Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults, and radiation is one of the main treatment modalities. However, cure rates remain low despite best available therapies. ...Immunotherapy is a promising modality that could work synergistically with radiation, which has been shown to increase antigen presentation and promote a proinflammatory tumor microenvironment. Programmed-death-1 (PD-1) is a surface receptor expressed on activated and exhausted T cells, which mediate T cell inhibition upon binding with its ligand PD-L1, expressed on many tumor types including human GBMs. We tested the combination of anti-PD-1 immunotherapy with stereotactic radiosurgery in a mouse orthotopic GBM model.
We performed intracranial implantation of mouse glioma cell line GL261 transfected with luciferase into C57BL/6 mice. Mice were stratified into 4 treatment groups: (1) control; (2) radiation only; (3) anti-PD-1 antibody only; and (4) radiation plus anti-PD-1 antibody. Overall survival was quantified. The mice were killed on day 21 after implantation to assess immunologic parameters in the brain/tumor, cervical lymph nodes, and spleen.
Improved survival was demonstrated with combination anti-PD-1 therapy plus radiation compared with either modality alone: median survival was 25 days in the control arm, 27 days in the anti-PD-1 antibody arm, 28 days in the radiation arm, and 53 days in the radiation plus anti-PD-1 therapy arm (P<.05 by log-rank Mantle-Cox). Long-term survival was seen only in the combined treatment arm, with a fraction (15%-40%) of animals alive at day 180+ after treatment. Immunologic data on day 21 after implantation showed increased tumor infiltration by cytotoxic T cells (CD8+/interferon-γ+/tumor necrosis factor-α+) and decreased regulatory T cells (CD4+/FOXP3) in the combined treatment group compared with the single modality arms.
The combination of PD-1 blockade and localized radiation therapy results in long-term survival in mice with orthotopic brain tumors. These studies provide strong preclinical evidence to support combination trials in patients with GBM.
Summary Background Biomarkers are urgently needed to dissect the heterogeneity of prostate cancer between patients to improve treatment and accelerate drug development. We analysed blood mRNA ...expression arrays to identify patients with metastatic castration-resistant prostate cancer with poorer outcome. Methods Whole blood was collected into PAXgene tubes from patients with castration-resistant prostate cancer and patients with prostate cancer selected for active surveillance. In stage I (derivation set), patients with castration-resistant prostate cancer were used as cases and patients under active surveillance were used as controls. These patients were recruited from The Royal Marsden Hospital NHS Foundation Trust (Sutton, UK) and The Beatson West of Scotland Cancer Centre (Glasgow, UK). In stage II (validation-set), patients with castration-resistant prostate cancer recruited from the Memorial Sloan-Kettering Cancer Center (New York, USA) were assessed. Whole-blood RNA was hybridised to Affymetrix U133plus2 microarrays. Expression profiles were analysed with Bayesian latent process decomposition (LPD) to identify RNA expression profiles associated with castration-resistant prostate cancer subgroups; these profiles were then confirmed by quantative reverse transcriptase (qRT) PCR studies and correlated with overall survival in both the test-set and validation-set. Findings LPD analyses of the mRNA expression data divided the evaluable patients in stage I (n=94) into four groups. All patients in LPD1 (14 of 14) and most in LPD2 (17 of 18) had castration-resistant prostate cancer. Patients with castration-resistant prostate cancer and those under active surveillance comprised LPD3 (15 of 31 castration-resistant prostate cancer) and LDP4 (12 of 21 castration-resistant prostate cancer). Patients with castration-resistant prostate cancer in the LPD1 subgroup had features associated with worse prognosis and poorer overall survival than patients with castration-resistant prostate cancer in other LPD subgroups (LPD1 overall survival 10·7 months 95% CI 4·1–17·2 vs non-LPD1 25·6 months 18·0–33·4; p<0·0001). A nine-gene signature verified by qRT-PCR classified patients into this LPD1 subgroup with a very low percentage of misclassification (1·2%). The ten patients who were initially unclassifiable by the LPD analyses were subclassified by this signature. We confirmed the prognostic utility of this nine-gene signature in the validation castration-resistant prostate cancer cohort, where LPD1 membership was also associated with worse overall survival (LPD1 9·2 months 95% CI 2·1–16·4 vs non-LPD1 21·6 months 7·5–35·6; p=0·001), and remained an independent prognostic factor in multivariable analyses for both cohorts. Interpretation Our results suggest that whole-blood gene profiling could identify gene-expression signatures that stratify patients with castration-resistant prostate cancer into distinct prognostic groups. Funding AstraZeneca, Experimental Cancer Medicine Centre, Prostate Cancer Charity, Prostate Cancer Foundation.
To optimize the combination of ionizing radiation and cellular immunotherapy using a preclinical autochthonous model of prostate cancer.
Transgenic mice expressing a model antigen under a ...prostate-specific promoter were treated using a platform that integrates cone-beam CT imaging with 3-dimensional conformal therapy. Using this technology we investigated the immunologic and therapeutic effects of combining ionizing radiation with granulocyte/macrophage colony-stimulating factor-secreting cellular immunotherapy for prostate cancer in mice bearing autochthonous prostate tumors.
The combination of ionizing radiation and immunotherapy resulted in a significant decrease in pathologic tumor grade and gross tumor bulk that was not evident with either single-modality therapy. Furthermore, combinatorial therapy resulted in improved overall survival in a preventive metastasis model and in the setting of established micrometastases. Mechanistically, combined therapy resulted in an increase of the ratio of effector-to-regulatory T cells for both CD4 and CD8 tumor-infiltrating lymphocytes.
Our preclinical model establishes a potential role for the use of combined radiation-immunotherapy in locally advanced prostate cancer, which warrants further exploration in a clinical setting.
Summary Checkpoint blockade immunotherapy has received mainstream attention as a result of striking and durable clinical responses in some patients with metastatic disease and a reasonable response ...rate in many tumour types. The activity of checkpoint blockade immunotherapy is not restricted to melanoma or lung cancer, and additional indications are expected in the future, with responses already reported in renal cancer, bladder cancer, and Hodgkin's lymphoma among many others. Additionally, the interactions between radiation and the immune system have been investigated, with several studies describing the synergistic effects on local and distant tumour control when radiation therapy is combined with immunotherapy. Clinical enthusiasm for this approach is strengthened by the many ongoing trials combining immunotherapy with definitive and palliative radiation. Herein, we discuss the biological and mechanistic rationale behind combining radiation with checkpoint blockade immunotherapy, with a focus on the preclinical data supporting this potentially synergistic combination. We explore potential hypotheses and important considerations for clinical trial designs. Finally, we reintroduce the notion of radiosensitising immunotherapy, akin to radiosensitising chemotherapy, as a potential definitive therapeutic modality.
An abstract of a study by Zimbrick-Rogers et al examining the association of exacerbations of somatic symptomatology (SS) with increased psychosocial stressors is presented. A total of 4,981 ...dependent children age 12-17 were included in the analysis. The median child age was 14 (IQR 2.0) and median parent/sponsor age was 39 (IQR 6.0); 44.2% of the children and 91.3% of the parent sponsors were male; 19.6% of the children had a mental health (MH) diagnosis (with adjustment reaction accounting for 44.8% of those diagnoses): 29.0% of the parents were deployed at some point during the study. Migraine headaches accounted for 68% of all SS diagnoses. Parental deployment was associated with a decrease in the number of SS visits. In adjusted analyses, as compared with adolescents whose parent did not deploy, there was a 27% decrease in the number of SS visits. Additionally, being female was associated with a 99% increase in number of SS visits, having a female parent/sponsor was associated with a 34% decrease in the number of SS visits, but the co-occurrence of a MH diagnosis was associated with an 85% increase in number of visits.
Abstract Introduction Few educational programs exist for medical students that address professionalism in surgery, even though this core competency is required for graduate medical education and ...maintenance of board certification. Lapses in professional behavior occur commonly in surgical disciplines, with a negative effect on the operative team and patient care. Therefore, education regarding professionalism should begin early in the surgeon's formative process, to improve behavior. The goal of this project was to enhance the attitudes and knowledge of medical students regarding professionalism, to help them understand the role of professionalism in a surgical practice. Methods We implemented a 4-h seminar, spread out as 1-h sessions over the course of their month-long rotation, for 4th-year medical students serving as acting interns (AIs) in General Surgery, a surgical subspecialty, Obstetrics/Gynecology, or Anesthesia. Teaching methods included lecture, small group discussion, case studies, and journal club. Topics included Cognitive/Ethical Basis of Professionalism, Behavioral/Social Components of Professionalism, Managing Yourself, and Leading While You Work. We assessed attitudes about professionalism with a pre-course survey and tracked effect on learning and behavior with a post-course questionnaire. We asked AIs to rate the egregiousness of 30 scenarios involving potential lapses in professionalism. Results A total of 104 AIs (mean age, 26.5 y; male to female ratio, 1.6:1) participated in our course on professionalism in surgery. Up to 17.8% of the AIs had an alternate career before coming to medical school. Distribution of intended careers was: General Surgery, 27.4%; surgical subspecialties, 46.6%; Obstetrics/Gynecology, 13.7%; and Anesthesia, 12.3%. Acting interns ranked professionalism as the third most important of the six core competencies, after clinical skills and medical knowledge, but only slightly ahead of communication. Most AIs believed that professionalism could be taught and learned, and that the largest obstacle was not enough time in the curriculum. The most effective reported teaching methods were mentoring and modeling; lecture and journal club were the effective. Regarding attitudes toward professionalism, the most egregious examples of misconduct were substance abuse, illegal billing, boundary issues, sexual harassment, and lying about patient data, whereas the least egregious examples were receiving textbooks or honoraria from drug companies, advertising, self-prescribing for family members, and exceeding work-hour restrictions. The most important attributes of the professional were integrity and honesty, whereas the least valued were autonomy and altruism. The AIs reported that the course significantly improved their ability to define professionalism, identify attributes of the professional, understand the importance of professionalism, and integrate these concepts into practice (all P < 0.01). Conclusions Although medical students interested in surgery may already have well-formed attitudes and sophisticated knowledge about professionalism, this core competency can still be taught to and learned by trainees pursuing a surgical career.
This article examines prostate cancer as a target for immunotherapy and investigates active immunotherapy for prostate cancer, combining conventional therapy with active immunotherapy, immune ...modulators (brakes and accelerators), and monoclonal antibodies.
Prostate cancer Attard, Gerhardt, MD; Parker, Chris, FRCR; Eeles, Ros A, FRCR ...
The Lancet (British edition),
2016, Letnik:
387, Številka:
10013
Journal Article
Recenzirano
Summary Much progress has been made in research for prostate cancer in the past decade. There is now greater understanding for the genetic basis of familial prostate cancer with identification of ...rare but high-risk mutations (eg, BRCA2, HOXB13 ) and low-risk but common alleles (77 identified so far by genome-wide association studies) that could lead to targeted screening of patients at risk. This is especially important because screening for prostate cancer based on prostate-specific antigen remains controversial due to the high rate of overdiagnosis and unnecessary prostate biopsies, despite evidence that it reduces mortality. Classification of prostate cancer into distinct molecular subtypes, including mutually exclusive ETS -gene-fusion-positive and SPINK1-overexpressing, CHD1-loss cancers, could allow stratification of patients for different management strategies. Presently, men with localised disease can have very different prognoses and treatment options, ranging from observation alone through to radical surgery, with few good-quality randomised trials to inform on the best approach for an individual patient. The survival of patients with metastatic prostate cancer progressing on androgen-deprivation therapy (castration-resistant prostate cancer) has improved substantially. In addition to docetaxel, which has been used for more than a decade, in the past 4 years five new drugs have shown efficacy with improvements in overall survival leading to licensing for the treatment of metastatic castration-resistant prostate cancer. Because of this rapid change in the therapeutic landscape, no robust data exist to inform on the selection of patients for a specific treatment for castration-resistant prostate cancer or the best sequence of administration. Moreover, the high cost of the newer drugs limits their widespread use in several countries. Data from continuing clinical and translational research are urgently needed to improve, and, crucially, to personalise management.
Summary Background Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after ...radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. Methods We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov , number NCT00861614. Findings From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5–12·7) with ipilimumab and 10·0 months (8·3–11·0) with placebo (hazard ratio HR 0·85, 0·72–1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0–5 months was 1·46 (95% CI 1·10–1·95), for 5–12 months was 0·65 (0·50–0·85), and beyond 12 months was 0·60 (0·43–0·86). The most common grade 3–4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3–4 adverse events included diarrhoea (64 16% of 393 patients in the ipilimumab group vs seven 2% of 396 in the placebo group), fatigue (40 11% vs 35 9%), anaemia (40 10% vs 43 11%), and colitis (18 5% vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. Interpretation Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. Funding Bristol-Myers Squibb.
For men who have hormone-refractory prostate cancer, current treatment options are somewhat limited, with docetaxel the only agent showing a significant prolongation of survival. Several groups have ...investigated therapeutic approaches involving stimulation of an immune response against progressive prostate cancer. Several features of prostate cancer suggest that it may be a good target for immunotherapy. Constant pressure by the immune system forces tumors to evolve multiple ways to escape immune assault, however, and it is thus unlikely that single-agent immunotherapy for prostate cancer will achieve maximal clinical benefit. Most likely, successful immunotherapy will eventually require either the combination of multiple immunologic approaches or the combination of immunologic approaches with conventional therapy.
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