过继免疫治疗中DC-CIK的研究进展

目前,免疫细胞生物学和免疫分子生物学发展迅猛,由于其具备低毒性和高效率的特性,肿瘤免疫治疗在恶性肿瘤治疗中所起的作用引起了学者们的广泛关注,其中细胞介导的过继免疫治疗为当前研究的热点之一。过继免疫治疗(adoptive cellular immunotherapy,ACI)是目前恶性肿瘤治疗的新方向,它通过向细胞免疫功能低下者回输具有抗肿瘤活性的免疫细胞,直接杀伤或间接杀伤肿瘤细胞,使其获得抗肿瘤免疫力。树突状细胞(Dendritic cell DC)是专职抗原递呈细胞(antigen presenting cell APC)之一,在机体免疫应答的启始、调节、维持中发挥核心作用。细胞因子诱导的杀伤(cytokine induced killer CIK)细胞具有高效的MHC非限制性溶瘤活性,具有极其广泛的杀瘤范围。近年来,国内外大量研究表明,联合培养的DC-CIK抗肿瘤活性提升明显,患者预后生存期延长,效果显著。本文就DC与CIK生物学特点及抗肿瘤作用予以简要综述。     

基于核酸适配体的肿瘤免疫治疗进展

肿瘤免疫治疗是通过调节机体的免疫功能来控制和杀伤肿瘤的一种治疗手段。针对免疫检查点的治疗等一系列临床突破使得肿瘤的免疫治疗受到了广泛重视。目前,抗体治疗和过继性细胞治疗是肿瘤免疫治疗的主要方式,但是这些方法仍具有副作用较强,实体瘤治疗难以实现,治疗费用高昂等缺点。因此改进和发展更加高效、安全、低成本的新技术仍十分必要。适配体是利用指数富集的配体系统进化技术筛选得到的单链寡核苷酸,有核酸"抗体"之称。适配体具有低免疫原性、组织穿透力强、易于化学合成与修饰等优势,且与其靶标的结合具有较好亲和力和特异性,可像抗体一样实现肿瘤的免疫治疗。对适配体在肿瘤免疫治疗相关技术中的新应用作一综述,主要包括基于免疫检查点的抗肿瘤作用、双特异性适配体的肿瘤免疫治疗、适配体靶向递送siRNA的肿瘤免疫治疗和适配体联合抗体的肿瘤免疫治疗等方面。     

肿瘤浸润淋巴细胞在实体肿瘤中作用的研究进展

肿瘤是21世纪威胁人类健康的主要疾患之一。临床上,实体瘤治疗仍以手术切除、放化疗和靶向治疗为主,但这些方法往往不能根除肿瘤病灶,易导致肿瘤复发和进展。肿瘤免疫治疗是利用人体的免疫系统,通过增强或恢复抗肿瘤免疫力实现控制和杀伤肿瘤的一种新的治疗模式。肿瘤免疫治疗能够在众多患者中产生持久反应,过继性免疫治疗和免疫检查点阻断剂治疗均可产生显著的抗原特异性免疫反应。肿瘤浸润淋巴细胞(TILs)是一种存在于肿瘤组织内部具有高度异质性的淋巴细胞,在宿主抗原特异性肿瘤免疫应答中发挥关键作用。最新研究表明,在肿瘤发生和治疗过程中,TILs的亚群组成和数量与患者预后密切相关;抗肿瘤的TILs介导的过继性免疫治疗方法已在多种实体瘤中取得了良好的疗效。文中就实体肿瘤中TILs的研究进展作一综述。     

脐血CIK细胞抗肿瘤研究及临床应用进展

肿瘤的生物治疗尤其是用免疫活性细胞输注的过继免疫治疗是目前研究热点之一,是继手术、放疗、化疗三大常规治疗的又一新的治疗肿瘤的方法。此疗法不仅是常规抗肿瘤治疗的补充,更是为晚期不宜手术或无法承受放疗化疗所带来的副作用的患者开辟了一个新的治疗途径,可取得常规方法无法达到的疗效,成为人类抗击肿瘤最有希望的战略措施之一。细胞因子诱导的杀伤细胞是用于肿瘤过继免疫治疗较为有效的免疫效应细胞之一,是目前所知杀伤活性最高的肿瘤杀伤细胞,具有增殖速度快、杀瘤活性高、杀瘤谱广的特点,对正常骨髓造血前体毒性小,已大量应用于临床。脐血CIK细胞增殖速度、杀瘤活性优于外周血CIK细胞,移植后移植物抗宿主病发生率更低等优点,因而受到广泛关注。本文就脐血CIK细胞的抗肿瘤研究的特点及临床应用进展作一综述。     

脐血CIK细胞抗肿瘤研究及临床应用进展

肿瘤的生物治疗尤其是用免疫活性细胞输注的过继免疫治疗是目前研究热点之一,是继手术、放疗、化疗三大常规治疗的又一新的治疗肿瘤的方法。此疗法不仅是常规抗肿瘤治疗的补充,更是为晚期不宜手术或无法承受放疗化疗所带来的副作用的患者开辟了一个新的治疗途径,可取得常规方法无法达到的疗效,成为人类抗击肿瘤最有希望的战略措施之一。细胞因子诱导的杀伤细胞是用于肿瘤过继免疫治疗较为有效的免疫效应细胞之一,是目前所知杀伤活性最高的肿瘤杀伤细胞,具有增殖速度快、杀瘤活性高、杀瘤谱广的特点,对正常骨髓造血前体毒性小,已大量应用于临床。脐血CIK细胞增殖速度、杀瘤活性优于外周血CIK细胞,移植后移植物抗宿主病发生率更低等优点,因而受到广泛关注。本文就脐血CIK细胞的抗肿瘤研究的特点及,临床应用进展作一综述。     

嵌合抗原受体T细胞对B细胞淋巴瘤的作用研究

过继性免疫治疗(adoptive cellular immunotherapy,ACI)是将供体的淋巴细胞转移给受体,增强其细胞免疫功能。这种治疗是目前较为有效的恶性肿瘤的治疗方法之一,已在实体瘤和血液肿瘤的临床治疗中取得较好疗效。近年来发展的嵌合抗原受体(chimeric antigen receptor,CAR)T细胞是利用基因技术改造得来的,它表达肿瘤特异性,并显示出靶向性、杀伤活性和持久性,这为过继性细胞免疫治疗注入了新的解决方案。CAR发展到现在共经历过三代改进,前人也就每代CAR进行了大量临床试验,得出对临床治疗具有现实意义的实验结果。本文就CAR技术对B细胞淋巴瘤的作用影响作一综述。     

鼻咽癌的免疫与靶向治疗

鼻咽癌的发生与EB病毒(Epstein-Barr virus,EBV)密切相关,当前临床主要运用单纯放疗或同步放化疗对鼻咽癌开展治疗。虽然该方法对放化疗敏感的患者有效,但是局部晚期或远处转移的鼻咽癌患者预后仍然不佳。随着近年来免疫治疗和分子靶向治疗的发展,过继性细胞疗法、免疫检查点以及多分子靶向治疗逐渐成为鼻咽癌临床治疗的研究热点。本文就鼻咽癌的免疫治疗和靶向治疗两方面展开综述,以期为鼻咽癌治疗手段和药物的发展提供一定依据。     

IL-15扩增的OT-Ⅰ细胞持续抑制小鼠黑色素瘤生长

过继免疫治疗(adoptive cell transfer,ACT)是肿瘤治疗中一种有效的免疫治疗手段,但是在没有化疗或者放疗等辅助治疗手段时,过继免疫治疗缓解肿瘤生长的效果非常短暂.为了探索一种更为有效的过继免疫治疗手段,我们使用白介素15(IL-15)体外扩增OT-ⅠCD8 T细胞,使其分化成为中央记忆性T细胞(central memory T cells,TCM),并将其过继转移至携带B16-OVA肿瘤的小鼠中.我们发现,与IL-2体外扩增的CD8 T细胞(effector T cells,TEFF)相比,TCM对肿瘤的生长具有长时间的缓解作用,而IL-2分化的TEFFs治疗肿瘤在短暂的缓解后反弹性生长.进一步的研究发现,TCM治疗的小鼠脾脏内肿瘤抗原特异性的T细胞数量和比例明显高于TEFF组,并且RT-PCR分析表明TCM治疗的小鼠肿瘤内细胞高表达MHCⅠ类分子.这些现象提示了抗原提呈对过继细胞转移治疗的效果具有重要作用.我们的研究对于发展更为有效的肿瘤免疫治疗具有提示意义.     

树突状细胞的靶向抗肿瘤治疗进

树突状细胞(dendritic cell,DC)是目前已知体内最强的抗原提呈细胞(ARC),其在肿瘤免疫中具有重要的作用.DC的靶向抗肿瘤治疗成为当今肿瘤免疫治疗的研究热点.本文就DC的抗肿瘤机制、DC基因修饰策略及DC疫苗的临床治疗进展进行综述.     

DC-CIK治疗大肠癌的研究进展

大肠癌是消化道常见的恶性肿瘤之一,发病率和死亡率均较高。过继免疫治疗是当今肿瘤治疗的热点,已逐步成为一些肿瘤的首选治疗方法。树突状细胞(DC)是目前已知功能最强大的抗原呈递细胞,具有呈递肿瘤抗原和抵制肿瘤细胞免疫逃逸及刺激T淋巴细胞产生免疫应答的作用。细胞因子诱导的杀伤细胞(CIK)由多种细胞因子诱导而成,具有T淋巴细胞及NK细胞抗肿瘤作用的特点。DC和CIK细胞有效结合可以同时促进DC细胞的增殖和免疫功能及加强CIK细胞的抗肿瘤作用。本文就近年来国内外应用DC-CIK治疗大肠癌的研究进展进行综述。     

卵巢癌生物治疗的现状与进展

由于卵巢癌的早期临床症状较不明显,大部分患者就诊时就处于晚期阶段,这对其有效治疗造成了很大困难,使其成为妇科病死率最高的恶性肿瘤,一直广受关注。但目前传统的手术与放化疗方法的治疗效果不佳。近年来随着基础研究工作的不断发展与深入,生物治疗作为新的肿瘤治疗方法引起了人们的重视。生物治疗作为第四种卵巢癌的治疗模式,其采取的针对不同靶位点和靶途径的策略很大程度上促进了卵巢癌治疗的理论和实践研究。生物治疗主要是运用基因治疗、免疫治疗和重组病毒治疗的方法对患者进行治疗,基因治疗包括细胞毒性或自杀基因治疗、纠错性基因治疗、免疫增强性基因治疗和抗肿瘤血管生成基因治疗等。而免疫治疗又分为主动和被动免疫治疗,前者包括树突状细胞疫苗、自体肿瘤疫苗和分子疫苗治疗等,后者如细胞因子治疗、单克隆抗体拮抗治疗以及细胞过继免疫治疗等。上述目前在卵巢癌治疗研究中已取得了一些成果,本文就其卵巢癌的生物治疗现状与进展做一综述。     

非小细胞肺癌的免疫治疗进展

肺癌是最致命的恶性肿瘤之一,也是男性肿瘤患者致死率最高的,5年生存率低于18%。尽管非小细胞肺癌(non-small cell lung cancer,NSCLC)在手术治疗、化疗、放疗以及靶向治疗方面均取得了一定的成果,但晚期NSCLC的预后依然很差。免疫治疗为NSCLC患者提供了一个新的治疗方向。免疫治疗目前主要研究方向在免疫检查点抑制剂(Ipilimumab、Nivolumab、MK-3475)和肿瘤疫苗(MAGE-A3,L-BLP25,TG4010,Belagenpumatucel-L)等。免疫治疗具有针对性强、副作用少、效率高的特点,并在Ⅱ、Ⅲ期临床试验中取得了较好的疗效,成为在手术、化疗、放疗以及靶向治疗后一种新的重要治疗手段。本文就当前非小细胞肺癌免疫治疗原理、临床试验及待解决问题作一综述。     

Adoptive cell therapy of prostate cancer using female mice-derived T cells that react with prostate antigens

In this study, we report a novel treatment strategy that could potentially be used to improve efficacy of adoptive cell therapy for patients with prostate cancer. We show that female C57BL/6 mice are able to effectively reject two syngeneic prostate tumors (TRAMP-C2 and RM1) in a T cell-dependent manner. The protective antitumor immunity appears to primarily involve T cell responses reactive against general prostate tumor/tissue antigens, rather than simply to male-specific H-Y antigen. For the first time we show that adoptive transfer of lymphocytes from TRAMP-C2-primed or naïve female mice effectively control prostate tumor growth in male mice, when combined with host pre-conditioning (i.e., non-myeloablative lymphodepletion) and IL-2 administration. No pathological autoimmune response was observed in the treated tumor-bearing male mice. Our studies provide new insights regarding the immune-mediated recognition of male-specific tissue, such as the prostate, and may offer new immunotherapy treatment strategies for advanced prostate cancer.     

Effect of adoptive T-cell immunotherapy on immunological parameters and prognosis in patients with advanced pancreatic cancer

Background aimsImmunotherapy is effective for many types of cancer, but its benefits in advanced pancreatic cancer, which has a poor prognosis, are not well established. In this study, the authors examined the effects of adoptive T-cell immunotherapy (ATI) on immune cell profiles and prognosis in patients with unresectable advanced pancreatic cancer.MethodsSeventy-seven patients with unresectable advanced pancreatic cancer were treated with six cycles of αβ T cells alone or in combination with chemotherapy or chemoradiation. Immune cell profiles in peripheral blood samples obtained before and after treatment were comprehensively evaluated by flow cytometry. Furthermore, associations between changes in immune cell frequencies and prognosis were determined.ResultsATI prolonged survival to 18.7 months compared with previous estimates of 6.2–11.1 months for patients treated with chemotherapy alone. ATI decreased CD3+CD4+CD8? T cell frequency in peripheral blood and increased CD3+CD4?CD8+ T cell frequency. An increase in CD3+ T cells and CD3+TCRγδ? T cells in peripheral blood after treatment was associated with a good prognosis.ConclusionsATI altered the immune profile in peripheral blood, including CD3+CD4?CD8+ T cells, and improved prognosis in pancreatic cancer.     

Detection of oligoclonal T lymphocytes in lymph nodes draining from advanced non-small-cell lung cancer

Despite the combined use of surgery and chemoradiotherapy, the poor prognosis of advanced non-smallcell lung cancer (NSCLC) requires the definition of new therapeutic approaches. The presence of T lymphocytes, with peculiar phenotypic, functional and molecular characteristics within the tumour, suggested the possible use of these cells, expanded in vitro, in protocols of adoptive immunotherapy. We have described how a population of oligoclonal T lymphocytes, derived from advanced NSCLC, can be expanded in vitro and has the capability of lysing autologous cancer cells. What is more important, we observed that patients with advanced NSCLC, treated with TIL expanded in vitro and recombinant interleukin-2, seemed to have a disease-free period longer than that of patients treated with conventional chemoradiotherapy. in an attempt to find new sources of specific lymphocytes for immunotherapy, we describe the analysis of the phenotypic, functional and molecular characteristics of T lymphocytes, derived from lymph nodes draining advanced NSCLC. In this paper we show that these cells, have restriction patterns of T cell receptor chain similar to those detectable in the population of infiltrating T lymphocytes. This finding suggests that T cells derived from draining lymph nodes of advanced NSCLC have peculiar characteristics and can be a suitable source of effector cells for protocols of adoptive immunotherapy in lung cancer treatment.     

Lymphokine-activated killer cell adoptive immunotherapy for cancer treatment and its significance]

New culture system, CDCS-T1, was developed for clinical conduction of lymphokine-activated killer (LAK) cell adoptive immunotherapy (AIT). Advanced or recurrent cancer patients of digestive tract were treated with AIT with LAK cells generated by CDCS-T1 in combination with plasma exchange. Partial responses were shown in 10 to 20% of patients treated. Long survival was found in some responders, indicating the significance of LAK therapy for cancer treatment. AIT with LAK cell transfer was also conducted in patients with esophageal cancer as postoperative adjuvant therapy. Better restoration of postoperative depression of immunological parameters was found in patients with postoperative LAK cell transfer. It is suggested that postoperative LAK cell transfer is a good candidate for adjuvant immunotherapy for cancer treatment.     

IL-12 enhances efficacy and shortens enrichment time in cytokine-induced killer cell immunotherapy

Cytokine-induced killer (CIK) cells are T cell derived ex vivo expanded cells with both NK and T cell properties. They exhibit potent anti-tumor efficacy against various malignancies in preclinical models and have proven safe and effective in clinical studies. We combined CIK cell adoptive immunotherapy with IL-12 cytokine immunotherapy in an immunocompetent preclinical breast cancer model. Combining CIK cells with IL-12 increased anti-tumor efficacy in vivo compared to either therapy alone. Combination led to full tumor remission and long-term protection in 75% of animals. IL-12 treatment sharply increased the anti-tumor efficacy of short-term cultured CIK cells that exhibited no therapeutic effect alone. Bioluminescence imaging based in vitro cytotoxicity and in vivo homing assays revealed that short-term cultured CIK cells exhibit full cytotoxicity in vitro, but display different tumor homing properties than fully expanded CIK cells in vivo. Our data suggest that short-term cultured CIK cells can be “educated” in vivo, producing fully expanded CIK cells upon IL-12 administration with anti-tumor efficacy in a mouse model. Our findings demonstrate the potential to improve current CIK cell-based immunotherapy by increasing efficacy and shortening ex vivo expansion time. This holds promise for a highly efficacious cancer therapy utilizing synergistic effects of cytokine and cellular immunotherapy.     

Neoadjuvant PD-1 blockade plus chemotherapy versus chemotherapy alone in locally advanced stage II-III gastric cancer: A single-centre retrospective study

BackgroundPD-1 blockade has been shown to have promising efficacy and acceptable safety profiles in advanced and metastatic gastric cancer; however, the efficacy and safety of neoadjuvant PD-1 blockade-based immunotherapy plus chemotherapy in locally advanced gastric cancer (LAGC) remain uncertain.MethodsWe performed a retrospective review of patients with LAGC who received neoadjuvant treatment followed by D2 radical resection at the Affiliated Hospital of Qingdao University from 2019 to 2021. The primary aim was to investigate the difference in pathological response rates between neoadjuvant PD-1 immunotherapy plus chemotherapy and neoadjuvant chemotherapy alone. Multivariable models for pathological complete response (pCR) were constructed to investigate the factors that facilitate pCR. Trial registration: QYFYWZLL27406.ResultsA total of 77 patients were included in the analysis, among whom 34 (44.2%) received neoadjuvant PD-1 blockade immunotherapy plus chemotherapy. A higher pCR rate was observed in the neoadjuvant PD-1 blockade immunotherapy plus chemotherapy group (8 of 34, 23.5% vs. 2 of 43, 4.7%, P=0.019). Multivariate logistic regression analysis of pCR revealed neoadjuvant PD-1 blockade plus chemotherapy regimen promoted pCR (OR 12.95, P=0.016). Regarding safety, 76.5% (26 of 34) of patients in the PD-1 blockade plus chemotherapy group and 76.7% (33 of 43) of patients in the chemotherapy group experienced treatment-related adverse events (TRAEs), and grade 3 or worse adverse events were 29.4% (10 of 34) and 34.9% (15 of 43), respectively.ConclusionNeoadjuvant PD-1 blockade plus chemotherapy induced a higher pCR rate than neoadjuvant chemotherapy, and the combined therapy was tolerable in LAGC patients.     

Ex vivo activation and expansion of natural killer cells from patients with advanced cancer with feeder cells from healthy volunteers

Background aimsCulturing natural killer (NK) cells from patients with advanced cancer is difficult and has restricted the generation of sufficient cell numbers for autologous adoptive NK-cell therapy. The aim of this study was to establish a novel method for ex vivo NK-cell expansion from patients with cancer.MethodsNK cells (CD3^?CD56⁺) were isolated from peripheral blood mononuclear cells from healthy volunteers and cancer patients, and NK^? fractions were used as feeder cells. Purified NK cells were co-cultured with feeder cells in AIM-V medium (Invitrogen, Carlsbad, CA, USA) supplemented with 5% human serum and 1000 units/mL human interleukin-2.ResultsNK cells co-cultured with feeder cells from healthy volunteers (feeder-HV) expanded more than NK cells co-cultured with feeder cells from cancer patients (feeder-CP). During the 14-day culture period, NK cells from patients with advanced cancer co-cultivated with feeder-HV expanded on average 300-fold. NK cells co-cultivated with feeder-CP expanded on average 169.4-fold. Cultures grown in the presence of feeder-HV contained 93.8 ± 7.0% (mean ± standard deviation; n = 6) CD3^?CD56⁺ NK cells, and cultures grown in the presence of feeder-CP contained 83.6 ± 15.9% CD3^?CD56⁺ NK cells. Feeder-HV caused a relative increase in CD3⁺CD4⁺ T cells, whereas feeder-CP did not induce changes. Interleukin-15, a cytokine that induces NK-cell proliferation, was detected in the culture supernatants of feeder-HV but not in those of feeder-CP.ConclusionsFeeder cells obtained from healthy volunteers have the potential to expand and activate NK cells from patients with advanced cancer. The novel NK-cell expansion method described here provides a technique for acquiring the large numbers of highly active NK cells from patients with cancer for autologous adoptive immunotherapy.     

Immunotherapy of cancer: promise and reality

The notion that the immune system regulates cancer development is now well established. An overwhelming amount of data from animal models, together with compelling data from human patients, indicate that the immune system is instrumental in scanning and irradicating tumors. Analysis of individuals with congenital or acquired immunodeficiencies or patients undergoing immunosuppressive therapy has documented a highly elevated incidence of virally induced malignancies and cancers compared with immunocompetent individuals [1-3]. During the last decade, thanks to the breakthoughts in understanding the molecular mechanisms responsible for immune activation, the tumor antigen identification, the dendritic cell biology, the immunogenecity of tumors, the immune escape mechanisms, the host-tumor relationship, we are facing a new area of tumor immunotherapy. The basic advances were translated in therapeutical applications and have changed the view of immunotherapy from "a dream scenario" to a clinical fourth modality to cancer treatments. Multiple cancer trials using active immunization with vaccines or adoptive immunotherapy have been conducted with only very limited success. There are still a number of issues that still need to be resolved including a better understanding of immune escape mechanisms. Cancer vaccines continue to be evaluated and may lead to the emergence of clinically useful new treatments. A comprehensive approach to define the intricate molecular program initiated by tumor cells to resist to escape and the immune system of the host may help in breaking down the barriers to a more adapted cancer immunotherapy.