Whole tumor lysates are promising antigen sources for dendritic cell (DC) therapy as they contain many relevant immunogenic epitopes to help prevent tumor escape. Two common methods of tumor lysate ...preparations are freeze-thaw processing and UVB irradiation to induce necrosis and apoptosis, respectively. Hypochlorous acid (HOCl) oxidation is a new method for inducing primary necrosis and enhancing the immunogenicity of tumor cells.
We compared the ability of DCs to engulf three different tumor lysate preparations, produce T-helper 1 (TH1)-priming cytokines and chemokines, stimulate mixed leukocyte reactions (MLR), and finally elicit T-cell responses capable of controlling tumor growth in vivo.
We showed that DCs engulfed HOCl-oxidized lysate most efficiently stimulated robust MLRs, and elicited strong tumor-specific IFN-γ secretions in autologous T cells. These DCs produced the highest levels of TH1-priming cytokines and chemokines, including interleukin (IL)-12. Mice vaccinated with HOCl-oxidized ID8-ova lysate-pulsed DCs developed T-cell responses that effectively controlled tumor growth. Safety, immunogenicity of autologous DCs pulsed with HOCl-oxidized autologous tumor lysate (OCDC vaccine), clinical efficacy, and progression-free survival (PFS) were evaluated in a pilot study of five subjects with recurrent ovarian cancer. OCDC vaccination produced few grade 1 toxicities and elicited potent T-cell responses against known ovarian tumor antigens. Circulating regulatory T cells and serum IL-10 were also reduced. Two subjects experienced durable PFS of 24 months or more after OCDC.
This is the first study showing the potential efficacy of a DC vaccine pulsed with HOCl-oxidized tumor lysate, a novel approach in preparing DC vaccine that is potentially applicable to many cancers.
T cells are important for controlling ovarian cancer (OC). We previously demonstrated that combinatorial use of a personalized whole-tumor lysate-pulsed dendritic cell vaccine (OCDC), bevacizumab ...(Bev), and cyclophosphamide (Cy) elicited neoantigen-specific T cells and prolonged OC survival. Here, we hypothesize that adding acetylsalicylic acid (ASA) and low-dose interleukin (IL)-2 would increase the vaccine efficacy in a recurrent advanced OC phase I trial (NCT01132014). By adding ASA and low-dose IL-2 to the OCDC-Bev-Cy combinatorial regimen, we elicited vaccine-specific T-cell responses that positively correlated with patients' prolonged time-to-progression and overall survival. In the ID8 ovarian model, animals receiving the same regimen showed prolonged survival, increased tumor-infiltrating perforin-producing T cells, increased neoantigen-specific CD8
T cells, and reduced endothelial Fas ligand expression and tumor-infiltrating T-regulatory cells. This combinatorial strategy was efficacious and also highlighted the predictive value of the ID8 model for future ovarian trial development.
The clinical implications of HER-2/neu (HER2) expression in ductal carcinoma in situ (DCIS) lesions have yet to be clearly elucidated; this despite the more frequent expression of HER2 in high-grade ...DCIS lesions
compared with invasive cancers. We hypothesized that HER2 overexpression in DCIS is associated with more rapid progression
to invasive disease. Immunohistochemical staining for estrogen receptor, progesterone receptor, and HER2 was done on DCIS
specimens. Univariate analysis and a multivariate logistic regression were done to determine whether estrogen receptor, progesterone
receptor, or HER2 status, comedo necrosis, nuclear grade, lesion size, or patient age predicted the presence of associated
invasive disease in patients with DCIS. Invasive foci were found in association with HER2 overexpressing DCIS at a higher
frequency than with DCIS that did not overexpress HER2. Although high nuclear grade, large lesion size, and HER2 overexpression
were all associated with the presence of invasive disease on univariate analysis, HER2 was the only significant predictor
for the presence of invasive disease after multivariate adjustment (odds ratio, 6.4; P = 0.01). These data indicate that HER2 overexpression in DCIS lesions predicts the presence of invasive foci in patients
with DCIS and suggest that targeting of HER2 in an early disease setting may forestall or prevent disease progression. (Cancer
Epidemiol Biomarkers Prev 2009;18(5):1386–9)
Ultrasound is becoming a fundamental first-line diagnostic tool for most medical specialties and an innovative tool to teach anatomy, physiology and pathophysiology to undergraduate and graduate ...students. However, availability of structured training programs during medical school is lagging behind and many physicians still acquire all their ultrasound skills during postgraduate training.There is wide variation in medical student ultrasound education worldwide. Sharing successful educational strategies from early adopter medical schools and learning from leading education programs should advance the integration of ultrasound into the university medical school curricula. In this overview, we present current approaches and suggestions by ultrasound societies concerning medical student educa-tion throughout the world. Based on these examples, we formulate a consensus statement with suggestions on how to integrate ultrasound teaching into the preclinical and clinical medical curricula.
To assess the radiology department chairs' opinions concerning current status and plans for teaching ultrasound to medical students, the American College Taskforce on Radiology Ultrasound Education, ...commissioned by the American College of Radiology, distributed a survey to 142 radiology chairs and a medical school dean subgroup.The response rate was 30% (42/142), and 76% indicated ultrasound was currently part of the medical student curriculum. In preclinical years, radiology involvement was only 6.4%. During clinical years, radiology led ultrasound education with 51.7% in general and 82.9% in elective rotations. Regarding actual content, top 4 results were evenly distributed between learning hands-on scanning (81.1%), diagnostic use of ultrasound (75.7%), anatomy/pathology (75.7%), and ultrasound guidance for procedures (54.0%). Educational leaders in preclinical courses were emergency medicine (72.7%) followed by radiology (45.4%) physicians. During clinical years, leaders were radiology (52.6%) and emergency medicine (47.4%) physicians. Most chairs stated that knowledge of diagnostic ultrasound should be mandatory (76.2%), stressing the importance of teaching the diagnostic capabilities and uses of ultrasound as the primary goal (78.8%). Perceived barriers to implementation were evenly distributed between lack of space in the curriculum (55.6%), lack of faculty (48.2%), lack of resources (44.4%), and lack of institutional support (40.7%). The American College Taskforce on Radiology Ultrasound Education survey shows that radiology's role in ultrasound undergraduate education occurs almost exclusively during clinical years, and the chairs voice a desire to improve upon this role. Barriers include both intradepartmental (faculty and resources) and institutional (curricular) factors.
We evaluated the feasibility, safety, and immunogenicity of mature, peptide-pulsed dendritic cell (DC) vaccines administered by different routes.
We performed a randomized, phase I, dose-escalation ...study in 27 patients with metastatic melanoma receiving four autologous peptide-pulsed DC vaccinations. Patients were randomly assigned to an intravenous (IV), intranodal (IN), or intradermal (ID) route of administration (ROA). For each route, primary end points were dose-limiting toxicity, maximum-tolerated dose, and T-cell sensitization. Sensitization was evaluated through tetramer staining, in vitro peptide recognition assays, and delayed-type hypersensitivity (DTH) responses.
Twenty-two (81.5%) of 27 patients completed all four vaccinations. Vaccinations were well tolerated; a few patients exhibited grade 1 to 2 toxicities including rash, fever, and injection site reaction. All routes of administration induced comparable increases in tetramer-staining CD8+ T cells (five of seven IV, four of seven IN, and four of six ID patients). However, the IN route induced significantly higher rates for de novo development of CD8+ T cells that respond by cytokine secretion to peptide-pulsed targets (six 85.7% of seven IN patients v two 33% of six ID patients v none 0% of six IV patients; P =.005) and de novo DTH (seven 87.5% of eight IN patients v two 33.3% of six ID patients v one 14.3% of seven IV patients; P =.01) compared with other routes.
Administration of this peptide-pulsed mature DC vaccine by IN, IV, or ID routes is feasible and safe. IN administration seems to result in superior T-cell sensitization as measured by de novo target-cell recognition and DTH priming, indicating that IN may be the preferred ROA for mature DC vaccines.
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