Twisting immune responses for allogeneic stem cell therapy

Stem cell-derived tissues and organs have the potential to change modern clinical science. However, rejection of allogeneic grafts by the host's immune system is an issue which needs to be addressed before embryonic stem cell-derived cells or tissues can be used as medicines. Mismatches in human leukocyte class I antigens and minor histocompatibility antigens are the central factors that are responsible for various graft-versus-host diseases. Traditional strategies usually involve suppressing the whole immune systems with drugs. There are many side effects associated with these methods. Here, we discuss an emerging strategy for manipulating the central immune tolerance by naturally "introducing" donor antigens to a host so a recipient can acquire tolerance specifically to the donor cells or tissues. This strategy has two distinct stages. The first stage restores the thymic function of adult patients with sex steroid inhibitory drugs (LHRH-A), keratinocyte growth factor (KGF), interleukin 7 (IL-7) and FMS-like tyrosine kinase 3 (FLT3). The second stage introduces hematopoietic stem cells and their downstream progenitors to the restored thymus by direct injection. Hematopoietic stem cells are used to introduce donor antigens because they have priority access to the thymus. We also review several clinical cases to explain this new strategy.     

Systemic antitumor protection by vascular-targeted photodynamic therapy involves cellular and humoral immunity

Vascular-targeted photodynamic therapy (VTP) takes advantage of intravascular excitation of a photosensitizer (PS) to produce cytotoxic reactive oxygen species (ROS). These ROS are potent mediators of vascular damage inducing rapid local thrombus formation, vascular occlusion, and tissue hypoxia. This light-controlled process is used for the eradication of solid tumors with Pd-bacteriochlorophyll derivatives (Bchl) as PS. Unlike classical photodynamic therapy (PDT), cancer cells are not the primary target for VTP but instead are destroyed by treatment-induced oxygen deprivation. VTP initiates acute local inflammation inside the illuminated area accompanied by massive tumor tissue death. Consequently, in the present study, we addressed the possibility of immune response induction by the treatment that may be considered as an integral part of the mechanism of VTP-mediated tumor eradication. The effect of VTP on the host immune system was investigated using WST11, which is now in phase II clinical trials for age-related macular degeneration and intended to be evaluated for cancer therapy. We found that a functional immune system is essential for successful VTP. Long-lasting systemic antitumor immunity was induced by VTP involving both cellular and humoral components. The antitumor effect was cross-protective against mismatched tumors, suggesting VTP-mediated production of overlapping tumor antigens, possibly from endothelial origin. Based on our findings we suggest that local VTP might be utilized in combination with other anticancer therapies (e.g., immunotherapy) for the enhancement of host antitumor immunity in the treatment of both local and disseminated disease. Y.S. and A.S are the incumbents of the Tillie and Charles Lubin Professorial Chair in Biochemical Endocrinology, and the Robert and Yaddele Sklare Professorial Chair in Biochemistry, respectively. S.J. is the incumbent of the Pauline Recanati Career Development Chair. D.P. in partial fulfillment of her PhD Thesis requirements at the Feinberg graduate school of the Weizmann Institute of Science.     

High-dose neoadjuvant chemoradiotherapy versus chemotherapy alone followed by surgery in potentially-resectable stage IIIA-N2 NSCLC. A multi-institutional retrospective study by the Oncologic Group for the Study of Lung Cancer (Spanish Radiation Oncology Society)

BackgroundThe optimal induction treatment in potentially-resectable stage IIIA-N2 NSCLC remains undefined.AimTo compare neoadjuvant high-dose chemoradiotherapy (CRT) to neoadjuvant chemotherapy (CHT) in patients with resectable, stage IIIA-N2 non-small-cell lung cancer (NSCLC).MethodsRetrospective, multicentre study of 99 patients diagnosed with stage cT1-T3N2M0 NSCLC who underwent neoadjuvant treatment (high-dose CRT or CHT) followed by surgery between January 2005 and December 2014.Results47 patients (47.5%) underwent CRT and 52 (52.5%) CHT, with a median follow-up of 41 months. Surgery consisted of lobectomy (87.2% and 82.7%, in the CRT and CHT groups, respectively) or pneumonectomy (12.8% vs. 17.3%). Nodal downstaging (to N1/N0) and Pathologic complete response (pCR; pT0pN0) rates were significantly higher in the CRT group (89.4% vs. 57.7% and 46.8% vs. 7.7%, respectively; p < 0.001)). Locoregional recurrence was significantly lower in the CRT group (8.5% vs. 13.5%; p = 0.047) but distant recurrence rates were similar in the two groups. Median PFS was 45 months (CHT) vs. “not reached” (CRT). Median OS was similar: 61 vs. 56 months (p = 0.803). No differences in grade ≥3 toxicity were observed. On the Cox regression analysis, advanced pT stage was associated with worse OS and PFS (p < 0.001) and persistent N2 disease (p = 0.002) was associated with worse PFS.ConclusionsCompared to neoadjuvant chemotherapy alone, a higher proportion of patients treated with preoperative CRT achieved nodal downstaging and pCR with better locoregional control. However, there were no differences in survival. More studies are needed to know the optimal treatment of these patients.     

老年结直肠癌患者肠道菌群变化与机体免疫炎症营养相关性

目的探讨老年结直肠癌患者肠道菌群变化与机体免疫、炎症、营养指标的相关性,为结直肠癌的防治提供参考。方法纳入2016年1月至2018年6月在我院接受治疗的老年结直肠癌患者30例和同期健康查体的老年人群30例,收集粪便标本,采用FloraCheck~(TM)高通量测序技术对粪便样本中所有细菌的16S rRNA V3-V4区进行DNA测序,序列通过MiSeq 16S宏基因组APP及QIIME软件,分析两组人群间属水平上显著差异性菌群。比较两组人群炎性指标(TNF-α、IL-6、IL-1、IL-12)、营养指标(总蛋白、白蛋白、前白蛋白、转铁蛋白)和免疫指标(CD3~+、CD4~+、CD8~+、NK)的差异。分析老年结直肠癌患者肠道菌群变化与营养、炎症、免疫的内在联系。结果老年结直肠癌组和老年健康组人群免疫指标CD3~+、CD4~+、CD8~+、NK和CD4~+/CD8~+比较差异无统计学意义;炎性指标老年结直肠癌组TNF-α含量较对照组明显增高(t=3.769,P=0.001),两组人群IL-1、IL-6、IL-12比较差异无统计学意义;营养指标老年结直肠癌组白蛋白、前白蛋白较对照组明显下降(t=-4.107,P=0.001;t=-4.366,P=0.001),两组人群总蛋白、转铁蛋白比较差异无统计学意义。老年结直肠癌组肠道差异性菌属变化,包括Eubacterium、Ruminococcaceae_UCG-002、Peptostreptococcus、Porphyromonas和部分炎症指标、营养指标、免疫指标有明显相关性。结论老年结直肠癌患者肠道菌群结构和功能异常,可能是导致患者机体免疫损伤、炎症反应、营养不佳的主要原因之一。有针对性地对肠道菌群结构进行优化,改善肠道菌群对宿主的影响,是一种帮助老年结直肠癌患者促进健康的策略。     

The efficacy and safety of adding bevacizumab in neoadjuvant therapy for locally advanced rectal cancer patients: A systematic review and meta-analysis

BackgroundPatients with locally advanced rectal cancer (LARC) are more likely to suffer local recurrence and distant metastases, contributing to worse prognoses. Considering the provided dramatic reduction of local recurrences, neoadjuvant CRT (nCRT) followed by curative resection with total mesorectal excision (TME) and adjuvant chemotherapy has been established as standard therapy for LARC patients. However, the efficacy of adding bevacizumab in neoadjuvant therapy, especially in induction therapy-containing nCRT for LARC patients remains uncertain.MaterialsPubMed, Embase, and Web of Science were searched to retrieve records on the application of bevacizumab in a neoadjuvant setting for LARC patients. The endpoints of interest were pCR and the rates of patients suffering Grade 3/4 bevacizumab-specific adverse events, namely bleeding, wound healing complications, and gastrointestinal perforation.Results29 cohorts covering 1134 subjects were included in this systematic review. The pooled pCR rate for bevacizumab-relevant cohorts was 21% (95% confidence interval (95% CI), 17–25%; I² = 61.8%), the pooled estimates of Grade 3/4 bleeding, Grade 3/4 wound healing complication, Grade 3/4 gastrointestinal perforation were 1% (95% CI, 0–3%; I² = 0%), 2% (95% CI, 1–5%; I² = 4.7%), and 2% (95% CI, 0–5%; I² = 0%), respectively.ConclusionThe addition of bevacizumab in the nCRT, especially in the TNT, for LARC patients provides promising efficacy and acceptable safety. However, the results should be interpreted cautiously due to the small amount of relevant data and need further confirmation by future studies.     

Patterns of post-operative irradiation in breast cancer patients submitted to neoadjuvant chemotherapy

Background/AimPost-operative radiation therapy (PORT) is associated with improvement in loco-regional control and survival rates in early breast cancer. However, the evidence of benefit in patients after treatment with neoadjuvant chemotherapy (NAC) is poor. We aimed to assess the impact of the type of surgery in the PORT plan and the role of the PORT fields in clinical outcomes in breast cancer patients who had undergone NAC followed by surgery.Materials and methodsWe performed a retrospective analysis of all non-metastatic breast cancer patients treated between 2008 and 2014 at our institution who had received NAC and PORT.ResultsA total of 528 women were included of whom 396 were submitted to mastectomy or nipple-sparing/skin-sparing mastectomy. Most (92.8%) of the patients had locally advanced disease (clinical stage IIB to IIIC). All patients underwent irradiation for breast or chest wall. Most patients received PORT to the supraclavicular and axillary (levels II and III) nodes (87.1% and 86.4% for breast-conserving surgery and 95.1% and 93.8% for mastectomy and nipple-sparing/skin-sparing mastectomy, respectively). Irradiation of level I axillary and internal mammary nodes was uncommon. The disease-free survival and overall survival rates at 3 years were 72% and 85%, respectively. There were no statistically significant differences in clinical outcomes according to the use of nodal irradiation.ConclusionsAfter NAC, most patients received irradiation of the breast/chest wall and axillary and supraclavicular nodes. In this setting, PORT to breast/chest wall with or without regional nodal irradiation was safe and effective, with acceptable disease-free and overall survival rates reported in this high-risk population.     

A 3-year experience of quality control and quality assurance in the multisite delivery of a lymphocyte-based cellular therapy for renal cell carcinoma

Autolymphocyte therapy (ALT) is outpatient-based adoptive immunotherapy using ex vivo-activated memory T-cells. To support the safe and reproducible delivery of ALT at three cell processing facilities (Boston, MA; Atlanta, GA; Orange, CA) we created a comprehensive quality assurance/quality control program compliant with recent FDA guidance relevant to activated lymphocytes and somatic cell therapies. Each facility performed extensive QC testing to ensure sterility, viability, and proper cell yield. Additonally, several QC tests were performed at Cellocr's centralized reference laboratory to monitor cell potency and identity of the ex vivo-processed lymphocytes. We report here the successful implementation of this QA/QC program for ALT which has resulted in the safe preparation and delivery of cell infusion products amounting to over 3600 treatments at seven clinical sites nationwide. We believe this program will serve as a model for other cellular therapies.     

稀土磁疗对开胸术后机体免疫功能及疼痛的影响

目的:研究稀土磁治疗床对食管癌、肺癌手术患者术后机体免疫力及切口疼痛的影响。方法:选食管癌患者37例,肺癌23例,采集手术前及稀土磁治疗床治疗后患者静脉血,检测T细胞亚群CD3 、CD4 、CD8 、CD4 /CD8 比值和NK细胞的比例变化,检查手术切口疼痛的恢复情况。结果:术后给予稀土磁治疗床治疗后与手术前相比较CD3 、CD4 、NK、CD4 /CD8 细胞有显著提高(P<0.05),也高于对照组术后的T细胞亚群水平(P<0.05)。结论:稀土磁治疗床可提高食管癌、肺癌患者术后的机体免疫力,减轻疼痛,有利于患者术后恢复。     

Intestinal immunity of Escherichia coli NISSLE 1917: a safe carrier for therapeutic molecules

The development of novel approaches that allow accurate targeting of therapeutics to the intestinal mucosa is a major task in the research on intestinal inflammation. For the first time, a live genetically modified bacterial strain has been approved by Dutch authorities as a therapeutic agent for experimental therapy of intestinal bowel disease (IBD) in humans. Genetically modified probiotics can very well be used as carriers for localized antigen delivery into the intestine. Therapeutic safety, however, of such a carrier organism, is crucial, especially when a specific probiotic strain has to be used under diseased conditions. In this study, we tested the potential of Escherichia coli NISSLE 1917 to serve as a safe carrier for targeted delivery of recombinant proteins to the intestinal mucosa. In a well-defined and very sensitive immunological system, we demonstrate that intestinal recombinant E. coli NISSLE 1917 has no effect on migration, clonal expansion and activation status of specific CD4+ T cells, neither in healthy mice nor in animals with acute colitis. Furthermore, recombinant E. coli NISSLE 1917 has no effect on the induction or breakdown of peripheral T-cell tolerance in an autoimmune environment. The excellent colonization properties of E. coli NISSLE 1917 render this strain an ideal candidate as carrier organism for gut-focused in situ synthesis of therapeutic molecules.     

The roles of interleukin-1 and interleukin-1 receptor antagonist in antigen-specific immune responses

Despite evidence that interleukin (IL)-1 promotes the proliferation of some T helper 2 (Th2) cell clones in vitro, the physiological role of IL-1 in the regulation of antigen-specific immune responses remains undefined. Using a liposome-DNA delivery system, we transiently expressed IL-1 receptor antagonist (IL-1Ra) to suppress IL-1 functions at the site of the antigen-specific primary immune response. Our data indicate, for the first time, that IL-1Ra downregulates antigen-specific IL-4 and IgE responses, with concomitant enhancement of interferon- and IgG2a responses in vivo. In addition, IL-1 can promote Th2 development in an IL-4-independent manner in vitro. Thus, the balance between endogenous IL-1 and IL-1Ra during the primary immune response can be an important factor in determining the antigen-specific effector function of T cells.     

Prognostic value of the post-operative red blood cell distribution width in patients with rectal cancer with neoadjuvant chemoradiation followed by surgery

Purposes: Several studies have reported that elevated red cell distribution width (RDW) is related to poor prognosis in several cancers; however, the prognostic significance of perioperative RDW in patients with rectal cancer that received neoadjuvant chemoradiation therapy (NACRT) is unclear.Methods: A total of 120 patients with rectal cancer who received NACRT followed surgery were retrospectively reviewed from Affiliated Cancer Hospital of Zhengzhou University between 2013 and 2015. Data for peripheral blood tests prior to the initiation of NACRT, before surgery and first chemotherapy after surgery were collected, respectively. The optimal cutoff values of RDW were determined by ROC analysis, respectively. The relationship between RDW and the prognosis of patients was evaluated by the Kaplan Meier method, respectively.Results: The post-operative RDW^High patients had significantly worse 5-year overall survival (OS, P=0.001) and disease-free survival (DFS, P<0.001) than the post-operative RDW^Low patients, respectively. Whereas high pre-operative RDW was the only marker correlated with worse DFS (P=0.005) than the pre-operative RDW^Low patients, no relationship was found between pre-RDW and prognosis (OS, P=0.069; DFS, P=0.133). Multivariate analysis showed post-operative RDW had better predictive value than pre-RDW and pre-operative RDW.Conclusion: Post-operative RDW might be a useful prognostic indicator in patients with rectal cancer received neoadjuvant chemoradiation.     

Condition-dependent alteration of cellular immunity by secondary symbionts in the pea aphid,Acyrthosiphon pisum

Endosymbionts can fundamentally alter host physiology. Whether such changes are beneficial or detrimental to one or both partners may depend on the dynamics of the symbiotic relationship. Here we investigate the relationship between facultative symbionts and host immune responses. The pea aphid, Acyrthosiphon pisum, maintains an obligate primary symbiont, but may also harbour one or more facultative, secondary symbionts. Given their more transient nature and relatively recent adoption of a symbiotic lifestyle compared to primary symbionts, secondary symbionts may present a challenge for the host immune system. We assessed the response of several key components of the cellular immune system (phenoloxidase activity, encapsulation, immune cell counts) in the presence of alternative secondary symbionts, investigating the role of host and secondary symbiont genotype in specific responses. There was no effect of secondary symbiont presence on the phenoloxidase response, but we found variation in the encapsulation response and in immune cell counts based largely on the secondary symbiont. Host genotype was less influential in determining immunity outcomes. Our results highlight the importance of secondary symbionts in shaping host immunity. Understanding the complex physiological responses that can be propagated by host-symbiont associations has important consequences for host ecology, including symbiont and pathogen transmission dynamics.     

Vaccination of colorectal cancer patients with TroVax given alongside chemotherapy (5-fluorouracil, leukovorin and irinotecan) is safe and induces potent immune responses

Modified vaccinia Ankara (MVA) encoding the tumor antigen 5T4 (TroVax) has been evaluated in an open label phase II study in metastatic colorectal cancer patients. The primary objective was to assess the safety and immunogenicity of TroVax injected before, during and after treatment with 5-fluorouracil, leukovorin and irinotecan. TroVax was administered to 19 patients with metastatic colorectal cancer. Twelve patients had blood samples taken following each of the six injections and were considered to be evaluable for assessment of immunological responses. Both antibody and cellular responses specific for the tumor antigen 5T4 and the viral vector MVA were monitored throughout the study. Administration of TroVax alongside chemotherapy was safe and well tolerated with no SAEs attributed to the vaccine and no enhancement of chemo-related toxicity. Of the 12 patients who were evaluable for assessment of immune responses, ten mounted 5T4-specific antibody responses with titers ranging from 10 to > 5,000. IFNgamma ELISPOT responses specific for 5T4 were detected in 11 patients with frequencies exceeding one in 1,000 PBMCs in five patients. Eight patients presented with elevated circulating CEA concentrations, six of whom showed decreases in excess of 50% during chemotherapy and four had CEA levels which remained stable for > 1 month following completion of chemotherapy. Of the 19 intention to treat (ITT) patients, one had a CR, six had PRs and five had SD. Potent 5T4-specific cellular and/or humoral immune responses were induced in all 12 evaluable patients and were detectable in most patients during the period in which chemotherapy was administered. These data demonstrate that TroVax can be layered on top of chemotherapy regimens without any evidence of enhanced toxicity or reduced immunological or therapeutic efficacy.     

The role of cellular proteostasis in antitumor immunity

Immune checkpoint blockade therapy is perhaps the most important development in cancer treatment in recent memory. It is based on decades of investigation into the biology of immune cells and the role of the immune system in controlling cancer growth. While the molecular circuitry that governs the immune system in general—and antitumor immunity in particular—is intensely studied, far less attention has been paid to the role of cellular stress in this process. Proteostasis, intimately linked to cell stress responses, refers to the dynamic regulation of the cellular proteome and is maintained through a complex network of systems that govern the synthesis, folding, and degradation of proteins in the cell. Disruption of these systems can result in the loss of protein function, altered protein function, the formation of toxic aggregates, or pathologies associated with cell stress. However, the importance of proteostasis extends beyond its role in maintaining proper protein function; proteostasis governs how tolerant cells may be to mutations in protein-coding genes and the overall half-life of proteins. Such gene expression changes may be associated with human diseases including neurodegenerative diseases, metabolic disease, and cancer and manifest at the protein level against the backdrop of the proteostasis network in any given cellular environment. In this review, we focus on the role of proteostasis in regulating immune responses against cancer as well the role of proteostasis in determining immunogenicity of cancer cells.     

Modulation of immune responses by Plasmodium falciparum infection in asymptomatic children living in the endemic region of Mbita,western Kenya

Individuals living in malaria endemic areas become clinically immune after multiple re-infections over time and remain infected without apparent symptoms. However, it is unclear why a long period is required to gain clinical immunity to malaria, and how such immunity is maintained. Although malaria infection is reported to induce inhibition of immune responses, studies on asymptomatic individuals living in endemic regions of malaria are relatively scarce. We conducted a cross-sectional study of immune responses in asymptomatic school children aged 4–16 years living in an area where Plasmodium falciparum and Schistosoma mansoni infections are co-endemic in Kenya. Peripheral blood mononuclear cells were subjected to flow cytometric analysis and cultured to determine proliferative responses and cytokine production. The proportions of cellular subsets in children positive for P. falciparum infection at the level of microscopy were comparable to the negative children, except for a reduction in central memory-phenotype CD8⁺ T cells and natural killer cells. In functional studies, the production of cytokines by peripheral blood mononuclear cells in response to P. falciparum crude antigens exhibited strong heterogeneity among children. In addition, production of IL-2 in response to anti-CD3 and anti-CD28 monoclonal antibodies was significantly reduced in P. falciparum-positive children as compared to -negative children, suggesting a state of unresponsiveness. These data suggest that the quality of T cell immune responses is heterogeneous among asymptomatic children living in the endemic region of P. falciparum, and that the responses are generally suppressed by active infection with Plasmodium parasites.     

Diagnostic potential of ionomic profile in the plasma of cervical cancer patients receiving neoadjuvant chemoradiotherapy

Background and aimMajor and trace elements play an important role in human body, and it has been reported that ionomic distribution differ greatly in tumor patients. The aim of the present study was to investigate the effects of cisplatin-based neoadjuvant chemoradiotherapy on the ionomic profile in human plasma as a potential biomarker for the therapeutic effects of cervical cancer.MethodThirty-seven patients with cervical cancer receiving neoadjuvant chemoradiotherapy were included in this study, pretherapy and post-treatment blood samples were collected and concentrations of 24 ions were analyzed by inductively coupled plasma mass spectrometry (ICP-MS).ResultsThe results showed that after cisplatin chemotherapy and radiotherapy, patients' plasma Pt level significantly increased, Na, Mg, P, K, Ca, Se, Cu, Zn, Se, Sr, Ba levels significantly decreased (P < 0.01), and Al, Cu ions were significantly correlated with the treatment effect (P < 0.05). In addition, the pattern of elemental correlations changed dramatically after the neoadjuvant chemoradiotherapy.ConclusionThe results indicated that the plasma ionomic profile may serve as a quick and convenient tool to reflect the therapeutic effect of cisplatin-based chemoradiotherapy in cervical cancer patients, and supplement of certain essential elements may be of great importance for the maintenance of ion homeostasis in human body and for the reduction of adverse effect of chemotherapy and radiotherapy.     

Induction of cellular immune responses against carcinoembryonic antigen in patients with metastatic tumors after vaccination with altered peptide ligand-loaded dendritic cells

Purpose: Dendritic cells (DCs) are characterized by their extraordinary capacity to induce T-cell responses, providing the opportunity of DC-based cancer vaccination protocols. In the present study, we conducted a phase I/II clinical trial to determine the capability of DCs differentiated from immunomagnetically isolated CD14+ monocytes and pulsed with a carcinoembyonic antigen-derived altered peptide (CEAalt) to induce specific CD8+ T cells in cancer patients. Experimental design: Nine patients with CEA-positive colorectal cancer (n=7) or lung cancer (n=2) were enrolled in this study. Autologous CD14+ monocytes were isolated by large-scale immunomagnetic separation and differentiated to mature DCs in sufficient numbers and at high purity. After incubation with the CEAalt peptide and keyhole limpet hemocyanin, DCs were administered to patients intravenously at dose levels of 1×10⁷ and 5×10⁷ cells. Patients received four immunizations every second week. Results: ELISPOT analysis revealed a vaccine-induced increase in the number of CEAalt peptide-specific Interferon (IFN)-gamma producing CD8+ T cells in five of nine patients and of CD8+ T lymphocytes recognizing the native CEA peptide in three of nine patients. In addition, CD8+ T lymphocytes derived from one patient exhibiting an immunological response after vaccination efficiently lysed peptide-loaded T2 cells and tumor cells. Immunization was well tolerated by all patients without severe signs of toxicity. Conclusion: Vaccination with CEAalt-pulsed DCs derived from immunomagnetically isolated CD14+ monocytes efficiently expand peptide-specific CD8+ T lymphocytes in vivo and may be a promising alternative for cancer immunotherapy.     

Differential requirements for CD80/86-CD28 costimulation in primary and memory CD4 T cell responses to vaccinia virus

Vaccinia virus infection can confer immunity to smallpox by inducing potent T cell and antibody responses. While the CD8 T cell response to vaccinia virus has been well characterized, less is known about factors required for priming and memory for the CD4 T cells. Focusing on two recently described epitopes, we show that after intranasal infection, both I1L and L4R epitopes are co-dominant during the acute response, but the I1L epitope dominates during memory. CD4 T cell priming was intact in the absence of CD80/86, however secondary responses were reduced. This contrasts with our previous data showing CD80/86–CD28 interaction is required for optimal primary and memory CD8 T cell responses. The absence of CD80/86 also changed the immunodominance hierarchy during memory, with the I1L and L4R responses becoming co-dominant in knockout mice. These data highlight different costimulatory requirements for primary CD4 and CD8 T cell responses to vaccinia virus.     

The current status of immunotherapy for cervical cancer

BackgroundImmunotherapy has been proven effective in several tumours, hence diverse immune checkpoint inhibitors are currently licensed for the treatment of melanoma, kidney cancer, lung cancer and most recently, tumours with microsatellite instability. There is much enthusiasm for investigating this approach in gynaecological cancers and the possibility that immunotherapy might become part of the therapeutic landscape for gynaecological malignancies.Cervical cancer is the fourth most frequent cancer in women worldwide and represents 7.9% of all female cancers with a higher burden of the disease and mortality in low- and middle-income countries. Cervical cancer is largely a preventable disease, since the introduction of screening tests, the recognition of the human papillomavirus (HPV) as an etiological agent, and the subsequent development of primary prophylaxis against high risk HPV subtypes. Treatment for relapsed/advanced disease has improved over the last 5 years, since the introduction of antiangiogenic therapy. However, despite advances, the median overall survival for advanced cervical cancer is 16.8 months and the 5-year overall survival for all stages is 68%. There is a need to improve outcomes and immunotherapy could offer this possibility. Clinical trials aim to understand the best timing for immunotherapy, either in the adjuvant setting or recurrent disease and whether immunotherapy, alone or in combination with other agents, improves outcomes.     

The potential use of Toll-like receptor agonists to restore the dysfunctional immunity induced by hepatitis C virus

Hepatitis C virus (HCV) infection is a major public health concern with approximately 3% of the world’s population is infected, posing social, economical and health burden. Less than 20% of the infected individuals clear the virus during the acute infection, while the rest develop chronic infection. The treatment of choice for HCV infection is pegylated interferon-α (IFN-α) in combination with ribavarin. Despite the cost and side effects of this treatment regimen, many patients fail this therapy and develop persistent HCV infection, leading to cirrhosis and hepatocellular carcinoma. Although the mechanisms underlying the failure to resolve HCV infection are poorly understood, the incapability of patients to develop effective anti-HCV immunity is a potential cause. We hypothesize that the dysfunctional anti-HCV immunity is due to the emergence of immunosuppressive cells coinciding with a decrease in the stimulatory dendritic cells (DCs) and natural killer (NK) cells. We further hypothesize that applying agents that can correct the imbalance between the immunosuppressive cells and stimulatory cells can results in resolution of chronic HCV. In this review article, we will discuss potential approaches, focusing on the use of Toll-like receptor agonists, to block the suppressive effects of the regulatory cells and restore the stimulatory effects of DCs and NK cells.