肿瘤浸润性淋巴细胞在白细胞介素-2、-4协同下局部过继免疫治疗膀胱癌的实验研究

目的　观察膀胱癌肿瘤浸润性淋巴细胞 (TIL)联合不同细胞因子瘤灶内过继免疫抗癌的效应及对机体全身抗肿瘤免疫机制的影响。方法　建立BTT73 9动物模型 ,分离、培养TIL。采用正交设计实验方法 ,将TIL、白细胞介素 (IL) 2、 4及三因素交互组合悬液分别直接注射至瘤体内 ,定期测量肿瘤体积 ,免疫治疗 2周后检测NK细胞活性、T淋巴细胞转刺激指数 ,观察组织学及超微结构变化。结果　比较对照组 ,治疗 2周时各TIL相关组均不同程度抑制了膀胱肿瘤体积的增长 ,且NK细胞活性及T淋巴细胞转化增殖能力得以提高 (P <0 .0 5 )。TIL/IL 2疗法明显抑制了瘤体的增长 ,免疫治疗 1周后即表现出协同增强效应 (P <0 .0 5 ) ,而NK细胞活性及T淋巴细胞转刺激指数也显著提高 (P <0 .0 5 )。TIL/IL 2 /IL 4组获得了较强的抗癌功效 ,但与TIL/IL 2组差异无显著性 (P >0 .0 5 )。超微结构变化显示出TIL强烈的溶癌现象。结论　TIL在细胞因子特别是IL 2协同下瘤灶内注射的局部免疫疗法 ,具有较强的抗膀胱癌效应 ,并显著提高了机体全身抗瘤免疫功能。     

Adjunctive intracameral application of corticosteroids in patients with endothelial immune reactions after penetrating keratoplasty: a pilot study

This study was performed to gain first experiences with a new adjunctive measure in the treatment of endothelial immune reactions after penetrating keratoplasty, i.e., intracameral injections of corticosteroids. In eight penetrating keratoplasty patients with mild endothelial immune reactions (IM1), 10 patients with moderate endothelial immune reactions (IM2) and 10 patients with severe endothelial immune reactions (IM3) intracameral injections of corticosteroids were performed within 24 h after referral to the clinic, following informed consent. All patients (IM1-3) received basic therapy of steroid eye drops and subconjunctival steroid injections; patients in group IM3 also received oral steroids. In IM1 patients eight of eight grafts, in IM2 eight of 10 grafts and in IM3 five of 10 grafts remained clear during a mean follow-up of 9.9 (1-20), 10.7 (3-17) and 9.6 (1-20) months after intraocular intervention. Only one of the 28 patients developed a further immune reaction during follow-up. No complications of intracameral injection were observed. Intracameral steroid injections thus seem to be a safe and helpful therapeutic measure in the treatment of moderate and severe endothelial immune reactions after penetrating keratoplasty. Further investigations in controlled randomized trials are necessary.     

Dendritic-cell- and peptide-based vaccination strategies for glioma

Despite advances in radiation and chemotherapy along with surgical resectioning, the prognosis of patients with malignant glioma is poor. Therefore, the development of a new treatment modality is extremely important. There are increasing reports demonstrating that systemic immunotherapy using dendritic cells and peptide is capable of inducing an antiglioma response. This review highlights dendritic-cell- and peptide-based immunotherapy for glioma patients. Dendritic-cell- and peptide-based immunotherapy strategies appear promising as an approach to successfully induce an antitumor immune response and increase survival in patients with glioma. Dendritic cell- and peptide-based therapy of glioma seems to be safe and without major side effects. There are several types of glioma; so to achieve effective therapy, it may be necessary to evaluate the molecular genetic abnormalities in individual patient tumors and design novel immunotherapeutic strategies based on the pharmacogenomic findings. Here, in this review, recent advances in dendritic-cell- and peptide-based immunotherapy approaches for patients with gliomas are discussed.     

中医药治疗骨肉瘤的研究进展

骨肉瘤是最常见的骨的原发恶性肿瘤,新辅助化疗联合保肢术、免疫治疗、分子靶向治疗、中医药等治疗为目前治疗骨肉瘤的主要方法,有效降低了骨肉瘤患者的致残率和致死率,但随着化疗的进展,患者的不良反应以及骨肉瘤细胞对化疗药物的耐药性成为临床治疗的现状,大量研究表明中医药具有控制病灶大小、防治骨肉瘤细胞远处转移、调节免疫功能紊乱、...     

Low-level laser reduces the production of TNF-α, IFN-γ, and IL-10 induced by OVA

Delayed, or type IV, hypersensitivity reactions are a useful model to study the effects of new substances on the immune system. In this study, the experimental model of the delayed type hypersensitivity (DTH) reaction to ovalbumin (OVA) was used to evaluate the immunomodulating effects of low-level laser therapy (LLLT), which is used as an adjuvant therapy in medicine, dentistry, and physical therapy because of its potential anti-inflammatory and analgesic effects observed in several studies. The effects of LLLT (λ 780 nm, 0.06 W/cm² of radiation, and fluency of 3.8 J/cm²) in reaction to ovalbumin in Balb/C mice were examined after the induction phase of the hypersensitivity reaction. The animals treated with azathioprine (AZA), the animals that received a vehicle instead of ovalbumin, and those not immunized served as controls (n?=?6 for each group). Footpad thickness measurements and hematoxylin–eosin histopathological exams were performed. Proliferation tests were also performed (spontaneous, in the presence of concanavalin A and ovalbumin) to determine the production in mononuclear cells cultures of tumor necrosis factor-alpha (TNF-α), INF-γ, and IL-10. In the group of animals irradiated with lasers and in the group treated with AZA, footpad thickness measurements were significantly reduced in comparison to the control group (p?<?0.05). This reduction was accompanied by a very significant reduction in the density of the inflammatory infiltrate and by a significant reduction in the levels of TNF-α, INF-γ, and IL-10. LLLT radiation was shown to have an immunomodulating effect on DTH to OVA in Balb/C mice.     

Rationale for immunotherapy of renal cell carcinoma

Summary Metastasis to distant organs is the principal cause of death from renal cell carcinoma (RCC). No commonly accepted therapy is available for disseminated RCC at present. Immunotherapy is a mode of therapy that either interferes with the immune system or makes use of drugs that have been derived from soluble mediators of the immune system. Several lines of evidence suggest that combinations of genetically engineered cytokines (e.g. interleukin-2 and interferon alpha) may be particularly active in the treatment of advanced RCC. There are two major rationales for considering immunotherapy for RCC: (1) there is currently no other therapy available, and (2) there is hardly any innovative approach besides immunotherapy. Still, immunotherapy is far from being a standard therapy for disseminated RCC.     

Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Metastatic Cancer Post Solid Organ Transplantation: A Case Report and Review of the Literature

Immunotherapy is expanding its role in cancer therapy, and in various tumor types it has now become the frontline treatment. Though generally better tolerated than traditional chemotherapy, its mechanism of activating the immune system results in a unique set of adverse reactions that maybe disastrous in the setting of post solid organ transplantation. We herein describe a case report of a patient who was post–renal transplant, developed metastatic, relapsed, refractory renal cell carcinoma, and was successfully treated with nivolumab for 6 cycles while maintaining renal graft function. We also reviewed the published case reports of immunotherapy administered in the post–renal transplantation setting.     

微波消融的抗肿瘤免疫效应及其机制研究进展

微波消融作为一种微创治疗技术,不仅通过高温直接灭活肿瘤,还能诱导产生特异性抗肿瘤免疫,成为杀灭肿瘤细胞的新途径.联合免疫治疗可以进一步增强微波消融的抗肿瘤免疫反应,对肿瘤原发灶和转移灶均能产生更强的抑制作用,从而降低肿瘤的复发转移.因此,联合微波消融与免疫治疗为实体肿瘤特别是进展期肿瘤的治疗提供了新思路.本文将就微波消融免疫效应的机制和应用的研究进展进行综述.     

Cancer treatment: what's ahead?

Surgery, chemotherapy, and radiation therapy are standard modalities for cancer treatment. Biological therapy (immunotherapy, biotherapy, or biological response modifier therapy) is a comparatively novel addition to this armamentarium. Biological therapies use the body's immune system, either directly or indirectly, to fight cancer or to lessen the side effects that may be caused by some cancer treatments. Biological therapeutic agents include interferons, interleukins, colony-stimulating factors, monoclonal antibodies, vaccines, gene therapy, and nonspecific immunomodulating agents. A promising form of cancer treatment is immunotherapy. Immunotherapy for cancer is essentially the stimulation of the immune system through a variety of reagents such as vaccines, infusion of T-cells, or cytokines. These reagents act through one of several mechanisms including stimulating the anti-tumor response, decreasing suppressor mechanisms, altering tumor cells to increase their immunogenicity and making them more susceptible to immunologic defenses, and improving tolerance to cytotoxic agents or radiotherapy. This review describes some novel approaches in the immunotherapy in cancer.     

Immunotherapy for glioma: promises and challenges

Novel immunotherapeutic modalities are being pursed in the treatment of high-grade gliomas. This article explains how tumors suppress immune function in the brain. It specifically describes the ways in which tumors limit effective communication with immune cells, secrete immune-inhibitory cytokines and molecules, and express molecules that induce apoptosis of immune cells. It also defines 3 different immunotherapeutic approaches to counteract this tumor-associated immunosuppression: cytokine therapy, passive immunotherapy (either serotherapy or adoptive immunotherapy), and active immunotherapy. Although immunotherapeutic approaches have met with mixed success so far, immunotherapy continues to be actively pursued because of its potential to attack infiltrating high-grade gliomas.     

胆管癌的免疫治疗进展

胆管癌是恶性程度高、预后差的实体肿瘤,手术切除仍然是主要治疗手段。靶向以及免疫治疗是近年来逐渐受到重视的抗肿瘤手段,尤其是免疫治疗。胆管癌的肿瘤微环境复杂,除了间质和内皮细胞外,还包括大量免疫细胞,天然和适应性免疫系统也发挥作用。本文总结了胆管癌的免疫相关研究以及最新的免疫治疗临床试验。     

免疫细胞过继转移治疗体系的建立及其在进展期胃癌围手术期的应用

近年来,对于胃肠道肿瘤的免疫治疗发展迅速．目前临床已经将其作为一种辅助疗法与手术、化疗、放疗联合应用,以提高肿瘤综合治疗的效果。免疫细胞过继转移治疗是对于进展期胃癌免疫治疗的一个重要方法．本文综述了其在进展期胃癌围手术期的应用．并结合自身经验及临床实验观察结果．提出对于进展期胃癌综合治疗的绿色治疗新模式。     

Immune status and immune therapy of renal cell carcinoma

At present, no sufficient therapy for metastatic renal cell carcinoma is available. Several immunotherapeutical protocols have been studied, success rates, however, were inconsistent. The purpose of this study was to assess the pretherapeutic immunological status of 13 patients with metastatic and 16 patients with nonmetastatic renal cell carcinoma and of 15 healthy volunteers. Determined were differential blood counts, lymphocyte subpopulations, beta 2-microglobulin, tumor necrosis factor (TNF), neopterin, immunoglobulin, fibronectin and ferritin. Additionally, these parameters were recorded for monitoring an immunotherapeutical approach with the xenogeneic biological response modifier Keyhole limpet hemocyanine (KLH) in 10 patients with metastatic and in 5 patients with nonmetastatic disease. The pretherapeutic immunological status of patients with metastatic disease was characterized by significantly reduced T4-, T8- and B-cell counts. Significantly increased were granulocyte counts, beta 2-microglobulin, neopterin and TNF. In patients who did not suffer from metastases, only beta 2-microglobulin and neopterin were increased significantly. During immunotherapy, in patients with metastases, there was a decline of lymphocyte subsets and of the T4/T8-ratio, which correlated with progress of the disease. Humoral immune parameters showed no changes compared to pretherapeutic values. In patients who did not suffer from metastases, cellular immune parameters showed stable values during immunotherapy; neopterin, beta 2-microglobulin and TNF increased considerably. These findings indicate immunosuppression in patients with metastatic renal cell carcinoma, increasing with progression of the disease and possibly impairing the immunostimulating effects of biological response modifiers during immunotherapy. In conclusion, the clinical response of metastatic renal cell carcinoma to immunotherapy might be improved if the immunostimulant is combined with agents suitable to overcome immunosuppression, i.e. low doses of cyclophosphamide or inhibitors of prostaglandin synthesis. In addition, assessment of immune parameters for monitoring the actual immune status of a patient and the immunological effects of therapy was found to be a necessary part of immunotherapy.     

Immunotherapy Following Regional Chemotherapy Treatment of Advanced Extremity Melanoma

Purpose

Following regional chemotherapy (RC) for melanoma, approximately 75 % of patients will progress. The role of immunotherapy after RC has not been well established.

Methods

A prospective, single-institution database of 243 patients with in-transit melanoma (1995–2013) was queried for patients who had progression of disease after RC with melphalan and subsequently received systemic immunotherapy. Fifteen patients received IL-2 only, 12 received ipilimumab only, and 6 received IL-2 followed by ipilimumab. Fisher’s exact test was used to determine if there was a difference in number of complete responders after immunotherapy.

Results

With IL-2 alone, all patients progressed. After ipilimumab alone, three patients had a complete response and nine had progressive disease. Six additional patients received IL-2 first then ipilimumab. All six progressed on IL-2 but three went on to have a complete response to ipilimumab while three progressed. The use of ipilimumab at any time in patients who progressed after RC was associated with higher rate of complete response compared to use of IL-2 alone (33 vs. 0 %; p = 0.021).

Conclusions

Patients with progression after regional therapy for melanoma may benefit from immunologic therapy. In this group of patients, immune checkpoint blockade with ipilimumab has a higher complete response rate than T cell stimulation with IL-2, with no complete responders in the IL-2 only group. Furthermore, the complete response rate for ipilimumab in our cohort is higher than reported response rates in the literature for ipilimumab alone, suggesting that the effects of immunotherapy may be bolstered by previous regional treatment.     

激光联合吡美莫司乳膏及他克莫司软膏治疗白癜风的临床效果

分析激光与吡美莫司乳膏及他克莫司软膏联合治疗白癜风的临床效果。方法 选取北京京城 皮肤医院皮肤科2022年6月-12月收治的82例白癜风患者为研究对象,采用随机数字表法分为常规组和联 合组,各41例。常规组予以激光治疗,联合组在激光治疗基础上应用吡美莫司乳膏及他克莫司软膏联合 治疗,比较两组临床疗效、免疫功能、症状改善情况及不良反应发生情况。结果 联合组治疗总有效率 为97.56%,高于常规组的82.93%,差异有统计学意义（P ＜0.05）;联合组治疗后IgA、IgM及IgG水平高 于常规组,差异有统计学意义（P ＜0.05）;联合组治疗后白斑数量少于常规组,白斑面积小于常规组, 差异有统计学意义（P ＜0.05）;联合组不良反应发生率为7.32%,低于常规组的29.27%,差异有统计学 意义（P＜0.05）。结论 激光与吡美莫司乳膏及他克莫司软膏联合治疗白癜风可提高治疗效果,提升机体 免疫功能,减少白斑个数和白斑面积,降低不良反应发生几率,值得临床应用。     

A Comparative Study of Intralesional Vitamin D3, Measles Mumps Rubella Vaccine,and Tuberculin Purified Protein Derivative in the Treatment of Recalcitrant Warts: An Approach to Solve a Therapeutic Conundrum

BackgroundHuman papilloma virus infects and proliferates in skin or mucosal cells to cause warts. Most of the current therapeutic modalities are ablative, act only on treated lesions, and lack a well-defined treatment endpoint. These being blind procedures, recurrence rates are high, owing to the remnant virus. Intralesional immunotherapy plays a significant role, as it potentially acts on treated and distant lesions.Objectives We sought to study and compare the efficacy, safety profile, and recurrence rates of intralesional immunotherapy modalities (vitamin D3; measles, mumps, and rubella [MMR] vaccine; and tuberculin purified protein derivative [PPD]) in treating viral warts. MethodsAn open-label interventional study of 60 cases of cutaneous viral warts was performed in a tertiary care center attached to a medical college after obtaining approval from the institutional ethics committee. Each patient was consecutively assigned into Group 1 (vitamin D3: 0.2mL of 15mg/mL), Group 2 (MMR: 0.5mL), or Group 3 (tuberculin PPD: 0.1mL of 10TU). One or two warts were injected per session every two weeks. Response was assessed. Adverse effects were noted. Cases were followed up monthly for three months. ResultsThe MMR group had the maximum patients with complete response (15 of 20, 75%) followed by tuberculin PPD group (13 of 20, 65%) and vitamin D3 group (12 of 20, 60%). No major adverse drug reactions were reported in any of the groups.ConclusionImmunotherapy offers a safe and promising approach in patients with extensive cutaneous viral warts in difficult to treat sites.     

免疫检查点抑制剂在乳腺癌免疫治疗中应用进展

乳腺癌已成为全球发病率最高的癌症，其异质性使得乳腺癌分类治疗进入了精准治疗时代。随着肿瘤免疫治疗的成功，既往被认为“弱免疫原性”的乳腺癌也跨入了免疫治疗阶段。目前，免疫检查点抑制剂在乳腺癌免疫治疗的临床应用中取得了重大进展，但乳腺癌免疫治疗单药的获益人群有限，联合方案成为新的研究热点。随着免疫检查点抑制剂在乳腺癌中的研究进展，有效联合免疫治疗和化疗可能提高乳腺癌病人的生存率，但用药时机和适用人群仍需合理评估。免疫治疗在乳腺癌中既有应用前景，也存在挑战。     

Sintilimab treatment for ureteral carcinoma following bladder cancer leads to leukopenia: a case report

Herein, we present a case report of sintilimab treatment for a patient with ureteral cancer reoccurring after bladder cancer, and exploration of the mechanism of adverse reactions from the aspects of intestinal flora and immunity. We have reported a case of leukopenia in a patient with recurrent ureteral cancer after bladder cancer who was treated with sintilimab. A 52-year-old Chinese man with a history of hypertension and diabetes presented with lower urinary tract symptoms, including painless hematuria, frequent and urgent urination, and micturition without pain. Computed tomography (CT) and 3-dimensional (3D) reconstruction suggested bladder space occupation, bladder cancer was pathologically confirmed after laser resection of the bladder tumor, which then recurred and was subject to reoperation. After 8 months, B-mode ultrasonography indicated left ureter occupation, and the patient began sintilimab immunotherapy according to the outcome of immunohistochemistry (IHC) and immune checkpoint inhibitor (ICI) evaluation. The patient was treated with sintilimab a total of 6 times. After the first treatment, the patient was in stable condition. The second treatment was discontinued due to renal insufficiency. The patient was then treated with renal and liver protection for 1.5 months, followed by 5 rounds of immunotherapy. After the sixth round of immunotherapy, the patient presented with leukopenia. In order to determine the causes of adverse reactions, we analyzed the changes of intestinal flora of patients before and after immunotherapy, and summarized the immune function indicators of patients during immunotherapy. The leucopenia induced by sintilimab may be related to intestinal flora and immunity.     

Adjuvant intravesical therapy based on an in vitro cytotoxicity assay in the management of superficial transitional cell cancer of the urinary bladder

OBJECTIVE: To investigate the utility of an individualized chemo/immunotherapy regimen of intravesical therapy based on the results of an assessment of in vitro cytotoxicity. PATIENTS AND METHODS: Intravesical adjuvant chemo/immunotherapy was given to 47 patients based on the results of in vitro cytotoxicity assay of the responses of cultured autologous tumour cells to various cytotoxic drugs (mitomycin-C, doxorubicin and cisplatin) and immunomodulating agents (bacillus Calmette-Guérin, BCG and interferon-alpha2b). Intravesical therapy was given as single- or double-drug regimens according to the assay results: 16 (34%) patients showed cytotoxicity to a single drug and 31 (66%) showed maximum cytotoxicity to a combination of immunomodulators and cytotoxic agents. The efficacy of treatment in terms of tumour-free survival and recurrence rate was compared with 40 patients receiving intravesical BCG according to International Protocol (control group). RESULTS: In the in vitro assay group, seven patients (15%) had tumour recurrence, compared to 15 (38%) in the control group (P = 0.02). In the in vitro group, one of 16 patients on a single drug and six on the double-drug regimen had a recurrence. The patients given BCG with cytotoxic drugs had no recurrences, but 29% of patients given interferon-alpha2b combinations had recurrences. Kaplan-Meier analysis showed a longer recurrence-free survival in the in vitro group (75%) than in the control group (49%) at 48 months of follow-up. CONCLUSION: Intravesical therapy based on an in vitro cytotoxicity assay is an attempt to give individualized therapy, and to increase tumour-free survival in these patients, with no side-effects. Recurrences in seven patients in the in vitro group might be due to a defective host immune response, or to expansion of a subclone of tumour cells resistant to all treatment.     

不同血浆置换方式在免疫性疾病及肾移植急性排斥反应中的应用分析

目的探究不同血浆置换方式在免疫性疾病及肾移植急性排斥反应中的应用,为临床实践提供理论依据。方法本研究纳入2016年4月至2018年3月西安市中心医院收治的100例免疫性疾病及肾移植急性排斥反应患者,分为对照组和研究组,每组各50例,对照组给予单重滤过血浆净化,研究组给予双重滤过血浆置换,对比两组患者生化指标、治疗情况、不良反应、预后情况,进行统计学分析。结果研究组治疗后的血浆免疫球蛋白G和抗肾小球基底膜抗体水平低于对照组,差异具有统计学意义(P<0.05)。研究组不良反应发生率明显低于对照组,差异具有统计学意义(P<0.05)。研究组患者住院时间、治疗费用均优于对照组,差异具有统计学意义(P<0.05)。研究组患者肾功能恢复率明显高于对照组,差异具有统计学意义(P<0.05)。结论免疫性疾病及肾移植急性排斥反应患者实施选择性双重滤过血浆净化,有效改善血液免疫球蛋白G与抗肾小球基底膜抗体水平,缩短治疗时间,提高治疗有效率,降低不良反应,治疗效果显著。