rejected', it is likely that there are alterations in the immune system. The basis for tumor growth in the face of immune activity remains to be determined.     

Human tumor antigens: implications for cancer vaccine development

The adoptive transfer of tumor-infiltrating lymphocytes along with interleukin 2 into autologous patients resulted in the objective regression of tumor in about 30% of patients with melanoma, indicating that these T cells play a role in tumor rejection. To understand the molecular basis of the T cell-cancer cell interaction we and others started to search for tumor antigens expressed on cancer cells recognized by T cells. This led to the identification of several major histocompatibility complex (MHC) class I restricted tumor antigens. These tumor antigens have been classified into several categories: tissue-specific differentiation antigens, tumor-specific shared antigens, and tumor-specific unique antigens. Because CD4+ T cells play a central role in orchestrating the host immune response against cancer, infectious diseases, and autoimmune diseases, a novel genetic approach has recently been developed to identify these MHC class II restricted tumor antigens. The identification of both MHC class I and II restricted tumor antigens provides new opportunities for the development of therapeutic strategies against cancer. This review summarizes the current status of tumor antigens and their potential applications to cancer treatment.     

DNA fusion gene vaccines against cancer: from the laboratory to the clinic

Summary: Vaccination against target antigens expressed by cancer cells has now become a realistic goal. DNA vaccines provide a direct link between identification of genetic markers in tumors and vaccine formulation. Simplicity of manufacture facilitates construction of vaccines against disease subsets or even for individual patients. To engage an immune system that exists to fight pathogens, we have developed fusion gene vaccines encoding tumor antigens fused to pathogen‐derived sequences. This strategy activates high levels of T‐cell help, the key to induction and maintenance of effective immunity. We have dissected the immunogenic tetanus toxin to obtain specific sequences able to activate antibody, CD4⁺, or CD8⁺ T cells to attack selected fused tumor antigens. Principles established in preclinical models are now being tested in patients. So far, objective immune responses against idiotypic antigen of neoplastic B cells have been observed in patients with B‐cell malignancies and in normal transplant donors. These responses provide a platform for testing physical methods to improve DNA delivery and strategies to boost responses. For cancer, demands are high, because vaccines have to activate powerful immunity against weak antigens, often in a setting of immune damage or tolerance. Vaccination strategies against cancer and against microbes are sharing knowledge and technology for mutual benefit.