Nonspecific Immunotherapy Research Articles

Immunotherapy of pancreatic cancer—weal and woe

We appreciated reading the commentary “Pancreatic ductal adenocarcinoma—a new hope?” of Irving and Lobo (1) on our recent paper in the British Journal of Cancer (2). Indeed, pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers in the world. At present, only multimodal treatment including surgical resection can prolong survival of patients with this disease (3). Therefore, new therapeutic approaches against PDAC are urgently needed. One new option is to apply immunotherapy for these patients. Immunotherapy possesses a bright spectrum of approaches: (I) passive immunotherapy includes a treatment of patients with monoclonal antibodies (specific immunotherapy) or checkpoint inhibitors (non-specific immunotherapy); (II) cancer vaccines and cellular therapy belong to the active immunotherapy as well as interferon treatment (non-specific immunotherapy).

Current Status and Future Prospects of Peptide-Based Cancer vaccines

Cancer immunotherapy has attracted attention worldwide owing to the recent development of immune checkpoint inhibitors. However, these therapies have shown limited efficacy, and further advancements are needed before these modalities can progress to widespread use. Immune checkpoint inhibitors are a type of nonspecific cancer immunotherapy, and antitumor effects are only observed when cancer-specific T cells are found within the nonspecifically activated T-cell group. In order to facilitate the development of potent immunotherapies, selective enhancement of cancer-specific T cells is essential. In this report, we discuss current and future perspectives, including the latest clinical trials of cancer-specific immunotherapies, particularly cancer peptide vaccines.

Intranasal administration of a polyvalent bacterial lysate induces self-restricted inflammation in the lungs and a Th1/Th17 memory signature

Respiratory tract infections are among the most frequent infections in humans causing millions of deaths especially in children and the elderly. Antibiotics and vaccines are the main available tools of control, but resistant strains are continuously arising and available vaccines only account for few of many pathogens involved. Non-specific immunotherapies are an emerging alternative to induce protective immunity at the airways. Mucosally administered polyvalent bacterial lysates (PBLs) have been widely used for decades for prevention of respiratory diseases, but the bases of their proposed therapeutic effectiveness are still controversial. Here, we show that PBL engages a pro-inflammatory gene expression program in macrophages and epithelial cells, induces an acute lung inflammatory response and elicits full protection against pneumococcal pneumonia. Chronic lung inflammation may have pathological consequences, so the capacity to regain local homeostasis after treatment is central. We found that local inflammation is fully resolved and 30 days after treatment lungs become undistinguishable from naïve mice. Nevertheless, this process leaves an immunological imprinting with a Th1/Th17 memory phenotype that may be a marker of the protective immunity elicited. Increasing our understanding of the mechanism of action of PBLs may improve the efficiency of these immunotherapies and expand their range of action.

Drug treatment of allergic rhinitis based on immunological mechanisms of progress

The current treatment of allergic rhinitis remains a challeng for clinician while developing non-specific immunotherapy can make up the disadvantages of routine medications.It has solved the problems like long treatment course of specific immunotherapy or adverse reactions;It has improved the theoretical basis and treatment methods of airway allergic disease.This article reviwed the recent clinical studies about mechanisms of allergic rhinitis.

Profiling the dynamic expression of checkpoint molecules on cytokine-induced killer cells from non-small-cell lung cancer patients

Immune checkpoints associate with dysfunctional T cells, which have a reduced ability to clear pathogens or cancer cells. T-cell checkpoint blockade may improve patient survival. However, checkpoint molecules on cytokine-induced killer (CIK) cell, a non-specific adoptive immunotherapy, remain unknown. In present study, we detected the dynamic expression of eight major checkpoint molecules (CTLA-4, PD-1, PD-L1, TIM-3, CEACAM-1, LAG-3, TIGIT and BTLA) on CIK cells from NSCLC patients. The majority of these molecules, except BTLA, were sharply elevated during the early stage of CIK cell culture. Thereafter, PD-1 and TIGIT expressions decreased gradually towards the initial level (day 0). Moreover, CTLA-4 faded away during the later stage of CIK culture. LAG-3 expression decreased but was still significantly higher than the initial level. Of note, PD-L1 remained stably upregulated during CIK culture compared with PD-1, indicating that PD-L1 might act as an inhibitory molecule on CIK cells instead of PD-1. Furthermore, TIM-3 and CEACAM1 were strongly expressed simultaneously during long-term CIK culture and showed a significant and mutually positive correlation. BTLA displayed a distinct pattern, and its expression gradually decreased throughout the CIK culture. These observations suggested that CIK cells might be partly exhausted before clinical transfusion, characterized by the high expression of PD-L1, LAG-3, TIM-3, and CEACAM-1 and the low expression of TIGIT, BTLA, PD-1, and CTLA-4 compared with initial culture. Our results imply that implementing combined treatment on CIK cells before transfusion via antibodies targeting PD-L1, LAG-3, TIM-3, and CEACAM-1 might improve the efficiency of CIK therapy for NSCLC patients.

Comparison of Phase I/II trials regarding antigen-specific versus non-specific anticancer immunotherapies

Comparison of Phase I/II trials regarding antigen-specific versus non-specific anticancer immunotherapies

Revisiting of cancer vaccine?-Specific immunotherapy comes to field with the biomarker.

Coley et al ., advocated a hypothesis of immune response against malignant tumors and he applied his concept by providing patients with the first cancer immunotherapy in 1906 (1). A few decades later, Bacillus Calmette-Guerin was introduced as a tumor immunotherapy by Old et al . (2). These non-specific immunotherapies have been promising cancer therapies, however, they were not widely accepted because of the unstable efficacy and a lack of understanding of the mechanisms of action. After understanding tumor-associated antigens and after discovering dendritic cells, the cancer immunotherapies primarily studied were specific cancer immunotherapies, such as cancer vaccines and dendritic cell vaccines.

Poly(I:C) potentiates Bacillus Calmette-Guérin immunotherapy for bladder cancer.

Non-specific immunotherapy consisting of intravesical instillation of Bacillus Calmette-Guérin (BCG) is currently the best available treatment to prevent non-muscle-invasive bladder tumor recurrence and progression. This treatment however is suboptimal, and more effective immunotherapeutic approaches are needed. Toll-like receptors (TLRs) play a major role in the activation of the immune system in response to pathogens and danger signals but also in anti-tumor responses. We previously showed that human urothelial cells express functional TLRs and respond to TLR2 and TLR3 agonists. In this study, we analyzed the potential of polyinosinic:polycytidylic acid [poly(I:C)], a TLR3 agonist, to replace or complement BCG in the treatment of non-muscle-invasive bladder cancer. We observed that poly(I:C) had an anti-proliferative, cytotoxic, and apoptotic effect in vitro on two low-grade human bladder cancer cell lines, MGH-U3 and RT4. In MGH-U3 cells, poly(I:C) induced growth arrest at the G1-S transition. Poly(I:C) also increased the immunogenicity of MGH-U3 and RT4 cells, inducing the secretion of MHC class I molecules and of pro-inflammatory cytokines. By comparison, poly(I:C) had less in vitro impact on two high-grade human bladder cancer cell lines, 5637 and T24, and on MBT-2 murine high-grade bladder cancer cells. The latter can be used as an immunocompetent model of bladder cancer. The combination poly(I:C)/BCG was much more effective in reducing MBT-2 tumor growth in mice than either treatment alone. It completely cured 29% of mice and also induced an immunological memory response. In conclusion, our study suggests that adding poly(I:C) to BCG may enhance the therapeutic effect of BCG.

Human papillomavirus infection mechanism and vaccine of vulva carcinoma

AbstractVulvar carcinoma is a rare tumor occurring in female patients. Though more than 40% of vulva cancers are due to the infection of human papillomavirus (HPV), understanding of HPV and vulvar carcinoma is insufficient. HPV expression is regulated by cellular and viral transcription factors that bind to specific elements within the ligase chain reaction. These proteins bind with different affinity to host cell proteins and disrupt normal epithelial differentiation and apoptosis. Immunotherapy does not target tumors, but instead targets the host immune system. Active immunotherapy is tumor-targeting or immune-targeting monoclonal antibodies and vaccines. Nonspecific active immunotherapy is mainly cytokine therapy. In the treatment and prevention of HPV, the most popular research projects were regarding peptide, recombinant protein and DNA-based vaccines, recombinant virus and other targets in HPV infection. Since the cervix and vulva are both susceptible areas, these studies may be able to help reduce prevalence of vulvar precancerous lesions and prevent all cancers caused by HPV.

Immunotherapy for Renal Cell Carcinoma

Renal cell carcinoma is characterised by chemo and radioresistance. Although drugs targeting angiogenesis and intracellular signaling have become the mainstay of systemic therapy for renal cell carcinoma in the last decade, latest immunotherapeutic approaches have achieved promising results. To review the development of immunotherapy for renal cell carcinoma, especially the results of published studies using novel immunotherapeutic agents including checkpoint inhibitors. It has long been known that nonspecific immunotherapy may result in long term complete remission in a small number of patients. Advances in immunology have led to the renewal of interest in the use of anticancer immunotherapy for metastatic renal cell carcinoma. Promising results in phase I and II studies have been achieved using monoclonal antibodies against PD 1 receptor and its ligand. Studies comparing immunotherapy to standard targeted therapies are ongoing.

POSSIBILITIES OF OPTIMIZATION OF PREOPERATIVE POLYCHEMOTHERAPY IN PATIENTS INVASIVE CERVICAL CANCER

A comparative evaluation of different methods of neoadjuvant chemotherapy in 67 patients with locally advanced cervical cancer (T1b2-2bN0-1M0 stages) in age from 25 to 48 years was done. Main group included patients, received neoadjuvant chemotherapy in combination with plasmapheresis and non-specific immunotherapy at the first stage of the treatment. The control group included patients who underwent standard neoadjuvant chemotherapy. In both groups the same cytostatics were used. It was established that using of neoadjuvant chemotherapy combined with plasmapheresis and immunotherapy helps to achieve pronounced clinical effect, improve disease-free survival, reduce the frequency and severity of complications of specific treatment and delay the relapse and metastasizing of the disease.

Salmonella enterica serovar Typhimurium combined with CHOP chemotherapy for non Hodgkin Lymphoma.

Salmonella enterica serovar Typhimurium combined with CHOP chemotherapy for non Hodgkin Lymphoma.

Active specific immunotherapy: Using tumor heterogeneity to successfully fight cancer

Active specific immunotherapy: Using tumor heterogeneity to successfully fight cancer

Synergistic effects of glycated chitosan with high-intensity focused ultrasound on suppression of metastases in a syngeneic breast tumor model.

Stimulation of the host immune system is crucial in cancer treatment. In particular, nonspecific immunotherapies, when combined with other traditional therapies such as radiation and chemotherapy, may induce immunity against primary and metastatic tumors. In this study, we demonstrate that a novel, non-toxic immunoadjuvant, glycated chitosan (GC), decreases the motility and invasion of mammalian breast cancer cells in vitro and in vivo. Lung metastatic ratios were reduced in 4T1 tumor-bearing mice when intratumoral GC injection was combined with local high-intensity focused ultrasound (HIFU) treatment. We postulate that this treatment modality stimulates the host immune system to combat cancer cells, as macrophage accumulation in tumor lesions was detected after GC-HIFU treatment. In addition, plasma collected from GC-HIFU-treated tumor-bearing mice exhibited tumor-specific cytotoxicity. We also investigated the effect of GC on epithelial–mesenchymal transition-related markers. Our results showed that GC decreased the expression of Twist-1 and Slug, proto-oncogenes commonly implicated in metastasis. Epithelial-cadherin, which is regulated by these genes, was also upregulated. Taken together, our current data suggest that GC alone can reduce cancer cell motility and invasion, whereas GC-HIFU treatment can induce immune responses to suppress tumor metastasis in vivo.

Adult-onset opsoclonus-myoclonus-ataxia syndrome as a manifestation of brazilian lyme disease-like syndrome: a case report and review of literature

Described in 1962, the opsoclonus-myoclonus-ataxia syndrome (OMAS) is a rare, neurologically debilitating disorder with distinct characteristics that may begin in childhood or adult life. Although many cases remain without etiological diagnosis, others are related to neoplasms and infectious diseases. We report a 41-year-old previously healthy male with an 8-day history of headache, vertigo, nausea, vomiting, and nystagmus. After a normal brain computed tomography and lymphocytic pleocytosis in cerebral spinal fluid (CSF), intravenous acyclovir therapy was initiated in the emergency room. On the third day of hospitalization, the diagnosis of OMAS was made based on the presence of chaotic and irregular eye movements, dysarthric speech, gait instability, generalized tremor, and myoclonic jerks. In the face of his neurological worsening, ampicillin followed by nonspecific immunotherapy (methylprednisolone and intravenous immunoglobulin) was prescribed, with mild clinical improvement. After a thorough laboratory workup, the definite diagnosis of neuroborreliosis was established and ceftriaxone (4 g/daily/3 wks) and doxycycline (200 mg/day/2 mo) was administered. Toward the end of the ceftriaxone regimen, the neurologic signs substantially improved. We believe this to be the first case description of OMAS as clinical presentation of Brazilian Lyme disease-like syndrome (Baggio-Yoshinari syndrome).

Successes and limitations of targeted therapies in renal cell carcinoma.

Until recently, the standard treatment for metastatic renal cell carcinoma (RCC) was nonspecific immunotherapy based on interleukin-2 or interferon-α. This was associated with a modest survival benefit and with significant clinical toxicities. The understanding of numerous molecular pathways in RCC, including HIF, VEGF, mTOR, and the consecutive use of targeted therapies since the beginning of 2005 have significantly improved outcomes for patients with metastatic RCC with an overall survival greater than 2 years. At present, at least 7 targeted agents are approved for first and consecutive lines of treatment of clear cell metastatic RCC. Long-term benefit and extended survival may be achieved through the optimal use of targeted therapies: optimal dosing, adverse event management and treatment duration and compliance. Advances in the finding of prognostic factors highlight the potential for personalizing treatment for patients with metastatic RCC. Data regarding the best sequencing of targeted therapies, predictive biomarkers, best timing of surgery, patient risk profiles, understanding of resistance mechanisms and safety of targeted therapies are growing and will provide a further step ahead in the management of advanced RCC. In parallel, a new class of therapeutics is emerging in RCC: immunotherapy; in particular check-point blockade antibodies are showing very promising results.

Au carrefour du cancer

Since the introduction of the concept of immunosurveillance in 1970 by Macfarlane Burnet and Lewis Thomas, cancer immunology has known a significant revolution and an explosion of discoveries. In this regard, manipulation of the immune system in cancer pathology has been a succession of enthusiasms and failures. Thanks to the fundamental achievements during the past three decades, non-specific passive immunotherapy of cancer has shifted to active specific immunotherapy. Thanks to the immunological arsenal (tumor peptides, dendritic cells), the clinical trials have increased but the results were not encouraging. It became clear that the escape of immunosurveillance by tumor cells is under the control of the complex tumor microenvironment and its heterogeneity, complexity and plasticity. The future of immunotherapy lies in an integrative approach to simultaneously boost the immune system and target the tumor microenvironment or combine immunotherapy with conventional treatments. In this review, we will focus on the development of cancer immunotherapy, its realities, failure and hope it raises as the fourth modality of cancer therapy.

Antagonism byGanoderma lucidumPolysaccharides Against the Suppression by Culture Supernatants of B16F10 Melanoma Cells on Macrophage

It is well-documented that macrophages have the functions to regulate antitumor immune response. Antitumor response can be launched by a series of events, starting with inflammation mediated by monocyte/macrophages, which stimulates natural killer and dendritic cells and finally activates the cytotoxic lymphoid system. Monocytes/macrophages may be the first line of defense in tumors. However, specific and nonspecific immunotherapy for human cancer has shown no success or limited success in clinical trials. Part of the reasons attribute to tumor-derived soluble factors that suppress functions of immune cells or induce apoptosis of these cells, including macrophages. Therefore, antagonism of the suppression on the macrophages is an important goal for tumor immunotherapy. To achieve this purpose, Ganoderma lucidum polysaccharides (Gl-PS) with multiple bioactivities were used on mouse peritoneal macrophages incubating with culture supernatants of B16F10 melanoma cells (B16F10-CS). It was shown that the viability, phagocytic activity, NO production, TNF-α production and activity in peritoneal macrophages after activation by lipopolysaccharide were suppressed by B16F10-CS, while the suppressions were fully or partially antagonized by Gl-PS. In conclusion, B16F10-CS is suppressive to the viability, phagocytic activity, NO production, TNF-α production and activity in peritoneal macrophages while Gl-PS had the antagonistic effects against this suppression, suggesting this potential of Gl-PS to facilitate cancer immunotherapy.

Targeted therapy in renal cell carcinoma: moving from molecular agents to specific immunotherapy

Non-specific immunotherapy has been for a long time a standard treatment option for patients with metastatic renal cell carcinoma but was redeemed by specific targeted molecular therapies, namely the VEGF and mTOR inhibitors. After moving treatment for mRCC to specific molecular agents with a well-defined mode of action, immunotherapy still needs this further development to increase its accuracy. Nowadays, an evolution from a rather non-specific cytokine treatment to sophisticated targeted approaches in specific immunotherapy led to a re-launch of immunotherapy in clinical studies. Recent steps in the development of immunotherapy strategies are discussed in this review with a special focus on peptide vaccination which aims at a tumor targeting by specific T lymphocytes. In addition, different combinatory strategies with immunomodulating agents like cyclophosphamide or sunitinib are outlined, and the effects of immune checkpoint modulators as anti-CTLA-4 or PD-1 antibodies are discussed.

Highlights of This Issue

The work of Julien and colleagues represents the joint effort of a public/private consortium to characterize a new collection of patient-derived colorectal cancer models and evaluate drug sensitivity as a means to improve the standard of care. Maintenance of this repository of clinical features, even with the highly heterogeneous colorectal cancers, is allowing correlation with drug sensitivity and patient clinical history. Beyond the cetuximab sensitivity shown to be associated with KRAS status, this collection opens up new avenues to evaluate new targeted therapies or biomarkers in experimental phase II trials. Moreover, the occurrence of metastases emphasizes the value of patient-derived xenograft models as preclinical models relevant for translational research.System xC− plays an important role in growth and progression of cancer and glutathione-based drug resistance. The xCT subunit of system xC− is stabilized by CD44 enabling better regulation of redox status. Baek and colleagues conducted an exploratory clinical trial with (4S)-4-(3-[18F]fluoropropyl)-L-glutamate ([18F]FSPG) in patients with non–small cell lung or breast cancer. The authors observed a high cancer detection rate of [18F]FSPG positron emission tomography (PET) and a correlation of [18F]FSPG uptake with the expression of the xCT subunit of system xC− together with CD44. These findings suggest that [18F]FSPG PET can be used to assess xC− transporter activity in cancer patients.Mixed bacterial vaccine (MBV; Coley's toxins) is a historical, vaguely defined preparation of heat-inactivated Streptococcus pyogenes and Serratia marcescens used as nonspecific immunotherapy in the treatment of cancer. Karbach and colleagues revisit Coley's toxins with a phase I clinical trial examining the immune-modulatory and clinical effects of a new, biochemically well-defined and cGMP-compliant MBV preparation. The study shows safety and evidence of in vivo MBV effects through the production of inflammatory cytokines. These findings clearly indicate that a strong “danger signal” evokes measurable inflammatory immune responses that render MBV as a potent adjuvant treatment in combination with different strategies to treat cancer, including cancer vaccines.Normal tissues are typically more sensitive to the size of daily doses (fractions) of radiotherapy than cancers are. However, recent evidence indicates that breast and prostate cancer are more sensitive to fraction size than is commonly assumed. Using human epidermis as a model, Somaiah and colleagues show that homologous recombination repair of radiation-induced DNA breaks is progressively activated during a course of radiotherapy. This finding correlates with the loss of fractionation sensitivity seen clinically. Adoption of homologous recombination, due to its high fidelity, may explain the loss of fractionation sensitivity in rapidly cycling normal and malignant tissues and suggests a potential approach to individualized treatment.