Strategies to optimize T cell-based cancer immunotherapy

Remarkable progress has been made in the field of tumor immunology in the past decade but active immunotherapy is not yet an established treatment modality. Tumor associated antigens (TAAs) presented in the form of peptides in association with MHC class 1 can be recognized by T cells and represent major targets of immunotherapy strategies to treat cancer patients. However, ineffective antigen presentation, tumor evasion and T cell tolerance limit anti-tumor immune responses. We have investigated several approaches aimed at improving induction of T cell responses and sensitization of tumor cells to T cell effector mechanisms, which are crucial steps for successful T cell-based immunotherapy. HER-2/neu (HER-2) is a self tumor antigen over-expressed in a variety of tumors and expressed at low levels by normal epithelial surfaces. To enhance the low immunogenicity of HER-2 we developed a series of peptide analogs of the HER-2.369 epitope to improve binding to HLA-A2 We found that one of the analogs (HER-2.369 V2V9) induced cytotoxic T lymphocytes (CTLs) both in vitro and in vivo in HLA-A2/Kb transgenic (tg) mice at 100-fold lower concentration than the wild-type epitope. Importantly, CTLs generated by the analog peptide were also able to recognize the wild-type epitope and HER-2+ tumors in a MHC-restricted manner. The analysis of thermodynamic parameters demonstrated that the high biological activity of the V2V9 peptide variant was associated with a slower dissociation kinetic profile, resulting in an epitope with greater HLA-A2 stability. Next we studied immune responses directed against HER-2 in HLA-A2/Db tg mice upon DNA vaccination. Unexpectedly we found that a DNA vaccine encoding for full length HER-2 protected mice from HER-2+ tumor challenge by a CTL independent mechanism. A strategy aimed at enhancing MHC class 1 processing by a multi-epitope DNA vaccine encoding for 3 HER-2 derived HLA-A2 peptides linked in a "string of epitopes" resulted in high numbers of peptide specific T cells but failed to induce tumor protection. We found that HER-2+ but not HER-2 tumor cells down-regulated MHC class 1 and components of the antigen processing pathway which impaired the capacity to produce and display MHC class 1 peptide-ligands to specific CTLs. These findings are important for the optimization of vaccines targeting HER-2, and suggest that, to be effective, vaccines should aim at inducing an integrated immune response where also CD4+ T cells and antibodies are important components. In searching for new means to improve MHC class I-restricted antigen presentation in malignant cells, we identified retinoic acid (RA) as a modulator of antigen presentation and sensitivity to T cell effector mechanisms in tumor cells. Treatment of neuroblastoma cells with RA resulted in increased expression of MHC class 1 and of proteolytic and regulatory subunits of the immunoproteasome, increased half-life of MHC class 1 complexes and enhanced sensitivity of neuroblastoma cells to both MHC class I-restricted peptide-specific and MHC non-restricted lysis by CTLs. In the next study we extended our investigation of the effects of RA to the uveal melanoma (UM) tumor model. The current therapy of UM metastases is inefficient and the development of new treatment modalities is needed. We found that RA suppresses proliferation and causes morphological changes compatible with differentiation in a panel of UM cells. RA treatment of UM resulted in G I/GO cell cycle arrest which correlated with an increase of p21, p27 and p53 protein levels and with significant down-modulation of the HER-2/neu proto-oncogene surface expression. Unlike neuroblastomas, UM cells failed to up-regulate components of the MHC class 1 antigen processing pathway upon RA-treatment. Nevertheless, RA-treated UM cells exhibited increased sensitivity to both MHC class I-restricted killing by cytotoxic T lymphocytes and NK cell-mediated lysis. These observations could be explained (at least in part) by more efficient conjugate formation between UM cells and killer lymphocytes. Taken together, our findings suggest that the application of retinoids in combination with T cell-based immunotherapy may be an effective therapy for the treatment of neuroblastoma and uveal melanoma

Additional file 2: of A systematic literature review of time to return to work and narcotic use after lumbar spinal fusion using minimal invasive and open surgery techniques

List of included studies. A list of studies that were finally included after title/abstract and full text evaluations in this SLR. (DOCX 18 kb

Use of classifiers to optimise the identification and characterisation of metastatic breast cancer in a nationwide administrative registry

Bakground The prognosis for patients with metastatic breast cancer (MBC) is substantially worse when compared with patients with earlier stage disease. Therefore, understanding the differences in epidemiology between these two patient groups is important. Studies using population–based cancer registries to identify MBC are hampered by the quality of reporting. Patients are registered once (at time of initial diagnosis); hence only data for patients with de novo MBC are identifiable, whereas data for patients with recurrent MBC are not. This makes accurate estimation of the epidemiology and healthcare utilisation of MBC challenging. This study aimed to investigate whether machine–learning could improve identification of MBC in national health registries. Material and methods Data for patients with confirmed MBC from a regional breast cancer registry were used to train machine–learning algorithms (or ‘classifiers’). The best performing classifier (accuracy 97.3%, positive predictive value 85.1%) was applied to Swedish national registries for 2008 to 2016. Results Mean yearly MBC incidence was estimated at 14 per 100,000 person–years (with 18% diagnosed de novo and 76% of the total with HR–positive MBC). Conclusion To our knowledge, this is the first study to use machine learning to identify MBC regardless of stage at diagnosis in health registries covering the entire population of Sweden

Socioeconomic cost of AML in Sweden—A population‐based study using multiple nation‐wide registers

Abstract Acute myeloid leukemia (AML) is associated with a high economic and clinical burden. Recently novel therapies have been added to standard treatment regimens. Here, we evaluated the economic impact of AML up until the introduction of these novel therapies. Individual data on 2954 adult patients diagnosed from 2007 to 2015 from five Swedish national population‐based registers were used, enabling analyses from diagnosis to either death or 5‐year follow‐up for survival, inpatient and outpatient costs, costs of prescribed drugs, sick leave, and early retirement. Costs per patient were stratified by age group, treatment options, and FLT3‐ITD status. The expected 5‐year costs per patient differed substantially between age groups. Patients aged 18–59 years had an expected mean cost per patient of €170,748, while age groups 60–69 years, 70–79 years, and >80 years incurred an expected mean cost of €92,252, €48,344, and €24,118, respectively, over 5 years. Patients <60 years undergoing stem cell transplantation had the highest costs (€228,525 over 5 years). About 60% of costs for these patients were from hospitalizations and 20% from sick leave and early retirement; cost per day was highest from the first admission to complete remission. This study provides a baseline for socioeconomic evaluations of novel therapies in AML in Sweden

Overall survival of patients with metastatic breast cancer in Sweden : a nationwide study

Background Breast cancer is the most common cancer among women in Sweden. Whereas survival for the overall breast cancer population is well-documented, survival of patients with metastatic breast cancer (MBC) is harder to quantify due to the lack of reliable data on disease recurrence in national cancer registers. Methods This study used machine learning to classify the total MBC population in Sweden diagnosed between 2009 and 2016 using national registers, with the aim to estimate overall survival (OS). Results The total population consisted of 13,832 patients-2528 (18.3%) had de novo MBC whereas 11,304 (81.7%) were classed as having a recurrent MBC. Median OS for patients with MBC was found to be 29.8 months 95% confidence interval (CI) [28.9, 30.6]. Hormone-receptor (HR)-positive MBC had a median OS of 37.0 months 95% CI [35.9, 38.3] compared to 9.9 months 95% CI [9.1, 11.0] for patients with HR-negative MBC. Conclusion This study covered the entire MBC population in Sweden during the study time and may serve as a baseline for assessing the effect of new treatment strategies in MBC introduced after the study period

Characterization of clinicopathological features, treatment practices, and outcomes among Finnish advanced breast cancer patients in real-life clinical practice

PurposeIn recent years, several new targeted therapies have emerged for advanced breast cancer (aBC). However, real-life data specific to aBC and different breast cancer subtypes are scarce. This retrospective cohort study was designed to describe the distribution of aBC subtypes, incidence, treatment patterns, survival, and PIK3CA hotspot mutation frequency.MethodsThe study included all patients in the Hospital District of Southwest Finland diagnosed with aBC between 2004 and 2013 and with a sample available in Auria Biobank. In addition to registry-based data collection, 161 HR+/HER2- aBCs were screened for PIK3CA mutations.ResultsAltogether, 54.7% of the 444 patients included in the study had luminal B subtype. The smallest representations were in HR-/HER2+ (4.5%) and triple-negative (5.6%) subgroups. The percentage of aBC among all diagnosed breast cancers increased until 2010, after which it remained stable. The triple-negative cancers were associated with shorter median overall survival (5.5 months) compared to other subgroups (16.5-24.6 months). Most (84%) triple-negative cancers also metastasized during the first two years, whereas this was more evenly distributed over time in other subgroups. Of the HR+/HER2- tumors, 32.3% harbored a PIK3CA hotspot mutation. These patients, however, did not have inferior survival compared to patients with PIK3CA wild-type cancers.ConclusionThis study described real-world aBC subgroups and indicated that the clinical outcomes of subgroups vary. Although PIK3CA hotspot mutations did not lead to inferior survival, they are relevant as possible treatment targets. Overall, these data could be utilized to further evaluate the subgroup-specific medical needs in breast cancer.Peer reviewe

Comparative antioxidant activity of tocotrienols and the novel chromanyl-polyisoprenyl molecule FeAox-6 in isolated membranes and intact cells

Oxidative stress plays a pivotal role in the pathogenesis of several chronic diseases and antioxidants may represent potential tools for the prevention of these diseases. Here, we investigated the antioxidant efficiency of different tocotrienol isoforms (\ue9-, \u3b4-, \u3b3-tocotrienols), and that of FeAox-6, a novel synthetic compound which combines, by a stable covalent bond, the chroman head of vitamin E and a polyisoprenyl sequence of four conjugated double bonds into a single molecule. The antioxidant efficiency was evaluated as the ability of the compounds to inhibit lipid peroxidation, reactive oxygen species (ROS) production, heat shock protein (hsp) expression in rat liver microsomal membranes as well as in RAT-1 immortalized fibroblasts challenged with different free radical sources, including 2,2\u2032-azobis(2-amidinopropane) (AAPH), tert-butyl hydroperoxide (tert-BOOH) and H2O2. Our results show that individual tocotrienols display different antioxidant potencies. Irrespective of the prooxidant used, the order of effectiveness was:\u3b4-tocotrienol > \u3b3-tocotrienol = \ue9-tocotrienol in both isolated membranes and intact cells. This is presumably due to the decreased methylation of \u3b4-tocotrienol chromane ring, which allows the molecule to be more easily incorporated into cell membranes. Moreover, we found that FeAox-6 showed an antioxidant potency greater than that of \u3b4-tocotrienol. Such an efficiency seems to depend on the concomitant presence of a chromane ring and a phytyl chain in the molecule, which because of four conjugated double bonds, may induce a greater mobility and a more uniform distribution within cell membrane. In view of these results, FeAox-6 represents a new potential preventive agent in chronic diseases in which oxidative stress plays a pathogenic rol

Economic burden of sickle cell disease in Sweden : a population-based national register study with 13 years follow up

Introduction: Sickle cell disease (SCD) describes a group of inherited disorders of hemoglobin. Globally, SCD occurs in approximately 300,000-400,000 births annually and is most prevalent in malaria-endemic countries. However, migration has impacted the epidemiology of SCD but data on the matter are scarce. The objective of this study was to describe the epidemiology, treatment uptake, and economic burden of SCD in Sweden, a country with substantial immigration over the last decades. Methods: This nationwide retrospective observational registry cohort study identified patients with SCD from 2001 to 2018 and followed them from 2006 to 2018. Using data from high-quality population-based Swedish registers, we estimated prevalence, treatment uptake, and SCD-related health care resource use, sick leave and disability pension. Results: Between 2006 and 2018 the number of patients with SCD increased from 504 to 670; inpatient hospital stays and outpatient visits increased by 200% and 300%, respectively. Patients with pain crises had approximately twice the number of inpatient episodes and outpatient visit per year, and had higher productivity losses compared to patients without crises. Conclusion: In an era of emerging treatments for SCD, we have, to the best of our knowledge, for the first time comprehensively described epidemiological and economic aspects of SCD in a country where the disease is still rare and not well recognized by the healthcare system