\u3cem\u3eMayer v. Monroe\u3c/em\u3e: The Seventh Circuit Sheds Freedom of Speech at the Classroom Door

During a curriculum-specified class discussion of the war in Iraq, a sixth grader asked her teacher, Ms. Mayer, if she would ever march to protest the war. The school dismissed the teacher for answering the student. In Mayer v. Monroe County Community School Corp., the Seventh Circuit ruled that no teacher has the First Amendment right to express an opinion in the classroom. The case inappropriately applied the U.S. Supreme Court\u27s recent Garcetti v. Ceballos decision in a way that overruled previous precedent. This Note will argue that the Seventh Circuit should have followed its earlier decisions by asking the school to show a legitimate pedagogical reason for its decision

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Hereditary inclusion body myopathy: single patient response to GNE gene Lipoplex therapy

Abstract Background Hereditary inclusion body myopathy (HIBM) is an autosomal recessive adult onset myopathy. It is characterized by mutations of the GNE (UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase) gene. Afflicted patients have no therapeutic options. In preclinical testing, we have previously demonstrated the ability to correct GNE gene function and the safety of delivery of wild type GNE gene using a liposomal delivery vehicle

Resident Memory T Cells and Their Effect on Cancer

Resident memory T (TRM) cells are a unique subset of CD8+ T cells that are present within certain tissues and do not recirculate through the blood. Long term memory establishment and maintenance are dependent on tissue population of memory T cells. They are characterized by dual CD69/CD103 positivity, and play a role in both response to viral infection and local cancer immunosurveillance. Human TRM cells demonstrate the increased expression of adhesion molecules to facilitate tissue retention, have reduced proliferation and produce both regulatory and immune responsive cytokines. TRM cell phenotype is often characterized by a distinct expression profile driven by Runx3, Blimp1, and Hobit transcription factors. The accumulation of TRM cells in tumors is associated with increased survival and response to immunotherapies, including anti-PD-1 and anti-CTLA-4. In this review, we explore potential mechanisms of TRM cell transformation and maintenance, as well as potential applications for the use of TRM cells in both the development of supportive therapies and establishing more accurate prognoses

Repurposing metformin, simvastatin and digoxin as a combination for targeted therapy for pancreatic ductal adenocarcinoma

Patients with pancreatic adenocarcinoma (PDAC) have a 5-year survival rate of 8%, the lowest of any cancer in the United States. Traditional chemotherapeutic regimens, such as gemcitabine- and fluorouracil-based regimens, often only prolong survival by months. Effective precision targeted therapy is therefore urgently needed to substantially improve survival. In an effort to expedite approval and delivery of targeted therapy to patients, we utilized a platform to develop a novel combination of FDA approved drugs that would target pancreaticoduodenal homeobox1 (PDX1) and baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5) utilizing super-promoters of the target genes to interrogate an FDA approved drug library. We identified and selected metformin, simvastatin and digoxin (C3) as a novel combination of FDA approved drugs, which were shown to effectively target PDX1 and BIRC5 in human PDAC tumors in mice with no toxicity

Randomized double-blind placebo-controlled trial of primary maintenance vigil immunotherapy (VITAL study) in stage III/IV ovarian cancer: Efficacy assessment in BRCA1/2-wt patients

6017 Background: Vigil is an autologous tumor cell vaccine constructed from autologous harvested tumor tissue transfected with a DNA plasmid encoding GMCSF and bi-shRNA-furin thereby creating TGFβ expression control. Methods: A randomized double-blind placebo-controlled trial of Vigil vs. placebo was performed in advanced stage frontline OC patients. Relapse-free survival (RFS) and safety were endpoints. Patients who achieved complete clinical response were randomized [1:1 to placebo (control group, CG) or Vigil (Vigil group, VG)] after completion of frontline surgery and chemotherapy. All patients received 1 x 10e7 cells/ml of Vigil or placebo intradermally once a month for up to 12 doses. Results: Ninety-two patients were randomized with 91 patients in the per-protocol population (PP), (VG n=46; CG n=45). 62 patients were tested for BRCA1/2 status. VG showed no added overall toxicity compared to CG and no grade 4/5 toxicities were observed. Grade 2/3 toxic events were observed in 18% of CG patients (most common bone pain, fatigue) compared to 8% of VG patients (most common nausea, musculoskeletal pain). From time of randomization median RFS for all 91 patients was favorable in the VG (HR 0.69, one-sided p 0.088).Stratified by BRCA status, an advantage in RFS was seen in the BRCA1/2-wt patients in VG (19.4 mo) compared to CG (8 mo) (HR 0.51, 90% CI 0.26 – 1.01, one-sided p 0.050) from time of randomization and HR of 0.49 (90% CI 0.25 – 0.97, one-sided p 0.038) from time of surgery. Median time from surgery to randomization was 208.5 days (6.9 mo) in VG vs. 200 days (6.6 mo) in CG. 37.5% BRCA1/2-wt Vigil treated patients relapsed compared to 71% of placebo at time of data snap for analysis (HR 0.51, one-sided p 0.05), (median follow-up of 34.3 mo for all n=91 subjects). Germline and somatic BRCA1/2 molecular testing via central third party is underway on all 91 patients under continued blinded conditions to validate activity in BRCA1/2-wt. Conclusions: Vigil immunotherapy as frontline maintenance in Stage III/IV ovarian cancer is well tolerated and showed RFS clinical benefit, particularly in BRCA1/2-wt disease. Clinical trial information: NCT02346747. [Table: see text

Gemogenovatucel-T (Vigil) immunotherapy as maintenance in frontline stage III/IV ovarian cancer (VITAL): a randomised, double-blind, placebo-controlled, phase 2b trial.

BACKGROUND: Gemogenovatucel-T is an autologous tumour cell vaccine manufactured from harvested tumour tissue, which specifically reduces expression of furin and downstream TGF-β1 and TGF-β2. The aim of this study was to determine the safety and efficacy of gemogenovatucel-T in front-line ovarian cancer maintenance. METHODS: This randomised, double-blind, placebo-controlled, phase 2b trial involved 25 hospitals in the USA. Women aged 18 years and older with stage III/IV high-grade serous, endometrioid, or clear cell ovarian cancer in clinical complete response after a combination of surgery and five to eight cycles of chemotherapy involving carboplatin and paclitaxel, and an Eastern Cooperative Oncology Group status of 0 or 1 were eligible for inclusion in the study. Patients were randomly assigned (1:1) to gemogenovatucel-T or placebo by an independent third party interactive response system after successful screening using randomly permuted block sizes of two and four and stratified by extent of surgical cytoreduction and neoadjuvant versus adjuvant chemotherapy. Gemogenovatucel-T (1 × 10 FINDINGS: Between Feb 11, 2015, and March 2, 2017, 310 patients consented to the study at 22 sites. 217 were excluded. 91 patients received gemogenovatucel-T (n=47) or placebo (n=44) and were analysed for safety and efficacy. The median follow-up from first dose of gemogenovatucel-T was 40·0 months (IQR 35·0-44·8) and from first dose of placebo was 39·8 months (35·5-44·6). Recurrence-free survival was 11·5 months (95% CI 7·5-not reached) for patients assigned to gemogenovatucel-T versus 8·4 months (7·9-15·5) for patients assigned to placebo (HR 0·69, 90% CI 0·44-1·07; one-sided p=0·078). Gemogenovatucel-T resulted in no grade 3 or 4 toxic effects. Two patients in the placebo group had five grade 3 toxic events, including arthralgia, bone pain, generalised muscle weakness, syncope, and dyspnea. Seven patients (four in the placebo group and three in the gemogenovatucel-T group) had 11 serious adverse events. No treatment-related deaths were reported in either of the groups. INTERPRETATION: Front-line use of gemogenovatucel-T immunotherapy as maintenance was well tolerated but the primary endpoint was not met. Further investigation of gemogenovatucel-T in patients stratified by BRCA mutation status is warranted. FUNDING: Gradalis