CAR-T细胞治疗多发性骨髓瘤：问题及对策

多发性骨髓瘤是骨髓中浆细胞异常增生导致的恶性肿瘤,是第二大常见的血液系统恶性肿瘤。日益增多的生物治疗 方法为多发性骨髓瘤治疗提供新的思路和方向,CAR-T细胞疗法更是为复发/难治性多发性骨髓瘤患者带来治愈新希望。已有 多种靶向多发性骨髓瘤特异性靶标分子CAR-T细胞在临床试验中显示出较好的疗效,然而CAR-T细胞疗法仍存在疗效持续时 间不够长、肿瘤易复发等问题,这可能与CAR-T细胞持续性不足、肿瘤细胞表面抗原表达丢失、抗原逃逸、免疫抑制微环境损害T 细胞活性等因素相关。已有临床研究通过优化CAR设计、调整制备过程以产生富含特定T细胞亚群的CAR-T细胞、构建健康志 愿者来源的通用型CAR-T细胞、引入修饰基因以调节免疫抑制微环境或改善CAR-T细胞增殖能力等方法来提高CAR-T细胞的 效应功能并延长其持续作用时间,通过降低CAR结构中抗体免疫原性、引入开关机制等方法来提高CAR-T细胞疗法安全性。众 多研究为多发性骨髓瘤的CAR-T细胞治疗注入新的活力,也为抗肿瘤免疫治疗提供新的方法与选择。     

BCMA CAR-T细胞治疗的耐药机制及优化策略研究

嵌合抗原受体T细胞（chimeric antigen receptor T cells,CAR-T）疗法在血液系统肿瘤治疗中已展示出卓越成效。BCMA抗原在骨髓瘤细胞表面普遍表达,是合适高效的CAR-T治疗靶抗原。尤其是对于复发/难治性多发性骨髓瘤患者,BCMA CAR-T细胞治疗缓解率高,多数患者在输注1年后仍可在体内检测到CAR-T细胞。但是耐药与疾病复发仍是目前临床管理中面对的关键问题。本文将从多发性骨髓瘤细胞免疫逃逸、CAR-T产品因素、既往治疗方案及肿瘤免疫微环境的抑制等几个方面来探讨BCMA CAR-T细胞疗法的应答响应因素及耐药诱导机制,并提出可能的优化策略,以期为未来探索提供参考意义。     

CAR-T细胞治疗的神经毒性副反应处理新策略

[摘要] 嵌合型抗原受体修饰T (chimeric antigen receptor modified T,CAR-T)细胞疗法是肿瘤免疫治疗的重要手段之一,CAR-T细胞的靶向性、杀伤活性、增殖性和持久性较常规T细胞明显提高,并且经过不断的改进演变,其在血液系统肿瘤治疗中取得了巨大的成效,受到广泛的关注。然而,其治疗过程中出现的神经毒性,也称CAR-T细胞相关脑病综合征(CAR-T cell relevant encephalopathy syndrome,CRES),影响了CAR-T疗法的临床应用。探索CRES的发病机制及其高风险因素、寻找相应的处理策略,对预防和治疗CRES具有重要意义。本文以CD19-CAR-T 细胞治疗为例,就CRES的发病症状、发病机制、高风险因素及应对策略作一综述,为临床治疗提供参考。     

乳腺癌过继性细胞免疫治疗的研究进展

目前国际上取得重大进展的四类过继性细胞免疫治疗（ACT）技术主要包括肿瘤浸润淋巴细胞（TIL）、CAR-T细胞、 TCR-T细胞和CAR-NK细胞治疗。乳腺癌相关研究结果表明,TIL能预测乳腺癌的预后,间质TIL增加与良好的预后相关;CAR-T 细胞免疫治疗在血液系统肿瘤治疗中取得巨大突破后,现已用于靶向实体肿瘤治疗,并在乳腺癌的治疗中开展了多种靶点的临 床试验;TCR-T细胞疗法依赖于MHC,可以识别MHC分子呈递的任何抗原,具有更广泛的靶抗原,在治疗实体瘤方面更有前景, 多项乳腺癌TCR-T细胞治疗临床试验正在进行中;CAR-NK细胞治疗是通过借鉴CAR-T细胞的结构而设计的,具有出色的抗肿 瘤能力,比CAR-T细胞疗法更安全,可能将为肿瘤免疫治疗带来新的更大发展。ACT在乳腺癌的研究和临床应用领域仍具挑 战,其中TIL疗法难以产生足量的特异性T细胞,CAR-T和CAR-NK细胞疗法均不同程度存在细胞的持久性、快速归巢到肿瘤 床、毒性和转导效率等问题。尽管存在不足,但随着基因工程、肿瘤免疫学和分子生物学等多学科的迅速发展,相信ACT技术有 望为乳腺癌患者治疗带来新的希望。     

嵌合抗原受体T细胞治疗胰腺癌的现状及未来策略

嵌合抗原受体（chimeric antigen receptor,CAR）T细胞作为肿瘤免疫治疗领域的新兴疗法在B细胞系血液系统肿瘤中已经获得了较为满意的疗效,因此,CAR-T细胞疗法也被列为包括胰腺癌在内的实体肿瘤治疗的新探索方向。尽管实体瘤本身的异质性、微环境的复杂性导致单纯的CAR-T细胞治疗效果不尽如人意,但随着新技术的开发,CAR结构的优化,各种免疫佐剂的联合应用使CAR-T细胞疗法值得进一步研究。该文就CAR-T细胞疗法的特点、治疗胰腺癌的现状及未来方向进行概述。     

CAR-T细胞治疗实体瘤的现存挑战及优化策略

近年来,嵌合抗原受体T细胞（chimeric antigen receptor T-cell,CAR-T）疗法在血液肿瘤治疗中取得了突破性进展。然而,由于实体瘤异于血液肿瘤的特性,CAR-T在实体瘤治疗中并未取得很好的疗效。限制CAR-T疗效的关键因素主要包括实体瘤细胞本身及其特殊的肿瘤微环境（tumor microenvironment,TME）两方面,在CAR-T向肿瘤组织部位浸润、CAR-T在TME中维持抗肿瘤活性以及CAR-T对肿瘤细胞的靶向性识别杀伤等多个过程中损害CAR-T功能。为了解决这些问题,越来越多的临床前研究提出了潜在有效的解决办法,相应的临床研究也相继开展。本文将对CAR-T细胞治疗实体瘤的现存挑战及相应的优化策略进行综述,以期为CAR-T疗法的未来探索提供参考。      

嵌合抗原受体T细胞联合免疫检查点抑制剂治疗恶性肿瘤的研究进展

近年来,嵌合抗原受体T细胞（chimeric antigen receptor T-cell,CAR-T）治疗在恶性肿瘤治疗中取得了较多成果,尤其在血液肿瘤治疗方面有所突破,实体瘤治疗研究前景较为广阔,有望成为更多复发难治性肿瘤患者的选择。免疫检查点抑制剂疗法在肿瘤治疗中同样具有疗效,如肝癌、难治性霍奇金淋巴瘤等多种恶性肿瘤,为晚期肿瘤患者带来了希望。但是上述两种治疗方法均存在不同程度的局限性。CAR-T联合免疫检查点抑制剂会削弱肿瘤微环境的免疫抑制作用,提高CAR-T治疗的有效率,延长生存期。本文旨在对CAR-T细胞和免疫检查点抑制剂治疗及二者联合应用的研究进展予以综述。      

CAR-T细胞治疗肿瘤后复发的机制

嵌合抗原受体基因修饰T淋巴细胞（chimeric antigen receptor gene modified-T lymphocytes,CAR-T）疗法是主要应用于血液肿瘤和多种实体瘤的一种治疗方法。尽管其临床疗效良好,有巨大的应用潜力和发展前景,但接受CAR-T细胞治疗后获得缓解的大部分患者病情会再次复发。近年来,随着CAR-T细胞疗法的不断探索,探明了越来越多的复发机制,主要为CAR-T细胞体内持久性有限,靶抗原丢失和调变等。本文结合近年来发表文献对CAR-T细胞治疗后复发的机制进行详解,并从CAR设计、T细胞亚型选择、CAR-T细胞制备、CAR-T细胞质控以及CAR-T细胞应用全链条的关注和管理对其应对策略进行总结。     

CAR-T免疫疗法所致细胞因子释放和神经毒性综合征的诊疗研究进展

嵌合抗原受体基因修饰T淋巴细胞（CAR-T）免疫治疗尤其在复发/难治性恶性血液病的临床应用中显示出卓越的疗 效,被认为是最有前景的肿瘤治疗方法之一,但是 CAR-T 免疫治疗中可引发独特的毒性作用,其中细胞因子释放综合征 （cytokine release syndrome,CRS）和免疫效应细胞相关神经毒性综合征（immune effector cell-associated neurotoxicity syndrome, ICANS）在临床应用中最为常见,并具有潜在的致死性,使得CRA-T疗法的广泛应用受到一定的限制,因此如何最大程度地利用 CAR-T免疫治疗的同时努力减少或预防CRS和ICANS的发生是目前临床研究的重点,深入了解CRS和ICANS的发生机制能为 新的预防措施提供思路。早期识别相关危险因素及鉴定生物预测标志物,熟悉其分级与治疗措施,有利于规范CAR-T免疫疗法 的临床应用和患者安全管理。本文就CRS和ICANS的危险因素、发生机制、临床表现、分级与治疗和预防措施等方面进行综述, 旨在为CAR-T疗法常见毒性作用的规范管理提供帮助。     

CAR-T细胞肿瘤治疗中若干问题的思考

［摘要］嵌合型抗原受体修饰T（chimeric antigen receptor modified T,CAR-T）细胞疗法在血液恶性肿瘤患者（尤其是CD19 阳性患者）中取得了较好的临床效果,被认为是近几年肿瘤治疗的重大进步,引起了研究者对开发CAR-T细胞治疗肿瘤的强烈兴趣。但是CAR-T细胞肿瘤治疗过程中也存在一些问题,如部分患者由于需要等待较长的CAR-T细胞培养时间,从而失去治疗机会;CAR-T细胞治疗过程中一些特有的不良反应甚至危及患者生命,CAR-T细胞治疗对实体瘤的疗效不尽人意,即使是对血液恶性肿瘤来说部分患者也终究会复发导致治疗失败;因此探索提高CAR-T细胞疗效的方法、及时发现CAR-T细胞治疗的不良反应并给予适当处理、扩大CAR-T细胞治疗的可能获益人群是目前CAR-T细胞治疗研究需要解决的问题。本文对目前CAR-T细胞治疗存在的一些问题进行归纳,包括通用型CAR-T细胞的前景、双靶点CAR-T细胞和CAR-T细胞在血液肿瘤治疗中的地位及作用、提高CAR-T细胞治疗疗效的策略以及CAR-T细胞特有的不良反应等进行阐述,为CAR-T细胞肿瘤治疗的基础研究和临床应用提供借鉴。     

Surgical approach to generalized lymphadenopathy in homosexual men

Sixty patients considered at risk for acquired immune deficiency syndrome (AIDS) were referred for evaluation of generalized lymphadenopathy. All patients were seropositive for antibody to human T-lymphotropic virus type III (HTLV-III). Multiple lymph node biopsies from different nodal areas were performed. The results were evaluated in order to see if the diagnostic yield is increased by the performance of multiple lymph node biopsies. In no case was additional diagnostic information provided by performing multiple biopsies. In patients with diffuse lymphadenopathy who are at risk for AIDS, single node excisional biopsy is indicated to rule out opportunistic infection or/and tumor.     

Adult onset hemophagocytic lymphohistiocytosis prognosis is affected by underlying disease and coexisting viral infection: analysis of a single institution series of 35 patients

Adult onset hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome, which can develop as a complication of many disorders. Early diagnosis is essential in order to avoid a fatal outcome. To confirm the diagnosis of acquired HLH made in a single institution series of adult patients with HLH‐04 criteria, we applied the HScore and evaluated prognostic factors associated with clinical outcome. The median age of 35 patients was 54 (range 17–81), M/F ratio was 20/15. In 26/35 (74.3%) patients, an underlying haematological disease was present (2 Multicentric Castleman Disease, 10 B‐cell Non‐Hodgkin Lymphoma [NHL] and 14 T/NK‐cell NHL); an autoimmune disorder was observed in four (11.4%) patients (one Still Disease, one undifferentiated connective tissue disease and two haemolytic anaemia); in five (14.3%), no underlying disease was identified. A concomitant infection by EBV was observed in 10 patients (28.6%), CMV in 8 (22.9%), HHV8 in 6 (17.1%) and HIV in 1 (2.9%). Hyperferritinemia, fever and splenomegaly were present in more than 90% of patients, whereas bone marrow hemophagocytosis in 51% of cases only. According to HScore, 34/35 patients had a >75% and 32/35 >93% probability of HLH. Four‐year overall survival and HLH‐free survival were 17.8% (CI 1.9–33.8) and 23.8% (CI 7.3–40.3), respectively. By multivariate analysis, presence of oedema and hyperbilirubinemia were predictors of death, whereas there was a statistically significant trend for viral infection as predictor of poor prognosis. B‐NHL diagnosis was confirmed as associated to a better prognosis in comparison with T/NK lymphoma (4‐year HFS 53.3% vs. 0%, p = 0.09) and similar to other aetiologies. Copyright © 2016 John Wiley & Sons, Ltd.     

Immune reconstitution inflammatory syndrome in cancer patients with pulmonary aspergillosis recovering from neutropenia: Proof of principle, description, and clinical and research implications

BACKGROUND: Assessing the outcome of patients with invasive pulmonary aspergillosis by using conventional criteria is difficult, particularly when clinical and radiologic worsening coincides with neutrophil recovery. Usually, it is assumed that this deterioration is related to progressive aspergillosis, prompting changes in patient management. However, its temporal relation with neutrophil recovery suggests that it may be caused by an immune reconstitution syndrome (IRIS). Galactomannan is an Aspergillus-specific polysaccharide that is released during aspergillosis and is detected by the serum galactomannan test, which has been approved by the United States Food and Drug Administration for the diagnosis of invasive aspergillosis. In this study, the authors used sequential galactomannan testing to distinguish IRIS responses from progressive aspergillosis. METHODS: From April 2001 to December 2006, patients with hematologic malignancies underwent galactomannan screening during periods when they were at risk. The clinical and laboratory findings from patients who had >or=2 consecutive positive galactomannan assays (optical density, >or=0.5) were reviewed. RESULTS: Nineteen neutropenic patients with aspergillosis developed clinical and radiologic pulmonary deterioration during neutrophil recovery. Deterioration coincided with microbiologic response, as documented by rapid normalization of serum galactomannan, and, in 16 patients, was followed by complete clinical response and survival at 3 months, although there were no changes in antifungal therapy. The 3 patients who died during the first month had no evidence of aspergillosis at autopsy examination. CONCLUSIONS: The authors propose that IRIS was responsible for the current findings and provide a definition for the syndrome. They also recommend serial galactomannan testing to guide aspergillosis management. Declining galactomannan values imply IRIS with an aspergillus response and obviate the need for invasive procedures and alternative antifungal therapies, whereas persistent galactomannan elevation indicates progressive aspergillosis and requires prompt treatment modification.     

Invasive fungal infections among inpatients with acquired immune deficiency syndrome at a Chinese university hospital

Invasive fungal infections (IFIs) have become a major cause of morbidity and mortality among people with acquired immune deficiency syndrome (AIDS), however, little is known about the clinical features and prognosis of IFI in AIDS in China. This study aimed to characterise the clinical features and prognosis of IFI in AIDS patients in China. We retrospectively reviewed the records of all HIV-infected patients at a Chinese university hospital between December 2004 and May 2006. We identified 35 patients with IFI. IFIs included thrush, oesophageal candidiasis, fungal pneumonia, cryptococcosis, penicilliosis and fungaemia, 44.4% of IFIs occurred in the digestive tract, 71.8% of IFIs occurred in patients with CD4(+)T-lymphocyte counts <100 cells mm(-3). Candida albicans accounted for 57.4% of fungal pathogens isolated. All the patients received both antiretroviral and antifungal therapy; 27 patients were cured and eight died. IFI is one of the most common opportunistic infections in AIDS patients in China. IFIs mainly occur in patients with low CD4(+)T-lymphocyte counts. The majority of IFIs occur in the digestive tract. The most common pathogen causing IFI is C. albicans. The mortality rate remains high although antiretroviral therapy and many newer antifungals are available in China.     

Cervical cancer in patients infected with the human immunodeficiency virus

BACKGROUND: The objective of this study was to compare the human immunodeficiency virus (HIV) viral load (VL) and CD4 counts in patients infected with HIV with and without cervical cancer. The authors hypothesized that HIV-positive women with cervical cancer would have a greater risk of immune suppression. METHODS: A case-control study was conducted that included all HIV-positive patients who were seen at the authors' institution from January 1, 1995 to April 20, 2006 with invasive cervical cancer (cases) and without invasive cervical cancer (controls). Patients were included only if they had a CD4 count recorded<6 months before or<3 months after their diagnosis of invasive cervical cancer (cases) or at their last gynecologic examination (controls). Controls were matched to cases on a 4:1 ratio according to current smoking history. Patients were considered immunocompetent if they had both a CD4 count>200 cells/microL and a VL<10,000 copies/mL. RESULTS: In total, 15 cases and 60 controls were identified. The median CD4 count for cases was 208 cells/microL (range, 18-1102 cells/microL) compared with 445 cells/microL (range, 20-1201 cells/microL) for controls (P=.03). The median VL was 16,918 copies/mL (range, 50-214,915 copies/mL) for cases compared with 1430 copies/mL (range, 50-571,000 copies/mL) for controls (P=.15). Only 1 of 14 cases (7%) was immunocompetent compared with 35 of 55 controls (64%; odds ratio, 0.04; 95% confidence interval, 0-0.37; P<.001). This significance was maintained after adjusting for other factors (P=.002). CONCLUSIONS: Women with HIV who were diagnosed with invasive cervical cancer appeared to have a much greater degree of immunosuppression than women with HIV without invasive cervical cancer.     

Is HLA type a possible cancer risk modifier in Lynch syndrome?

Lynch syndrome (LS) is the most common inherited cancer syndrome. It is inherited via a monoallelic germline variant in one of the DNA mismatch repair (MMR) genes. LS carriers have a broad 30% to 80% risk of developing various malignancies, and more precise, individual risk estimations would be of high clinical value, allowing tailored cancer prevention and surveillance. Due to MMR deficiency, LS cancers are characterized by the accumulation of frameshift mutations leading to highly immunogenic frameshift peptides (FSPs). Thus, immune surveillance is proposed to inhibit the outgrowth of MMR-deficient cell clones. Recent studies have shown that immunoediting during the evolution of MMR-deficient cancers leads to a counter-selection of highly immunogenic antigens. The immunogenicity of FSPs is dependent on the antigen presentation. One crucial factor determining antigen presentation is the HLA genotype. Hence, a LS carrier's HLA genotype plays an important role in the presentation of FSP antigens to the immune system, and may influence the likelihood of progression from precancerous lesions to cancer. To address the challenge of clarifying this possibility including diverse populations with different HLA types, we have established the INDICATE initiative (Individual cancer risk by HLA type, http://indicate-lynch.org/ ), an international network aiming at a systematic evaluation of the HLA genotype as a possible cancer risk modifier in LS. Here we summarize the current knowledge on the role of HLA type in cancer risk and outline future research directions to delineate possible association in the scenario of LS with genetically defined risk population and highly immunogenic tumors.     

免疫检查点抑制剂相关胆管型肝毒性发生机制及治疗策略

肿瘤免疫检查点抑制剂（ICI）治疗近年来因疗效显著而备受瞩目。ICI引起的免疫介导肝毒性（IMH）是一类较常见的免疫相关不良反应（irAE）,但IMH中的一种亚分型,胆管型IMH(BIMH),却是一种少见的、对其认知极不充分、缺乏诊疗规范的irAE,存在临床隐患。BIMH以胆管酶显著升高、高胆红素血症为临床特点,组织病理学表现为胆管炎症、胆管损伤和消失。胆汁淤积阶段的BIMH对于免疫抑制治疗反应不佳,预后差。提高对BIMH的认识,早期诊断和干预是提高BIMH预后的关键。对BIMH流行病学特征、临床特征、组织病理学特点和发生机制及BIMH全程管理中存在之问题等认识的不断提高,有助于提出针对BIMH的有效诊疗策略。     

New insights into hepatosplenic candidosis, a manifestation of chronic disseminated candidosis

Chronic disseminated candidosis, often referred to as hepatosplenic candidosis (HSC), is an infection due to Candida spp. that mainly involves the liver and spleen. HSC occurs mostly in patients after profound and prolonged neutropenia, which is more often seen in patients with acute haematological malignancies. The incidence of HSC ranges from 3% to 29% in patients suffering from Acute Leukaemia. However, it is now seen less frequently with the widespread use of antifungal agents as prophylaxis or as preemptive therapy. Early and adequate diagnosis and treatment of HSC are crucial, as treatment delays can negatively affect the prognosis of the underlying condition. The pathogenesis is not well understood, but it is believed that it may be due to an unbalanced adaptive immune response that leads to an exacerbated inflammatory reaction, resulting in an Immune Reconstitution Inflammatory Syndrome. In this context, new therapeutic approaches such as the use of adjuvant high-dose corticosteroids have been shown beneficial. This article will focus on the clinical, diagnostic and therapeutic aspects of HSC and provide an accurate review of recent pathophysiological data.