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Chimeric antigen receptor (CAR) T cells provide new therapeutic options for patients with relapsed/refractory hematologic malignancies. However, neurotoxicity is a frequent, and potentially fatal, complication. The spectrum of manifestations ranges from delirium and language dysfunction to seizures, coma, and fatal cerebral edema. This novel syndrome has been designated immune effector cell–associated neurotoxicity syndrome (ICANS). In this review, we draw an arc from our current understanding of how systemic and potentially local cytokine release act on the CNS, toward possible preventive and therapeutic approaches. We systematically review reported correlations of secreted inflammatory mediators in the serum/plasma and cerebrospinal fluid with the risk of ICANS in patients receiving CAR T cell therapy. Possible pathophysiologic impacts on the CNS are covered in detail for the most promising candidate cytokines, including IL-1, IL-6, IL-15, and GM-CSF. To provide insight into possible final common pathways of CNS inflammation, we place ICANS into the context of other systemic inflammatory conditions that are associated with neurologic dysfunction, including sepsis-associated encephalopathy, cerebral malaria, thrombotic microangiopathy, CNS infections, and hepatic encephalopathy. We then review in detail what is known about systemic cytokine interaction with components of the neurovascular unit, including endothelial cells, pericytes, and astrocytes, and how microglia and neurons respond to systemic inflammatory challenges. Current therapeutic approaches, including corticosteroids and blockade of IL-1 and IL-6 signaling, are reviewed in the context of what is known about the role of cytokines in ICANS. Throughout, we point out gaps in knowledge and possible new approaches for the investigation of the mechanism, prevention, and treatment of ICANS.

The use of immunotherapy in the treatment of chronic inflammatory conditions has demonstrated important clinical utility across a range of conditions including organ allograft maintenance and autoimmune disorders. However, the observation of increased cancer risk with broadly active immune suppression and concern about increased cancer risk with more targeted immune modulation remain as persistent challenges for clinicians, patients, and regulators. A strong relationship between immune status and cancer outcomes in human populations has been established based on the accumulated epidemiology findings in humans with immune deficiencies, clinical observational and biomarker data from patients, and mechanistic/experimental data. These data have refined our understanding of the role of the immune system in either promoting or suppressing tumor development and growth, and the reciprocal effects on the immune system driven by the tumor. The integration of the epidemiological, clinical and mechanistic data have given rise to several modern conceptual paradigms that capture the complex interactions between tumors and the immune system. Under the Immunoediting Model, tumors and the host immune system co-evolve, and the selective pressure of the immune system can either eliminate the cancer, establish a state of equilibrium, or lead to tumor variants that escape immune surveillance. The Inflammation Model captures the role of chronic inflammation in promoting tumor growth in association with certain cancers. The observation of increased B cell malignancies in patients with either immune deficiencies or chronic immune activation likely results from the unique sensitivity of chronically activated B cells to genetic injury (B cell Lymphoma Model). Finally, because a viral etiology has been identified for a number of cancers, alterations in immune-mediated viral surveillance may underlie cancer risk in humans (Oncogenic Virus Model). The models described above demonstrate formidable complexity when trying to understand the potential risks associated with alterations in immune status that arise from use of therapeutic immunomodulators. These models can be used to guide our assessments when assessing or predicting the risk of cancer associated with immunomodulation, and can be used to guide mechanistic experiments to understand the role of specific components of immunity in regulating or contributing to cancer risk.

In recent years Ecuador has grown a very vital underground cinema industry that relies on three key factors for its current success: First, its strong independence from the traditional and centralized film industry and the exclusiveness of education and means for filmmaking since the production of these underground films is in most of the cases run by non-professional crews (from script writing and direction to acting and post-production). Second, these films have placed their production and reception arena out of the economic and political centers of Quito and Guayaquil, giving space to “lo local” to be represented, but also to be watched on the screen by the same people in their own space of projection. This is due the use of mostly local, legal and pirate, distribution channels. Finally, as we analyze this movement, we propose that what is behind the success of the new “Cine Bajo Tierra” is a vigorous response to, and sometimes a critique of, the disastrous consequences of the application of neoliberal policies in Ecuador. Boasting titles such as Sicarios manabitas [Hitmen from Manabí], Doble trampa [Double trap], El regreso del llanero vengador [The return of the avenging cowboy], Drogas: el comienzo del fin [Drugs: the beginning of the end], Avaricia [Greed], and El ángel de los sicarios [The hitmen’s angel], these films depict scenarios of crude violence, poverty, and merciless surviving behaviors that have found an “appreciation” from their local viewers as a dialectical relationship of self-awareness between filmmakers and audiences who ultimately have suffered the same under the long neoliberal night.

Profound immunosuppression (e.g., AIDS, transplant therapy) is epidemiologically associated with an increased cancer risk, and often with oncogenic viruses. It is currently unclear how broadly this association translates to therapeutics that modulate immunity. A workshop co-sponsored by the FDA and HESI examined how perturbing the immune system may contribute to carcinogenesis, and highlighted priorities for improving non-clinical risk assessment of targeted immunomodulatory therapies. Conclusions from the workshop were as follows. 1) While profound altered immunity can promote tumorigenesis, not all components of the immune system are equally important in defense against or promotion of cancer and a similar cancer risk for all immunomodulatory molecules should not be assumed. 2) Rodent carcinogenicity studies have limitations and are generally not reliable predictors of cancer risk associated with immunosuppression. 3) Cancer risk needs to be evaluated based on mechanism-based weight-of-evidence, including data from immune function tests most relevant to tumor immunosurveillance or promotion. 4) Information from nonclinical experiments, clinical epidemiology and immunomodulatory therapeutics show that immunosurveillance involves a complex network of cells and mediators. To support a weight-of-evidence approach, an increased focus on understanding the quantitative relationship between changes in relevant immune function tests and cancer risk is needed.

Tumor necrosis factor (TNF) is a highly pleiotropic cytokine with multiple activities other than its originally discovered role of tumor necrosis in rodents. TNF is now understood to play a contextual role in driving either tumor elimination or promotion. Using both animal and human data, this review examines the role of TNF in cancer development and the effect of TNF and TNF inhibitors (TNFis) on malignancy risk.A literature review was performed using relevant search terms for TNF and malignancy.Although administration of TNF can cause tumor regression in specific rodent tumor models, human expression polymorphisms suggest that TNF can be a tumor-promoting cytokine, whereas blocking the TNF pathway in a variety of tumor models inhibits tumor growth. In addition to direct effects of TNF on tumors, TNF can variously affect immunity and the tumor microenvironment. Whereas TNF can promote immune surveillance designed to eliminate tumors, it can also drive chronic inflammation, autoimmunity, angiogenesis, and other processes that promote tumor initiation, growth, and spread. Key players in TNF signaling that shape this response include NF-κB and JNK, and malignant-inflammatory cell interactions, each of which may have different responses to TNF signaling. Focusing on rheumatoid arthritis (RA) patients, where clinical experience is most extensive, a review of the clinical literature shows no increased risk of overall malignancy or solid tumors such as breast and lung cancers with exposure to TNFis. Lymphoma rates are not increased with use of TNFis. Conflicting data exist regarding the risks of melanoma and nonmelanoma skin cancer. Data regarding the risk of recurrent malignancy are limited.Overall, the available data indicate that elevated TNF is a risk factor for cancer, whereas its inhibition in RA patients is not generally associated with an increased cancer risk. In particular, TNF inhibition is not associated with cancers linked to immune suppression. A better understanding of the tumor microenvironment, molecular events underlying specific tumors, and epidemiologic studies of malignancies within specific disease indications should enable more focused pharmacovigilance studies and a better understanding of the potential risks of TNFis.

Chimeric antigen receptor (CAR) T-cell immunotherapy has revolutionized the treatment of refractory leukemias and lymphomas, but is associated with significant toxicities, namely cytokine release syndrome (CRS) and neurotoxicity. A major barrier to developing therapeutics to prevent CAR T cell–mediated neurotoxicity is the lack of clinically relevant models. Accordingly, we developed a rhesus macaque (RM) model of neurotoxicity via adoptive transfer of autologous CD20-specific CAR T cells. Following cyclophosphamide lymphodepletion, CD20 CAR T cells expand to 272 to 4,450 cells/μL after 7 to 8 days and elicit CRS and neurotoxicity. Toxicities are associated with elevated serum IL6, IL8, IL1RA, MIG, and I-TAC levels, and disproportionately high cerebrospinal fluid (CSF) IL6, IL2, GM-CSF, and VEGF levels. During neurotoxicity, both CD20 CAR and non-CAR T cells accumulate in the CSF and in the brain parenchyma. This RM model demonstrates that CAR T cell–mediated neurotoxicity is associated with proinflammatory CSF cytokines and a pan–T cell encephalitis. Significance: We provide the first immunologically relevant, nonhuman primate model of B cell–directed CAR T-cell therapy–mediated CRS and neurotoxicity. We demonstrate CAR and non-CAR T-cell infiltration in the CSF and in the brain during neurotoxicity resulting in pan-encephalitis, accompanied by increased levels of proinflammatory cytokines in the CSF. Cancer Discov; 8(6); 750–63. ©2018 AACR. This article is highlighted in the In This Issue feature, p. 663

Background The epidemiology of disseminated Mycobacterium avium complex (DMAC) infection in the United States is changing. Previously most DMAC occurred in adults with advanced AIDS. Since the development of effective antiretroviral therapy, the incidence of DMAC in AIDS has fallen more than 10-fold. Malignancy, immunosuppression, and tumor necrosis factor inhibitors are known risk factors for DMAC. We sought to describe the epidemiology of DMAC disease in HIV seronegative patients in the United States. Methods We performed a retrospective analysis of a commercial database (Explorys Inc., Cleveland, OH). This database contains an aggregate of Electronic Health Record data from 26 major integrated healthcare systems in the United States from 1999 to present. Explorys contains de-identified information from over 50 million patients, 360 hospitals, and over 317,000 providers. We identified a total of 571 persons diagnosed with DMAC, based on Systemized Nomenclature of Medicine-Clinical Terms. We excluded 80 HIV-infected and identified association of the infection with known risk factors. Results Of 570 patients, 491 HIV-uninfected patients with DMAC were studied. Underlying structural pulmonary diseases were COPD and bronchiectasis (51% and 47%, respectively). Two hundred ten patients had concomitant malignancy of which lung cancer was the most frequent (43%). Seventy-nine percent were receiving corticosteroids and 10 patients (2%) were on TNF inhibitors (2%). Conclusion In this study, majority of patients with DMAC are HIV-uninfected. Larger studies should focus on identifying the prevalence and risk factors of DMAC in the post-AIDS era. Table: Distribution of the Sample According to Associated Conditions N = 490 (%) Age, years Senior (>65) 330 (67%) Adult (18–65) 160 (33%) Female 310 (63) Smoking history 420 (86) Bronchiectasis 230 (47) Previous pulmonary tuberculosis 40 (8) COPD 250 (51) HTN 310 (63) Diabetes mellitus 130 (27) Chronic kidney disease 110 (22) Interstitial lung disease 90 (18) Inflammatory bowel disease 20 (4) Concomitant malignancy 210 (43) Lung 60 (28) GI 50 (23) Head and neck 40 (19) Hematological 40 (19) Renal 30 (14) Chronic oral corticosteroid treatment 390 (79) Tumor necrosis factor alpha inhibitor therapy 10 (2) COPD; chronic obstructive pulmonary disease, HTN; hypertension, GI gastrointestinal. Disclosures All authors: No reported disclosures.

Background Extended-spectrum β-lactamase-producing Enterobacteriaceae (ESBL-PE) were described first in relation to hospital-acquired infections. However, infections by these organisms acquired in the community have become a public health problem. There are no well-known risk factors for acquisition of these bacteria in the community. Surface waters and sanitation conditions may serve as reservoir and transmission. Methods We conducted a retrospective study over 12 months of patients who had positive cultures with ESBL-PE in our laboratory. We excluded patients with hospitalization in the previous 3 months, those in skilled nursing facilities, and those whose culture was taken 3 or more days after hospitalization. Geographic Information System analysis was performed based on patient’s residence, population, and sewer overflow public data. Results Among 485 patients with cultures positive for ESBL-PE in 2018, 64 were included in the study. Mean age was 54, and 68.7% were females. Organisms isolated were E. coli (78.2%) and K. pneumoniae ESBL (21.8%). These were isolated from urine 47 (73.4%), blood 5 (7.8%), abscess 6 (9.3%), ulcers 5 (7.8%), and sputum 1 (1.5%). Antibiotic exposure in the preceding 3 months was noted in 12 patients (18.7%). Spatial distribution of patients in the community was not random based on nearest neighbor analysis (Z score = −2.6). Kernel density estimation showed clustering of cases. Infection rates were calculated per census tracts. There was poor correlation between infection rate and mean family income (R2 = 0.18, P = 0.017). Analysis of Kernel density estimations showed that sewer overflow distribution explained over 50% of the variance of distribution of cases with ESBL-PE (R2 = 0.51, P < 0.001). Conclusion Patients presenting with infections due to ESBL-PE acquired in the community did not have a random spatial distribution. Other factors besides prior antibiotic use and financial status should be investigated. Proximity to sanitary sewer overflows may be a contributing factor. Location of residence within a community may aid in identifying patients at risk for acquisition of ESBL-PE. Disclosures All Authors: No reported Disclosures.

Oncolytic viruses that selectively lyse tumor cells with minimal damage to normal cells are a new area of therapeutic development in oncology. An attenuated herpesvirus encoding the granulocyte-macrophage colony stimulating factor (GM-CSF), known as talimogene laherparepvec (T-VEC), has been identified as an attractive oncolytic virus for cancer therapy based on preclinical tumor studies and results from early-phase clinical trials and a large randomized Phase III study in melanoma. In this review, we discuss the basic biology of T-VEC, describe the role of GM-CSF as an immune adjuvant, summarize the preclinical data, and report the outcomes of published clinical trials using T-VEC. The emerging data suggest that T-VEC is a safe and potentially effective antitumor therapy in malignant melanoma and represents the first oncolytic virus to demonstrate therapeutic activity against human cancer in a randomized, controlled Phase III study.

The PAU (Physics of the Accelerating Universe) project goal is the study of dark energy with a new photometric technique aiming at obtaining photo-z resolution for Luminous Red Galaxies (LRGs) roughly one order of magnitude better than current photometric surveys. To accomplish this, a new large field of view camera (PAUCam) has been built and commissioned at the William Herschel Telescope (WHT). With the current WHT corrector, the camera covers ~1 degree diameter Field of View (FoV). The focal plane consists of 18 2kx4k Hamamatsu fully depleted CCDs, with high quantum efficiency up to 1 μm. To maximize the detector coverage within the FoV, filters are placed in front of the CCD's inside the camera cryostat (made of carbon fiber material) using a challenging movable tray system. The camera uses a set of 40 narrow band filters ranging from ~4400 to ~8600 angstroms complemented with six standard broad-band filters, ugrizY. Here, we describe the camera and its first commissioning results. The PAU project aims to cover roughly 100 square degrees and to obtain accurate photometric redshifts for galaxies down to iAB ~ 22:5 detecting also galaxies down to iAB ~ 24 with less precision in redshift. With this data set we will obtain competitive constraints in cosmological parameters using both weak lensing and galaxy clustering as main observational probes.

Regulatory T-cell (Treg) modulation is developing as an important therapeutic opportunity for the treatment of a number of important diseases, including cancer, autoimmunity, infection, and organ transplant rejection. However, as demonstrated with IL-2 and TGN-1412, our understanding of the complex immunological interactions that occur with Treg modulation in both non-clinical models and in patients remains limited and appears highly contextual. This lack of understanding will challenge our ability to identify the patient population who might derive the highest benefit from Treg modulation and creates special challenges as we transition these therapeutics from non-clinical models into humans. Thus, in vivo testing in the most representative animal model systems, with careful progress in the clinic, will remain critical in developing therapeutics targeting Treg and understanding their clinical utility. Moreover, toxicology models can inform some of the potential liabilities associated with Treg modulation,...

Background Schistosomiasis is to a degree a disease of contact with fecally contaminated surface waters, rather than ingestion. Repeated treatments with praziquantel reduce schistosomiasis prevalence and morbidity; however, transmission persists and prevalence of infection often recover within a few years. Methods In a community in rural Bahia, Brazil that straddles a shallow river, we surveyed and treated all individuals that tested positive for schistosomiasis by Kato Katz in stools in 2009, 2012, 2013, 2015, and 2017. Upstream and downstream, as well as common water contact sites along the river were sampled and analyzed by microbial source tracking for human fecal indicator markers. The location of each home and water contact site was registered with a handheld GPS unit. Spatial analyses were performed by using QGIS software, version 2.14. Results The population in the village was 460 in 2009, with minimal fluctuation over the study period. In 2009, schistosomiasis prevalence was 45%. After successive rounds of community-wide treatment with praziquantel, in the years 2012, 2013, 2015, and 2017, prevalence decreased to 24%, 16%, 13%, and 1.6%, respectively. Among the river water samples, human fecal indicator markers were detectable in minimal quantities upstream of the village. The highest concentrations were found in the downstream sections of the village. Hotspot analysis, raster calculator, and nearest neighbor analysis were used to display and analyze the prevalence of schistosomiasis. Distribution of infection was widespread initially and clustered in the downstream sections of the village after successive treatments. Conclusion In this rural community in Brazil, sustained decrease in schistosomiasis prevalence was seen after multiple community-wide treatments over 5 years. Reinfection was not distributed randomly but concentrated in the downstream portion of the village, where human fecal water contamination is increased. Targeting sanitation in key areas may decrease sources of transmission persistence after cessation of community-wide treatment efforts. Disclosures All authors: No reported disclosures.

Dietary factors influence the development of cardiovascular disease (CVD). The diet of Alaskan Eskimos differs from that of other populations. We surveyed Eskimo adults in Northwest Alaska to document their usual dietary intakes, differences based on gender and age, and sources of selected nutrients, and to generate appropriate dietary advice to reduce CVD. Interviewers surveyed 850 men and women 17-92 y old, using a quantitative food-frequency instrument. We observed many significant (chi(2) analysis P < 0.05) differences in nutrient intakes among 3 age-groups. Energy intake from carbohydrate was negatively related to participant age-group (P < or = 0.01). Energy intake from all fats (P < 0.001) and polyunsaturated fat (P < or = 0.01) was positively related to age-group among both men and women in contrast to other studies in which age differences were either not observed or decreased with age. Native foods were major sources of monounsaturated and polyunsaturated fats, including 56% of (n-3) fatty acids primarily from seal oil and salmon. However, Native foods contributed significantly less to the diets of young adults than to those of elders, especially among women. Store-bought foods were the main sources of energy, carbohydrate, fat, saturated fat, and fiber for all adults. Based on their nutrient density and potential to inhibit CVD, continued consumption of traditional foods is recommended. Variations in intake by age may portend changing eating patterns that will influence CVD as participants age. These data will contribute to understanding dietary risk factors for cardiovascular disease in this population.

This paper presents a novel approach for the problem of detecting and extracting the QRS complex of electrocardiogram signals for different kinds of arrhythmias. First, an autocorrelation function is used in order to obtain the period of an electrocardiagram signal and then the Hilbert transform is applied to obtain R-peaks and beats. Twenty three different records extracted from the MIT-BIH arrhythmia database were used to validate the proposed approach. In this testing has been observed a 99.9 % of accuracy in detecting the QRS complexity, being a positive result in comparison with other recent researches.

For patients undergoing transrectal ultrasound-guided biopsy of the prostate (TRUBP), use of rectal screening culture results to guide antimicrobial prophylaxis was effective for prevention of fluoro-quinolone-resistant Escherichia coli infections. In practice, elimination of infections after TRUBP required the rectal screening protocol and addition of gentamicin for patients missing prior screening.

This paper presents a method for modeling and identification of electrocardiogram signals; the proposed method consists of two phases; the first one is focused on obtaining the period of an ECG signal using a procedure of autocorrelation. The second phase obtains R-peaks using the Hilbert transform. Finally, an Artificial Neural Network using a retraining technique is applied for the prediction stage; this has been validated using the record 100 from the MIT-BIH arrhythmia database. Results confirm that the presented approach for detection of the ECG complex obtains 100% accuracy. The performance of the prediction method is promising due to the root mean squared errors of the prediction are of 0.029, 0.04, and 0.059 of the ECG amplitude, for 1, 2, and 3 steps ahead, respectively.

Nonclinical to clinical correlations of biotherapeutics generally support the utility of nonclinical studies for predicting adverse clinical responses, if the fidelity of the pharmacodynamics of human biotherapeutics is maintained in nonclinical models. However, toxicities associated with immunomodulation—opportunistic infections, cytokine release syndrome, and other indirect outcomes of immunomodulation—are less likely to be predicted by routine nonclinical studies. Predicting adverse reactions to biotherapeutics is further complicated by the rapidly expanding array of modalities. Predicting adverse reactions to biotherapeutics is further complicated by the rapidly expanding array of modalities. In this chapter, we discuss safety considerations for establishing the safety profiles for various modalities of biotherapeutics in early nonclinical development and provide examples of adverse events, with special emphasis on immunotoxicity. Special approaches to predicting immunotoxicity due to on-target and off-target toxicities to ensure the well-being of healthy volunteers as well as patients are also discussed. Novel and scientifically appropriate additional nonclinical studies are necessary to make informed drug development decisions in addition to information gathered from routine nonclinical studies.

The Physics of the Accelerating Universe (PAU) is a project whose main goal is the study of dark energy. For this purpose, a new large field of view camera (the PAU Camera, PAUCam) is being built. PAUCam is designed to carry out a wide area imaging survey with narrow and broad band filters spanning the optical wavelength range. The PAU Camera is now at an advance stage of construction. PAUCam will be mounted at the prime focus of the William Herschel Telescope. With the current WHT corrector, it will cover a 1 degree diameter field of view. PAUCam mounts eighteen 2k×4k Hamamatsu fully depleted CCDs, with high quantum efficiency up to 1 μm. Filter trays are placed in front of the CCDs with a technologically challenging system of moving filter trays inside the cryostat. The PAU Camera will use a new set of 42 narrow band filters ranging from ~4400 to ~8600 angstroms complemented with six standard broad-band filters, ugrizY. With PAUCam at the WHT we will carry out a cosmological imaging survey in both narrow and broad band filters that will perform as a low resolution spectroscopic survey. With the current survey strategy, we will obtain accurate photometric redshifts for galaxies down to i AB ~22.5 detecting also galaxies down to i AB ~24 with less precision in redshift. With this data set we will obtain competitive constraints in cosmological parameters using both weak lensing and galaxy clustering as main observational probes.

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) S9 is the first international regulatory guidance document devoted to a specific therapeutic area, highlighting its importance in harmonizing regulatory expectations for the nonclinical development of therapeutics designed to treat advanced cancer. ICH S9 successfully outlines the core requirements for the nonclinical development of novel oncology therapeutics, and the unique risk-benefit considerations for expediting drug development to treat these most grievous diseases. However, development companies and regulatory agencies have had limited opportunity to apply this guidance, so our collective experience in developing therapeutics under the guidance is limited. Discussed here are several key areas of ambiguity in the guidance, including identification of the patient population, selection of the initial safe dose for first-in-human trials, and requirements for nonclinical recovery data.

An important safety consideration for developing new therapeutics is assessing the potential that the therapy will increase the risk of cancer. For biotherapeutics, traditional two-year rodent bioassays are often not scientifically applicable or feasible. This paper is a collaborative effort of industry toxicologists to review past and current practice regarding carcinogenicity assessments of biotherapeutics and to provide recommendations. Publicly available information on eighty marketed protein biotherapeutics was reviewed. In this review, no assessments related to carcinogenicity or tumor growth promotion were identified for fifty-one of the eighty molecules. For the twenty-nine biotherapeutics in which assessments related to carcinogenicity were identified, various experimental approaches were employed. This review also discusses several key principles to aid in the assessment of carcinogenic potential, including (1) careful consideration of mechanism of action to identify theoretical risks, (2) careful investigation of existing data for indications of proliferative or immunosuppressive potential, and (3) characterization of any proliferative or immunosuppressive signals detected. Traditional two-year carcinogenicity assays should not be considered as the default method for assessing the carcinogenicity potential of biotherapeutics. If experimentation is considered warranted, it should be hypothesis driven and may include a variety of experimental models. Ultimately, it is important that preclinical data provide useful guidance in product labeling.

In Mexico the computer science security is growing, but not therefore the initiatives of law nor the standards in the matter of computer science security, although they exist international standard of computer science security the recommendations are not adopted due to infrastructure differences and that contain there, and that cannot be adopted by the Mexican companies. The main idea to propose a methodology and architecture for the small and medium companies is with the purpose of providing a tool that allows the companies to count on basic a computer science security system that allows diminishing the security problems.

Talimogene laherparepvec is an investigational oncolytic immunotherapy based on a modified herpes simplex virus type-1 (HSV-1) designed to selectively replicate in tumors and to initiate a systemic immune response to target cancer cells that have metastasized. Intralesional administration of talimogene laherparepvec is intended to result in oncolysis within injected tumors. Iterative viral replication of virus within permissive tumor tissue results in lytic cell destruction and local release of progeny virus and tumor derived antigens. GM-CSF, a product of the viral transgene, is also produced locally such that it can recruit and stimulate antigen presenting cells which, in addition to relevant tumor-derived antigens, are required for the initiation of a systemic antitumor immune response. Recently, in a retrospective analysis of a Phase III melanoma trial investigators found that about two-thirds of the lesions injected with talimogene laherparepvec shrank 50% or more. And the same effect was seen in about a third of all uninjected tumors in the skin and lymph nodes and about a sixth of uninjected visceral lesions providing an indication that the treatment is triggering the desired immune system effect. Ongoing clinical trials are investigating T-VEC in combination with the immune checkpoint inhibiting antibodies ipilimumab and pembrolizumab in advanced melanoma. We sought to determine if the combination of intratumoral injection of talimogene laherparepvec and the systemic delivery of the checkpoint anti-PD1 antibody could increase the anti-tumor efficacy in a preclinical syngeneic contralateral tumor model. Using established MC-38 colon carcinoma tumors in C57Bl/6 mice, we delivered three intratumoral injections three days apart of the talimogene laherparepvec surrogate OncoVEXmuGM-CSF and twice weekly systemic injections of an antagonistic anti-PD-1 antibody. Either OncoVEXmuGM-CSF or anti-PD-1 alone induced modest tumor growth inhibition/tumor regressions of contralateral tumors. In combination, the OncoVEXmuGM-CSF injected tumor displayed 8/10 complete regressions and the distant tumors had 2/10 complete regressions. Peripheral blood was analyzed at 4 days and 10 days post the initial OncoVEXmuGM-CSF and anti-PD-1 antibody injections. OncoVEXmuGM-CSF increased the percent of PD-L1+ CD4 and CD8 T cells and the combination increased the percent of activated CD8+ T cells. Our findings demonstrate that localized therapy with talimogene laherparepvec augments the systemic anti-tumor immune response seen with anti-PD-1 therapy, providing a strong rationale for continued investigation of such combinations in the clinic. Citation Format: Julia Piasecki, Tiep le, Rafael Ponce, Courtney Beers. Talilmogene laherparepvec increases the anti-tumor efficacy of the anti-PD-1 immune checkpoint blockade. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 258. doi:10.1158/1538-7445.AM2015-258

Talimogene laherparepvec is an investigational oncolytic immunotherapy based on a modified herpes simplex virus type-1 (HSV-1) immunotherapy designed to selectively replicate in tumors and to initiate an anti-tumor immune response. Intralesional administration of talimogene laherparepvec is intended to result in oncolysis within injected tumors. Iterative replication of virus within permissive tumor tissue results in lytic cell destruction and local release of progeny virus and tumor derived antigens. GM-CSF, a product of the viral transgene, is also produced locally such that it can recruit and stimulate antigen presenting cells which, in addition to relevant tumor-derived antigens, are required for the initiation of a systemic antitumor immune response. The talimogene laherparepvec-induced immune mediated mechanism of action in both the virus-injected and distant tumors have yet to be fully understood therefore, we evaluated viral replication, tumor cell lysis, and the changes in immune cell populations in both the injected and distant tumors using syngeneic contralateral tumor models. Animals received a single intratumoral dose of the murine surrogate of talimogene laherparepvec (OncoVEXmuGM-CSF), which induced regression in the majority of virus-injected tumors and tumor growth inhibition/regression in the contralateral (uninjected) tumors. HSV-1 antigen was only detected by IHC in the virus-injected tumor and not the contralateral tumor (and no other tissues). Virally-mediated tumor destruction (oncolysis) was also localized to only the virus-injected tumor. In preliminary experiments, morphometric analysis of the tumor tissue revealed that the percent area of CD3+ and CD8+ lymphocytes were significantly increased in both the virus-injected and contralateral tumors compared to the formulation control mice. In addition, the percent area occupied by CD103+ cells (a marker found on potent cytotoxic T cell stimulating dendritic cells) was increased in the virus-injected tumor compared to the contralateral tumor and the tumors in the control animals. Although cellular infiltration was increased in both virus-injected and contralateral tumors and was inversely correlated with tumor volume, the decreased volume of injected tumors was attributed to viral oncolysis. Taken together these data supports that talimogene laheparepvec activates a systemic T cell mediated anti-tumor immune response. Citation Format: Julia Piasecki, Jim Rottman, Tiep Le, Rafael Ponce, Courtney Beers. Talimogene laherparepvec activates systemic T-cell-mediated anti-tumor immunity. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4287. doi:10.1158/1538-7445.AM2015-4287

This paper presents a novel approach for QRS complex detection and extraction of electrocardiogram signals for different types of arrhythmias. Firstly, the ECG signal is filtered by a band pass filter, and then it is differentiated. After that, the Hilbert transform and the adaptive threshold technique are applied for QRS detection. Finally, the Principal Component Analysis is implemented to extract features from the ECG signal. Nineteen different records from the MIT-BIH arrhythmia database have been used to test the proposed method. A 96.28% of sensitivity and a 99.71% of positive predictivity are reported in this testing for QRS complexity detection, being a positive result in comparison with recent researches. All Rights Reserved © 2015 Universidad Nacional Autonoma de Mexico, Centro de Ciencias Aplicadas y Desarrollo Tecnologico. This is an open access item distributed under the Creative Commons CC License BY-NC-ND 4.0.