Immunotherapy

Most cytotoxic drugs have gross effects on the immune system, such as neutropenia and lymphopenia. However, their effects on tumor-specific immune responses are unknown. Gemcitabine is a nucleoside analogue that is frequently used to treat non-small cell lung cancer. It is also active in other malignancies, either alone or in combination with cisplatin. Here, we investigate its effects on antigen-specific antitumor immunity using a murine tumor cell line transfected to express influenza virus hemagglutinin (HA). CD4(+), CD8(+), and B220(+) lymphocyte numbers all decreased during chemotherapy (120 microg/g, i.p., every third day for five doses), but B cells were selectively depleted. Gemcitabine induced a profound suppression of the IgG antibody response to HA, and this was unrelated to tumor size. In contrast, in vitro T-lymphocyte recall responses to the class I- and class II-restricted dominant peptide epitopes of HA were enhanced in tumor-bearing, gemcitabine-treated mice. We fou...

The manufacturing of cellular products for immunotherapy, such as chimeric antigen receptor T cells, requires successful collection of mononuclear cells. Collections from children with high-risk leukemia present a challenge, especially because the established COBE Spectra apheresis device is being replaced by the novel Spectra Optia device (Optia) in many institutions. Published experience for mononuclear cell collections in children with Optia is lacking. Our aim was to compare the two collection devices and describe modified settings on the Optia to optimize mononuclear cell collections. As a quality initiative, we retrospectively collected and compared data from mononuclear cell collections on both devices. Collected data included patient's clinical characteristics; collection parameters, including precollection lymphocyte/CD3 counts, total blood volumes processed, runtimes, and side effects (including complete blood count and electrolyte changes); and product characteristics...

Background Subcutaneous immunotherapy is effective for the treatment of respiratory allergy, and it is largely used in Italy, but no systematic safety assessment has been carried out so far.Objective To assess prospectively the safety of injection immunotherapy in a multicentre, real-life survey.Methods Eleven Italian allergy departments recorded the clinical characteristics of systemic reactions (SRs) due to immunotherapy. Vaccines were prescribed according to guidelines; only standardized depot extracts were used. SRs were graded according to the EAACI recommendations, and were classified as immediate or delayed.Results One thousand seven hundred and thirty-eight patients (847 males, age range 5–71) received immunotherapy from eight different manufacturers, for a total of 2038 courses (300 patients received two extracts). A total of 60 785 injections were given over a mean immunotherapy duration of 3 years. Overall, 95 reactions were observed in 57 patients (3.28%), corresponding to 4.7% of the courses and 1.56/1000 injections. Twenty-five patients experienced more than one adverse event. There were 34 grade 2, 60 grade 3 and one grade 4 reactions and no fatality. SRs occurred more frequently in patients with asthma than in patients with rhinitis alone (4.1% vs. 1.1%), and were equally distributed between the build-up and the maintenance phase. Ragweed and grass extracts caused significantly more side effects than other allergens.Conclusion In this large prospective study, the rate of SRs was low, thus confirming that injection immunotherapy has an acceptable risk/benefit ratio when prescribed and carried out according to recommendations.

Monoclonal antibodies (mAbs) are being increasingly used in cancer therapy owing to their ability to recognize specifically cancer cells and to activate complement-and cell-mediated cytotoxicity and/or to induce growth arrest or apoptosis. The therapeutic potential of anticancer antibodies is significantly limited due to the ability of cancer cells to block killing by complement. Of the multiple resistance strategies exploited by cancer cells, the expression of membrane complement regulatory proteins (mCRPs), such as CD46 (membrane cofactor protein (MCP)), CD55 (decay-accelerating factor (DAF)), CD35 (complement receptor type-1 (CR1)) and CD59, has received most attention. CD46, CD55 and CD35 block the complement cascade at the C3 activation stage and CD59 prevents assembly of the membrane attack complex of complement (MAC). These proteins protect normal tissues from accidental injury by activated complement, but also confer resistance on cancer cells, thereby limiting the effect of complement-fixing monoclonal antibodies. Expression of mCRPs on malignant cells is highly variable, yet there is clear indication that certain tumors express higher mCRP levels than the normal tissue from which they have evolved. mCRP level of expression and cellular location may also vary during malignant transformation and between differentiated and undifferentiated tumors. Neutralizing anti-mCRP mAbs have been used in vitro to elucidate the significance of mCRP expression to the tumor complement resistance phenotype. In general, CD59 appears to be the most effective mCRP protecting tumor cells from complement-mediated lysis. Nevertheless, it acts additively, and in certain tumors even synergistically, with CD55 and CD46. It is envisaged that treatment of cancer patients with mCRP blocking antibodies targeted specifically to cancer cells in combination with anticancer complement-fixing antibodies will improve the therapeutic efficacy.

... The role of major histocompatibility complex class I antigens in tumorigenesis: future applications in cancer therapy. Auteur(s) / Author(s). NAPOLITANO L. (1) ; VOGEL J. ; JAY G. ; Affiliation(s) du ou des auteurs / Author(s) Affiliation(s). ... Tumor. ; Antígeno histocompatibilidad clase ...

Cancer immunotherapy comprises a variety of treatment approaches, incorporating the tremendous specificity of the adaptive immune system (T cells and antibodies) as well as the diverse and potent cytotoxic weaponry of both adaptive and innate immunity. Immunotherapy strategies include antitumor monoclonal antibodies, cancer vaccines, adoptive transfer of ex vivo activated T and natural killer cells, and administration of antibodies or recombinant proteins that either costimulate immune cells or block immune inhibitory pathways (so-called immune checkpoints). Although clear clinical efficacy has been demonstrated with antitumor antibodies since the late 1990s, other immunotherapies had not been shown to be effective until recently, when a spate of successes established the broad potential of this therapeutic modality. These successes are based on fundamental scientific advances demonstrating the toleragenic nature of cancer and the pivotal role of the tumor immune microenvironment in...

Peripheral arterial disease (PAD) is a common manifestation of atherosclerosis that affects more than 10 million people in the United States. The risk factors associated with PAD are similar to those found in patients with coronary artery disease and cerebrovascular disease. Medical therapy of PAD must include modification of cardiovascular risk factors with application of strict secondary prevention guidelines. For improvement in quality of life, a structured exercise rehabilitation program remains the most effective noninterventional treatment strategy, but it is difficult to employ from economic and patient-compliance perspectives. Newer pharmacologic therapies have demonstrated efficacy in patients with intermittent claudication. Emerging strategies for management of these patients include revascularization and maximal medical therapy for improvement of physical function as well as reduction in risk for subsequent major cardiovascular events. This article will review the clinical data supporting aggressive medical interventions for patients with PAD.

A systematic review and network meta-analysis were conducted to evaluate the efficacy of pembrolizumab + pemetrexed + platinum relative to other regimens in metastatic nonsquamous non-smallcell lung cancer (NSq-NSCLC). Patients & methods: Eligible studies evaluated first-line regimens in NSq-NSCLC patients without known targetable mutations. Relative treatment effects were synthesized with random effects proportional hazards Bayesian network meta-analyses. Results: The hazard ratio (HR) for overall survival (OS) for pembrolizumab + pemetrexed + platinum was statistically significant over all platinum-doublet (HR range: 0.42-0.61), platinum-doublet + bevacizumab (HR range: 0.44-0.53) and platinum-doublet + atezolizumab regimens (HR range: 0.56-0.62). Additionally, pembrolizumab + pemetrexed + platinum numerically improved OS over atezolizumab + paclitaxel + carboplatin + bevacizumab (HR: 0.65; 95% credible interval: 0.43, 1.01). Pembrolizumab + pemetrexed + platinum had 95.6% probability of being the best treatment regimen for OS. Conclusion: Pembrolizumab + pemetrexed + platinum is likely the most efficacious first-line regimen for metastatic NSq-NSCLC.

Acute and chronic symptoms of allergic rhinitis (AR) can disrupt school and leisure activities, significantly reducing quality of life. Symptoms often impair sleep, resulting in tiredness and poor concentration. Children with seasonal AR perform significantly worse in summer exams, relative to their mock exam results, when compared with their peers. Those individuals showing most symptoms are also likely to be affected by other allergic diseases, magnifying the detrimental impact on quality of life. Nasal blockage is the most common complaint associated with chronic AR, with acute exacerbations causing sneezing, clear nasal discharge and itchy eyes following exposure to the relevant airborne triggers. Allergen avoidance measures should be instituted according to seasonal or perennial symptomatology guided by allergy testing, alongside nonsedating antihistamines such as cetirizine or loratadine. Continued symptoms should be treated with regular intranasal steroid spray. Anti-leukotri...

Many studies have explored the effects of immunotherapy, alone or in combination with conventional therapies, on both experimental and human cancers. Evidence has been provided that combined treatments with thymosin alpha 1 (T a 1) and low doses of interferon (IFN) or interleukin (IL)-2 are highly effective in restoring several immune responses depressed by tumor growth and/or cytostatic drugs. In addition, when combined with specific chemotherapy, they are able to increase the anti-tumor effect of chemotherapy while markedly reducing the general toxicity of the treatment. The advantages of using this combined chemo-immunotherapeutic approach in experimental and human cancers are reviewed in this issue. : S 0 1 9 2 -0 5 6 1 ( 0 0 ) 0 0 0 7 5 -8 E. Garaci et al.

Extracellular vesicles (EV) form a heterogeneous population of mostly spherical membrane structures released by almost all cells, including tumour cells, both in vivo and in vitro. Their size varies from 30 nm to 1 µm, and size is one of the main criteria of the selection of two categories of EV: small (30-100 nm), more homogeneous exosomes and larger fragments (0.1-1 µm) called membrane microvesicles or ectosomes. The presence of EV has already been detected in many human body fluids: blood, urine, saliva, semen and amniotic fluid. Formation of EV is tightly controlled, and their function and biochemical composition depend on the cell type they originate from. EV are the "vehicles" of bioactive molecules, such as proteins, mRNA and microRNA, and may play an important role in intercellular communication and modulation

Immunotherapy is becoming the standard of care for melanoma. However, resistance to therapy is a major problem. Previously, we showed that tumor-specific, cytotoxic CD4+ T cells from tyrosinase-related protein 1 transgenic mice could overcome second- ary resistance to recurring melanoma when anti–programmed cell death 1 ligand (PD-L1) checkpoint blockade was combined with either anti–lymphocyte-activated gene 3 (LAG-3) Abs or depletion of tumor-specific regulatory T (Treg) cells. In this study, we show that PD-L1 expressed by the host, not B16 melanoma, plays a major role in the early stages of exhaustion or primary resistance. We observed durable regression of melanoma in tumor-bearing PD-L12/2RAG2/2 mice with transfer of naive tumor- specific CD4+ T cells. However, exhausted tumor-specific CD4+ T cells, which included tumor-specific Treg cells, failed to maintain durable regression of tumors in PD-L12/2RAG2/2 mice unless tumor-specific Treg cells were eliminated, showing nonredundant pathways of resistance to immunotherapy were present. Translating these findings to a clinically relevant model of cancer immunotherapy, we unexpectedly showed that anti–PD-L1 checkpoint blockade mildly improved immunotherapy with tumor- specific CD4+ T cells and irradiation in wild-type mice. Instead, anti–LAG-3 checkpoint blockade, in combination with tumor- specific CD4+ T cells and irradiation, overcame primary resistance and treated established tumors resulting in fewer recurrences. Because LAG-3 negatively regulates effector T cell function and activates Treg cells, LAG-3 blockade may be more beneficial in overcoming primary resistance in combination immunotherapies using adoptive cellular therapy and irradiation than blockade of PD-L1. The Journal of Immunology, 2018, 200: 3304–3311.

Antibodies directed against tumourassociated antigens on cell surfaces can be used to carry cytotoxic agents specifically to tumour cells provided the antibody and agent are covalently bound. Physically adsorbed, but non-covalently bound, antibody/cytotoxic drug mixtures dissociate under in-vivo conditions and do not form satisfactory carrier complexes, but the antibody is still able to augment the cytotoxic action of the drug by another mechanism.

Despite recent advances in lymphoma treatment, mantle cell lymphoma (MCL) remains incurable and we are still unable to identify patients who will not benefit from the current standard-of-care. Here, we explore the prognostic value of recurrent genetic aberrations in diagnostic bone marrow (BM) specimens from 183 younger MCL patients from the Nordic MCL2 and MCL3 trials, which represent current standard-of-care regimens. In the univariate model, mutations of TP53 (11%) and NOTCH1 (4%), and deletions of TP53 (16%) and CDKN2A (20%) were significantly associated with inferior outcomes (together with MIPI, MIPI-c, Blastoid morphology and Ki67>30%); however, in multivariate analyses only TP53 mutations (HR=6.2, p<0.0001) retained prognostic impact for overall survival (OS), while TP53 mutations (HR=6.9, p<0.0001) and MIPI-c high-risk (HR=2.6, p=0.003) had independent prognostic impact on time to relapse. TP53-mutated cases had a dismal outcome with a median OS of 1.8 years and 50...

Idiotypes, that is the collections of any immunoglobulin's specific epitopes, have been historically used in different ways for cancer treatment as immunotherapy tools. Inherently, the way they are actually employed mostly depends on the type of tumor cell target. The first such attempts consisted in the administration of monoclonal, antiidiotype antibodies to patients with B-cell-lymphoma. They were able to show clinical activity, but were later abandoned due to both logistical constrains and the emergence of idiotype variants which could escape their action. Later, idiotype antibodies were also used as vaccines to stimulate the patient's immune system against the same type of tumors, a setting in which our group has provided the first formal proof of principle of clinical benefit associated with the use of a human cancer vaccine. Several approaches to enhance the efficacy of these idiotype vaccines have been described in recent years, some of them with encouraging results.

Rationale: Standard therapy for Wegener's granulomatosis is fraught with substantial toxicity and not always effective. B lymphocytes have been implicated in the pathogenesis of Wegener's granulomatosis. Their depletion has been proposed as salvage therapy for refractory disease. Earlier encouraging reports are confounded by concomitant immunosuppressive medications and include only limited available biomarker data. Objectives: To evaluate the efficacy and safety of rituximab for remission induction in refractory Wegener's granulomatosis.

Dendritic cells (DCs) exposed to tumor antigens followed by treatment with T h 1-polarizing differentiation signals have paved the way for the development of DC-based cancer vaccines. Critical parameters for assessment of the optimal functional state of DCs and prediction of the vaccine potency of activated DCs have in the past been based on measurements of differentiation surface markers like HLA-DR, CD80, CD83, CD86, and CCR7 and the level of secreted cytokines like interleukin-12p70. However, the level of these markers does not provide a complete picture of the DC phenotype and may be insufficient for prediction of clinical outcome for DC-based therapy. We therefore looked for additional biomarkers by investigating the differential expression of microRNAs (miRNAs) in mature DCs relative to immature DCs. A microarray-based screening revealed that 12 miRNAs were differentially expressed in the two DC phenotypes. Of these, four miRNAs, hsa-miR-155, hsa-miR-146a, hsa-miR-125a-5p, and hsa-miR-29a, were validated by real-time polymerase chain reaction and northern blotting. The matured DCs from 12 individual donors were divided into two groups of highly and less differentiated DCs, respectively. A pronounced difference at the level of miRNA induction between these two groups was observed, suggesting that quantitative evaluation of selected miRNAs potentially can predict the immunogenicity of DC vaccines. ᭧

Development of drug resistance represents the major cause of cancer therapy failure, determines disease progression and results in poor prognosis for cancer patients. Different mechanisms are responsible for drug resistance. Intrinsic genetic modifications of cancer cells induce the alteration of expression of gene controlling specific pathways that regulate drug resistance: drug transport and metabolism; alteration of drug targets; DNA damage repair; and deregulation of apoptosis, autophagy, and pro-survival signaling. On the other hand, a complex signaling network among the entire cell component characterizes tumor microenvironment and regulates the pathways involved in the development of drug resistance. Gut microbiota represents a new player in the regulation of a patient’s response to cancer therapies, including chemotherapy and immunotherapy. In particular, commensal bacteria can regulate the efficacy of immune checkpoint inhibitor therapy by modulating the activation of immune responses to cancer. Commensal bacteria can also regulate the efficacy of chemotherapeutic drugs, such as oxaliplatin, gemcitabine, and cyclophosphamide. Recently, it has been shown that such bacteria can produce extracellular vesicles (EVs) that can mediate intercellular communication with human host cells. Indeed, bacterial EVs carry RNA molecules with gene expression regulatory ability that can be delivered to recipient cells of the host and potentially regulate the expression of genes involved in controlling the resistance to cancer therapy. On the other hand, host cells can also deliver human EVs to commensal bacteria and similarly, regulate gene expression. EV-mediated intercellular communication between commensal bacteria and host cells may thus represent a novel research area into potential mechanisms regulating the efficacy of cancer therapy.

To test the hypothesis that homoeopathy is a placebo by examining its effect in patients with allergic rhinitis and so contest the evidence from three previous trials in this series. Randomised, double blind, placebo controlled, parallel group, multicentre study. Four general practices and a hospital ear, nose, and throat outpatient department. 51 patients with perennial allergic rhinitis. Random assignment to an oral 30c homoeopathic preparation of principal inhalant allergen or to placebo. Changes from baseline in nasal inspiratory peak flow and symptom visual analogue scale score over third and fourth weeks after randomisation. Fifty patients completed the study. The homoeopathy group had a significant objective improvement in nasal airflow compared with the placebo group (mean difference 19.8 l/min, 95% confidence interval 10.4 to 29.1, P=0.0001). Both groups reported improvement in symptoms, with patients taking homoeopathy reporting more improvement in all but one of the centr...

Natural killer (NK) cells are potent innate immune system effector lymphocytes armed with multiple mechanisms for killing cancer cells. Given the dynamic roles of NK cells in tumor surveillance, they are fast becoming a next-generation tool for adoptive immunotherapy. Many strategies are being employed to increase their number and improve their ability to overcome cancer resistance and the immunosuppressive tumor microenvironment. These include the use of cytokines and synthetic compounds to bolster propagation and killing capacity, targeting immune-function checkpoints, addition of chimeric antigen receptors (CARs) to provide cancer specificity and genetic ablation of inhibitory molecules. The next generation of NK cell products will ideally be readily available as an “off-the-shelf” product and stem cell derived to enable potentially unlimited supply. However, several considerations regarding NK cell source, genetic modification and scale up first need addressing. Understanding NK...

Two rabies post-exposure therapies were comparatively evaluated: BALB/c mice were challenged at day 0 with rabies virus and then received either a single dose of rabies DNA vaccine administered at day 0, or five doses of cell culture-derived rabies vaccine administered at days 0, 3, 7, 15 and 28. Both regimens, rapidly triggered protective levels of neutralizing antibodies against rabies virus in vaccinated mice. In addition, one injection of DNA vaccine protected 53% of the challenged mice, compared to 40% of mice protected after five injections of cell culture-derived vaccine. We conclude that rabies post-exposure vaccination in BALB/c mice, based on a single administration of rabies DNA vaccine might be at least as effective as five injections of cell culture-derived vaccine.

It is generally accepted that human and experimental tumor cells can lose major histocompatibility complex (MHC) class I molecules. These human leukocyte antigen (HLA) losses are detected when the primary tumor breaks the basal membrane, invades the surrounding tissues, and starts to metastasize. These altered HLA class I phenotypes probably constitute the major tumor escape mechanism facing anti-tumor T-cell mediated responses. Thus, it is important to characterize these phenotypes in clinical tumor samples, analyze the mechanism(s) responsible for them, and counsel patients before and during peptide anti-cancer immunotherapy. The present paper summarizes the most relevant altered HLA class I phenotypes found in human tumor samples, indicates their frequency, and outlines the mechanisms implicated. This review also points out that the natural killer (NK) escape mechanism of HLA class I deficient cancer cells is yet to be defined. Knowledge accumulated to date reveals that HLA class I molecules are an important crossroad in tumor immunology. Human Immunology 61, 65-73 (2000).

Allergic rhinitis (AR) is one of the most common diseases affecting adults. It is the most common chronic disease in children in the United States today and the fifth most common chronic disease in the United States overall. AR is estimated to affect nearly 1 in every 6 Americans and generates $2 to $5 billion in direct health expenditures annually. It can impair quality of life and, through loss of work and school attendance, is responsible for as much as $2 to $4 billion in lost productivity annually. Not surprisingly, myriad diagnostic tests and treatments are used in managing this disorder, yet there is considerable variation in their use. This clinical practice guideline was undertaken to optimize the care of patients with AR by addressing quality improvement opportunities through an evaluation of the available evidence and an assessment of the harm-benefit balance of various diagnostic and management options. The primary purpose of this guideline is to address quality improvem...

This study concerns a woman with a very specific phobia of free-flying wasps. Her underlying and disabling belief was that she was allergic to wasp venom and, if stung, would certainly die. A behavioural approach, such as systematic desensitization and exposure, was not thought suitable because of the patient's pattern of fear. Instead, the treatment of choice was an allergy test to directly challenge her belief. The allergy test was negative and led to a dramatic improvement which was maintained 1 year after treatment. r

Cocaine is more and more used and abused in France. Cocaine dependence is quite serious and is associated with numerous adverse health consequences. No effective pharmacotherapy for cocaine dependence is yet available. Recent advances in neurobiology, brain imaging and some clinical trials suggest that certain medications that modulate GABAergic, dopaminergic, and glutamatergic systems, as well as immunotherapy, show promise in the treatment of cocaine addiction. Recent controlled clinical studies have tested some of these drugs, which act on the various neurobiological circuits modified by cocaine exposure and clinically improve patients' symptoms. Pharmacological agents such as modafinil, GABAergic agents (baclofen, topiramate, tiagabin, and vigabatrin), disulfiram, aripiprazole, N-acetylcysteine and cocaine vaccine seem very promising in the treatment of cocaine dependence. However, this must be confirmed in larger patient populations.