Medical Treatment of Lung Cancer: Can Immune Cells Predict the Response? A Systematic Review.

The landscape for medical treatment of lung cancer has irreversibly changed since the development of immuno-oncology (IO). Yet, while immune checkpoint blockade (ICB) revealed that T lymphocytes play a major role in lung cancer, the precise dynamic of innate and adaptive immune cells induced by anticancer treatments including chemotherapy, targeted therapy, and/or ICB is poorly understood. In lung cancer, studies evaluating specific immune cell populations as predictors of response to medical treatment are scarce, and knowledge is fragmented. Here, we review the different techniques allowing the detection of immune cells in the tumor and blood (multiplex immunohistochemistry and immunofluorescence, RNA-seq, DNA methylation pattern, mass cytometry, functional tests). In addition, we present data that consider different baseline immune cell populations as predictors of response to medical treatments of lung cancer. We also review the potential for assessing dynamic changes in cell populations during treatment as a biomarker. As powerful tools for immune cell detection and data analysis are available, clinicians and researchers could increase understanding of mechanisms of efficacy and resistance in addition to identifying new targets for IO by developing translational studies that decipher the role of different immune cell populations during lung cancer treatments.

Cellular senescence: Immunosurveillance and future immunotherapy.

In response to persistent DNA damage, induction into cell senescence promotes an immunogenic program which facilitates immune clearance of these damaged cells. Under physiological conditions, senescent cells can activate both innate and adaptive immune responses, functioning to maintain tissue homeostasis. In addition, emerging findings suggest that programmed induction of cell senescence may be important for regulating reproductive processes, partly facilitated by immune clearance. However, likely owing to ageing of the immune system, a failure to eliminate senescent cells can contribute to their persistence in tissues, leading to the development and progression of age-related diseases. Such immune failure may in part be due to activation of the senescence program in immune cells, leading to their dysfunction. Furthermore, senescent cells under certain biological contexts have been shown to instead promote immune suppression, a response that may reflect differences between an acute verses chronic senescent phenotype. In this review, we provide an overview of the research to date concerning senescence immunosurviellance, including a focused discussion on the mechanisms by which macrophages may recognise senescent cells. Senescence immunotherapy strategies as an alternative to senolytics for the removal of senescent cells will also be discussed.

Inmunonutrición: metodología y aplicaciones / Immunonutrition: methodology and applications

La Inmunonutrición es una materia emergente e interdisciplinar, ya que abarca distintos aspectos relacionados con la Nutrición, la Inmunidad, la Infección, la Inflamación y la Injuria o daño tisular, lo que se ha denominado como la Nutrición y las 4 'Ies'. En estas interacciones se encuentran implicados los sistemas endocrino, nervioso e inmune, formando parte la microbiota de este último. Actualmente la microbiota intestinal tiene un papel fundamental no solo a nivel del tracto gastrointestinal sino que presenta además un eje de conexión bilateral con el sistema nervioso. Para el estudio de la Inmunonutrición existen diferentes biomarcadores del sistema inmune que proporcionan información acerca del estado nutricional del individuo. Sin embargo, se debe tener en cuenta que no existe un solo parámetro para evaluar la relación causa-efecto de la nutrición sobre el sistema inmunitario, sino que es un conjunto de biomarcadores a tener en cuenta dependiendo de las distintas situaciones nutricionales. Si bien está claro que se trata de una materia multidisciplinar, no solo se deben focalizar los estudios sobre las interacciones entre la nutrición y el sistema inmune de manera aislada, sino sobre otros sistemas del organismo teniendo en cuenta un gran abanico de factores de confusión y determinantes derivados de las condiciones idiosincrásicas de cada individuo, su genética y su estilo de vida. Por todo ello, la Inmunonutrición permite llevar a cabo una serie de estudios basados fundamentalmente en cuatro líneas de investigación: 1) Evaluación de poblaciones supuestamente sanas pero con riesgo de malnutrición (niños, adolescentes, adultos, gestantes, lactantes, personas mayores y deportistas), 2) Estudio de la evolución de pacientes con enfermedades relacionadas con la nutrición y el sistema inmunitario, 3) Estudio de los efectos de nutrientes, compuestos bioactivos y alimentos convencionales y funcionales sobre el sistema inmunitario; 4) Estudio del impacto del estilo de vida sobre el comportamiento del sistema inmunitario, teniendo como determinantes principales la dieta, el comportamiento alimentario, la actividad física, el sedentarismo, la calidad y cantidad de sueño, y como factor clave, el estrés (AU)

Immunonutrition is an emergent and interdisciplinary subject, since it comprises several aspects related to Nutrition, Immunity, Infection, Inflammation, and Injury or tissue damage, what is known as Nutrition and 4 'Is'. Within these interactions the endocrine, nervous and immune systems are involved, microbiota being a part of the last one. Nowadays, gut microbiota has been shown to play an essential role, not only in the gastrointestinal tract but also into the nervous system, because of its bilateral connection. There are several methods to study Immunonutrition, which allow measuring different immunological biomarkers to provide information about the nutritional status. However, it should be taken into account that there is not a single gold standard parameter to evaluate the cause-effect relationship between nutrition and the immune system. On the contrary, a combination of biomarkers have to be assessed depending on the different nutritional situations. Since Immunonutrition is a multidisciplinary matter as mentioned above, the study on the interactions between nutrition and the immune system has not been exclusively focused as such, but bearing in mind other systems of the organisms as well as a wide range of confounding factors and determinants coming from idiosyncratic features, genes and lifestyle of each individual. Therefore, Immunonutrition allows to study the following research fields: 1) Evaluation of nutritional status in presumably healthy people with risk of malnutrition (children, adolescents, adults, pregnant women, elderly, and sportspeople); 2) Assessment of the evolution and progress of patients with nutrition and immune-related diseases, such as food allergies, eating and metabolic disorders; 3) Evaluation of the effects of nutrients, bioactive compounds and both conventional and functional foods on the immune system; 4) Evaluation of impact of lifestyle determinants on the immune system, such as diet, food behaviour, physical activity, sedentariness, sleep quality and quantity, and as a key factor, stress (AU)

Immunological monitoring to prevent and treat sepsis.

The clinical, human and economic burden associated with sepsis is huge. Initiatives such as the Surviving Sepsis Campaign aim to effectively reduce risk of death from severe sepsis and septic shock. Nonetheless, although substantial benefits raised from the implementation of this campaign have been obtained, much work remains if we are to realise the full potential promised by this strategy. A deeper understanding of the processes leading to sepsis is necessary before we can design an effective suite of interventions. Dysregulation of the immune response to infection is acknowledged to contribute to the pathogenesis of the disease. Production of both proinflammatory and immunosuppressive cytokines is observed from the very first hours following diagnosis. In addition, hypogammaglobulinemia is often present in patients with septic shock. Moreover, levels of IgG, IgM and IgA at diagnosis correlate directly with survival. In turn, nonsurvivors have lower levels of C4 (a protein of the complement system) than the survivors. Natural killer cell counts and function also seem to have an important role in this disease. HLA-DR in the surface of monocytes and counts of CD4+CD25+ T-regulatory cells in blood could also be useful biomarkers for sepsis. At the genomic level, repression of networks corresponding to major histocompatibility complex antigen presentation is observed in septic shock. In consequence, cumulative evidence supports the potential role of immunological monitoring to guide measures to prevent or treat sepsis in a personalised and timely manner (early antibiotic administration, immunoglobulin replacement, immunomodulation). In conclusion, although diffuse and limited, current available information supports the development of large comprehensive studies aimed to urgently evaluate immunological monitoring as a tool to prevent sepsis, guide its treatment and, as a consequence, diminish the morbidity and mortality associated with this severe condition.

Tratamiento de la enfermedad ósea de Paget / Treatment of Paget's disease of bone

La enfermedad ósea de Paget es el paradigma de alteración focal esquelética con remodelado óseo acelerado. A lo largo de los años se han utilizado diferentes fármacos para el control de la actividad pero, desde la introducción de los bifosfonatos en la terapéutica de esta enfermedad, éstos se han convertido en el tratamiento de elección. A lo largo de esta revisión se abordarán de manera actualizada las indicaciones terapéuticas, los fármacos disponibles y la monitorización de la respuesta (AU)

Paget's disease of bone is the paradigm of bone focal distortion with accelerated bone turnover. Over the years, a number of different drugs have been used to control its activity but, since biphosphonates were introduced for the treatment of the disease, they have become the preferred treatment. This review will update the therapeutic indications, available drugs and therapeutic response monitoring (AU)

Immunological monitoring of the tumor immunoenvironment for clinical trials.

Monitoring of immunotherapeutic clinical trials has undergone a considerable change in the last decade resulting in a general agreement that immune monitoring should guide the development of cancer vaccines. The emphasis on immune cell functions and quantitation of antigen-specific T cells have been playing a major role in the attempts to establish meaningful correlations between therapy-induced alterations in immune responses and clinical endpoints. However, one significant unresolved issue in modern immunotherapy is that when a tumor-specific cellular immune response is observed following the course of immunotherapy, it does not always lead to clinically proven cancer regression. This disappointing lack of a correlation between the tumor-specific cytotoxic immune responses and the clinical efficacy of immunotherapy may be explained, among other reasons, by the notion that the analysis of any single immunological parameter is not sufficient to provide clinically feasible information about the complex interactions between different cell subsets in the peripheral blood and immune, tumor, and stromal cells in the tumor milieu. By contrast, a systemic approach is required for improving the quality of a serial monitoring to ensure that it adequately and reliably measures potential changes induced in patients by administered vaccines or immunomodulators. Comprehensive evaluation of the balance between the immunostimulatory and immunosuppressive compartments of the immune system could be critical for a better understanding of how a given immunotherapy works or does not work in a particular clinical trial. New approaches to characterize tumor-infiltrating leukocytes, their phenotypic, biochemical, and genetic characteristics within the tumor microenvironment need to be developed and validated and should complement current monitoring techniques. These immune-monitoring assays for the local tumor immunoenvironment should be developed, validated, and standardized for reliability and consistency in order to establish the overall performance standards.

Conference Scene: Immunotherapy reaches new milestones in cancer eradication.

Biotherapy is widely considered as the fourth treatment modality for patients with cancer, and uses the constantly increasing knowledge in molecular biology, cell biology and immunology. Biotherapy uses naturally occurring biological molecules (e.g., cytokines and antibodies) or works by the manipulation of normal biological mechanisms (controlling or inhibiting tumor growth). Important achievements in anticancer drug development are immunotherapeutic strategies recently approved by the US FDA as well as clinical data of the cancer patients treated in clinical trials. There is a need to expand these novel cancer immunotherapeutic modalities for cancer patients all over the world. To meet that goal, it is essential to spread the information, to summarize the new clinical data and to draw the conclusions from the clinical and preclinical investigations. These frontline tasks can be well advanced by organizing international conferences in this domain in less scientifically developed countries, with a significant tumor burden statistics. Therefore, special efforts were done to organize the 2nd International Cancer Immunotherapy and Immunomonitoring Conference (CITIM-2011) in Hungary.

Screening of mortality in transplant patients using an assay for immune function.

BACKGROUND: So far, the ImmuKnow Immune Cell Function Assay (Cylex, Inc., Columbia, MD, USA) has been used to assess risks of infection and rejection in transplant patients. We hypothesized that the ImmuKnow assay might be used for mortality screening in transplant patients overall. METHODS: In the period of February 2007 to December 2009, at the Uppsala University Hospital, 362 patients who received either kidney, kidney+pancreas, kidney+islet cells, liver or liver+kidney allografts were randomly screened using the ImmuKnow assay. All causes of mortality were compared between two groups: patients with at least one ImmuKnow assay below 175ng/mL and patients with all ImmuKnow assays from 175ng/mL and above. Subsequently, the frequency of rejection within thirty days of the ImmuKnow assay was compared between these two groups. RESULTS: The study included 1031 ImmuKnow assays obtained from the 362 patients. A total of 111 patients had at least one ImmuKnow below 175ng/mL and 251 patients had all their ImmuKnow assays from 175ng/mL and above. By January 31st 2010, 16 of 111 patients (14.4%) with at least one ImmuKnow assay below 175ng/mL were deceased, compared to 13 of 251 patients (5.2%) with all ImmuKnow assays from 175ng/mL and above (p=0.0053, Fisher's exact test). There was no difference in the frequency of rejection between the two groups (19.8% versus 17.5%, p=0.66). CONCLUSIONS: In addition to assessing relative risks of infection and rejection in transplant patients, the ImmuKnow assay may be used to identify patients with increased risk of short-term mortality. Transplant patients being highly overimmunosuppressed as assessed by the ImmuKnow assay do not seem to have a lower risk of short-term rejection.

Novel strategies for immune monitoring in kidney transplant recipients.

The ongoing quandary in kidney transplantation is discovering methods to prolong graft survival. To achieve this, there is a search for optimal methods to use immunosuppressive therapy, where rejection and chronic graft damage is minimized without causing an increased risk of infections, malignancy, or toxicities. The purpose of this review was to discuss the limitations of current immunosuppressant drug monitoring as well as the clinical application of novel methods of monitoring both immunosuppressants and the immune reaction within the allograft.

The current trend of induction and maintenance treatment in patient of different PRA levels: a report on OPTN/UNOS Kidney Transplant Registry data.

We investigate the status of sensitization in kidney transplant recipients and analyze the trend of induction and maintenance therapy in patients of different PRA levels. Despite the fact of the decreased percentages of kidney transplant recipients with presensitization history, the mean PRA levels of all kidney recipients has been increasing in the last 7 years, which is possibly due to the introduction of more sensitive antibody testing techniques or the tendency for kidney allocation organization and clinicians to give priority to patients with elevated PRA once a compatible donor kidney becomes available. The percentage of patients with treated rejection episodes within one year post-transplant were significantly higher in sensitized patients (PRA = 50-100:14.3%, and PRA = 1-49%: 13.9%) than in non-sensitized patients (12.4%). Both 1- and 5-yr graft survival rates have improved in the last 10 years; this was more significant in high PRA patients. Thymoglobulin was the most commonly used induction agent in last 10 years. Its users increased from 10% to 46% in non-sensitized patients, from 12% to 57% in PRA = 1-49% patients, and from 19% to 63% in PRA = 50-100% patients. The users of Campath, IVIg, and Rituximab have been increasing and reached 16%, 20%, and 11% in highly sensitized patients. In the last 5 years, steroid-free patients were 33-36%, 30-37%, and 10-25% for patients with PRA levels of 0, 1-49, and 50-100 respectively. Almost 90% of patients were on Prograf at discharge. Myfortic users have been increasing since 2005 and it may soon replace MMF if long-term follow-up study confirms its safety and efficacy.

Quantitative PET reporter gene imaging of CD8+ T cells specific for a melanoma-expressed self-antigen.

Adoptive transfer (AT) T-cell therapy provides significant clinical benefits in patients with advanced melanoma. However, approaches to non-invasively visualize the persistence of transferred T cells are lacking. We examined whether positron emission tomography (PET) can monitor the distribution of self-antigen-specific T cells engineered to express an herpes simplex virus 1 thymidine kinase (sr39tk) PET reporter gene. Micro-PET imaging using the sr39tk-specific substrate 9-[4-[(18)F]fluoro-3-(hydroxymethyl)-butyl]guanine ([(18)F]FHBG) enabled the detection of transplanted T cells in secondary lymphoid organs of recipient mice over a 3-week period. Tumor responses could be predicted as early as 3 days following AT when a >25-fold increase of micro-PET signal in the spleen and 2-fold increase in lymph nodes (LNs) were observed in mice receiving combined immunotherapy versus control mice. The lower limit of detection was approximately 7 x 10(5) T cells in the spleen and 1 x 10(4) T cells in LNs. Quantification of transplanted T cells in the tumor was hampered by the sr39tk-independent trapping of [(18)F]FHBG within the tumor architecture. These data support the feasibility of using PET to visualize the expansion, homing and persistence of transferred T cells. PET may have significant clinical utility by providing the means to quantify anti-tumor T cells throughout the body and provide early correlates for treatment efficacy.

Detection of human cytomegalovirus-specific T lymphocytes in human blood: comparison of two methods.

BACKGROUND: Human cytomegalovirus (HCMV) infection remains a major cause of morbidity and mortality in immunocompromised patients undergoing allogeneic stem cell transplantation (SCT). In the case of HCMV reactivation, the well-defined detection of virus-specific effector cells in patients might positively impact antiviral treatment. METHODS: We examined blood samples from healthy volunteers serologically typed for HCMV IgG. Based on multicolor flow cytometry analysis, we addressed HCMV-specific CD8(+) effector T lymphocytes using HCMV-specific tetramers for the respective major histocompatibility complex (MHC) class I type. As a second approach, we employed the cytokine secretion assay (CSA), which allows the indirect detection of target-specific CD4(+) and CD8(+) T cells via their interferon (IFN)-gamma secretion upon HCMV pp65 in vitro stimulation. RESULTS: We hypothesized the detection of HCMV-specific lymphocytes in >50% of healthy Caucasians that were IgG-seropositive for HCMV. In terms of specificity, both assays showed comparably good results (specificity 100%, confidence interval >95%). Regarding sensitivity, both assays met the zero hypothesis. However, with 45/52 (86.5%) the tetramer technology was superior to the CSA, which detected 34/52 (65.4%) based on CD8(+) T cells and 41/52 (78.8%) based on both CD4(+) and CD8(+) T cells. DISCUSSION: A good correlation was observed between both assays, although the tetramers addressed only CD8(+) HCMV-specific T cells, whereas IFN-gamma secretion was detected on all T-cell types. Disadvantages of the CSA are the time-consuming stimulation, the extensive cell washing steps and the fact that the target cells are detected indirectly. The analysis with tetramers is rapid and reliable but their general use is hampered because of the restriction to a few HLA types.

Monitoring of minimal residual disease in leukemia, advantages and pitfalls.

The term 'minimal residual disease' (MRD) defines the level of disease detectable in patients in clinical remission during therapy, below the detection limit of conventional methods. Very sensitive methods can be used, able to identify one leukemic cell out of 10,000 normal lymphocytes. In vivo measurements of leukemia cytoreduction reflect the combined effect of clinical and biological variables, thus providing direct information on the effectiveness of treatment in each patient. Thus, these methods can potentially be used for tailoring treatment and personalize the cure. Although MRD studies are becoming an integral part of the modern management of patients with leukemia, several parameters are critical for the application and interpretation of MRD studies, including therapeutic context, timing of sampling, target genes and sensitivity of the polymerase chain reaction (PCR) assay, inter-laboratory standardization (particularly relevant in multicenter studies), selection of patients, retrospective or prospective nature of the study. Methodologies and pitfalls as well as results of clinical uses of MRD will be reviewed in this article by selecting significant examples of its clinical impact in the management of patients with leukemia.

Cancer immunosurveillance and immunoediting: the roles of immunity in suppressing tumor development and shaping tumor immunogenicity.

Cellular transformation and tumor development result from an accumulation of mutational and epigenetic changes that alter normal cell growth and survival pathways. For the last 100 years, there has been a vigorous debate as to whether the unmanipulated immune system can detect and eliminate such altered host derived cells despite the fact that cancer cells frequently express either abnormal proteins or abnormal levels of normal cellular proteins that function as tumor antigens. In this review, we discuss the current state of this argument and point out some of the recent key experiments demonstrating that immunity not only protects the host from cancer development (i.e., provides a cancer immunosurveillance function) but also can promote tumor growth, sometimes by generating more aggressive tumors. The terminology "cancer immunoediting" has been used to describe this dual host protective and tumor promoting action of immunity, and herein we summarize the ever-increasing experimental and clinical data that support the validity of this concept.

Mechanisms of immune evasion by tumors.

In the past decade, basic studies in animal models have begun to elucidate the physiological barriers which impede a successful antitumor immune response. These barriers operate at a number of levels, and involve the tumor, the tumor microenvironment and various components of the innate and adaptive immune systems. In this review, we discuss the multiple mechanisms by which tumors evade an immune response, with an emphasis on clinically relevant strategies to overcome these inhibitory checkpoints.

18th Annual Scientific Meeting of the International Society for Biological Therapy of Cancer. 30 October-2 November 2003, Bethesda, Maryland, USA.

The 18th Annual Scientific Meeting of the International Society for Biological Therapy of Cancer (iSBTc) was held at the Hyatt Regency, Bethesda, MD, close to the National Institutes of Health (NIH) campus. The meeting was organised on behalf of the society by Neil Berinstein from Aventis Pasteur, Toronto, Canada, Janice P Dutcher from Our Lady of Mercy Medical Center, Bronx, NY and Francesco M Marincola from the NIH, Bethesda, MD. The 2003 meeting included 57 oral presentations and > 100 poster presentations. There were > 800 registrants to the Annual Meeting and the multiple satellite symposia. The iSBTc, formerly the Society of Biological Therapy (SBT), was founded by R Oldham in 1984. Its membership has been rapidly growing of late, with > 500 members at present. The purpose of the iSBTc is to bring together those diverse individuals actively investigating biologic agents and biological response modifiers in the treatment of cancer, including clinicians and basic scientists from industry, government and academia. The President of the Society is Dr Michael B Atkins from Beth Israel Deaconess Medical Center, Boston, MA and the Vice President is Ulrich Keilholz from UKBF, Free University Berlin, Germany.

Immune profiling: molecular monitoring in renal transplantation.

Molecular techniques have become a mainstay for most biomedical research. In particular, sensitive methods for gene transcript detection and advanced flow cytometry have been crucial in fostering our understanding of the basic mechanisms promoting allosensitization and adaptive immune regulation. These technologies have been validated in vitro, and in pre-clinical settings, and as such their clinical application is now clearly appropriate. It is becoming increasingly clear that these robust techniques hold much promise to better elucidate human transplant biology, and more importantly, guide clinical decision making with mechanistically-based information. This article will discuss our laboratory's use of several novel technologies, including gene polymorphism analysis, real-time polymerase chain reaction transcript quantification, and multi-color flow cytometry in clinical human renal transplantation. Specific technical methodology will be presented outlining keys for effective clinical application. Clinical correlations will be presented as examples of how these techniques may have clinical relevance. Suggestions for the adaptation of these methods for therapeutic intervention will be given. We propose that clinical transplantation should proceed in close step with modern molecular diagnostics.

Monitoring early inflammation in CF. Infant pulmonary function testing.

Infant pulmonary function tests (iPFTs) have primarily been used as research tools to further define physiologic pulmonary abnormalities in infants and young children with cystic fibrosis (CF). Methodologies used to measure pulmonary function in infants are described, with particular relevance to CF. A comprehensive review of studies and findings in CF infants using iPFTs is presented. Further goals in improving methodologies and in defining pulmonary disease in CF are presented.