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"Mayer, Gina"
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Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer
Background
Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC).
Methods
We generated autologous DCs from the peripheral blood of HLA-A2
+
patients with PC. DCs were pulsed with three distinct A2-restricted peptides: 1) human telomerase reverse transcriptase (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin (SRV.A2). Patients received four intradermal injections of 1 × 10
7
peptide-pulsed DC vaccines every 2 weeks (Day 0, 14, 28, and 42). Concurrently, patients received intramuscular administration of Poly-ICLC at 30 μg/Kg on vaccination days (i.e., day 0, 14, 28, and 42), as well as on days 3, 17, 21, 31, 37, and 45. Our key objective was to assess safety and feasibility. The effect of DC vaccination on immune response was measured at each DC injection time point by enumerating the phenotype and function of patient T cells.
Results
Twelve patients underwent apheresis: nine patients with metastatic disease, and three patients with locally advanced unresectable disease. Vaccines were successfully manufactured from all individuals. We found that this treatment was well-tolerated, with the most common symptoms being fatigue and/or self-limiting flu-like symptoms. Among the eight patients who underwent imaging on day 56, four patients experienced stable disease while four patients had disease progression. The median overall survival was 7.7 months. One patient survived for 28 months post leukapheresis. MHC class I –tetramer analysis before and after vaccination revealed effective generation of antigen-specific T cells in three patients with stable disease.
Conclusion
Vaccination with peptide-pulsed DCs in combination with poly-ICLC is safe and induces a measurable tumor specific T cell population in patients with advanced PC.
Trial registration
NCT01410968
; Name of registry: clinicaltrials.gov; Date of registration: 08/04/2011).
Journal Article
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Book
Improved Humoral Immunity and Protection against Influenza Virus Infection with a 3d Porous Biomaterial Vaccine
New vaccine platforms that activate humoral immunity and generate neutralizing antibodies are required to combat emerging pathogens, including influenza virus. A slurry of antigen‐loaded hydrogel microparticles that anneal to form a porous scaffold with high surface area for antigen uptake by infiltrating immune cells as the biomaterial degrades is demonstrated to enhance humoral immunity. Antigen‐loaded‐microgels elicited a robust cellular humoral immune response, with increased CD4 + T follicular helper (Tfh) cells and prolonged germinal center (GC) B cells comparable to the commonly used adjuvant, aluminum hydroxide (Alum). Increasing the weight fraction of polymer material led to increased material stiffness and antigen‐specific antibody titers superior to Alum. Vaccinating mice with inactivated influenza virus loaded into this more highly cross‐linked formulation elicited a strong antibody response and provided protection against a high dose viral challenge. By tuning physical and chemical properties, adjuvanticity can be enhanced leading to humoral immunity and protection against a pathogen, leveraging two different types of antigenic material: individual protein antigen and inactivated virus. The flexibility of the platform may enable design of new vaccines to enhance innate and adaptive immune cell programming to generate and tune high affinity antibodies, a promising approach to generate long‐lasting immunity.
Journal Article
SurvivorCHESS to increase physical activity in colon cancer survivors: can we get them moving?
PurposeThis randomized controlled trial evaluated the impact of SurvivorCHESS, an eHealth intervention, on physical activity in colon cancer survivors and to explore the impact of SurvivorCHESS on quality of life and distress.MethodsThis was a two-arm single-blinded multi-site randomized controlled trial comparing a control group to an intervention group receiving a smartphone with the SurvivorCHESS program.ResultsParticipants using SurvivorCHESS (n = 144) increased their moderate to vigorous physical activities from 19.4 min at baseline to 50 min compared to the control group (n = 140) increasing from 15.5 to 40.3 min at 6 months (p = .083) but was not sustained 3 months after the study ended. No significant differences were found between groups over time for quality of life or distress items. Reports of physical symptoms were greater than other categories for distress items. Patients who had a higher body mass index and number of comorbid conditions were less likely to increase their physical activity. Self-determination theory including autonomous motivation and relatedness was not associated with the outcomes.ConclusionsPhysical activity did increase over time in both groups and was not significantly different with the use of the eHealth intervention, SurvivorCHESS, compared to the control group. The amount of SurvivorCHESS use was not associated with physical activity.Implications for cancer survivorsIncreasing physical activity in colon cancer survivors has the potential to improve quality of life and reduce recurrences. Using smartphone-tracking devices may be useful in helping to change this health behavior.
Journal Article
Maximizing the impact of HIV prevention technologies in sub‐Saharan Africa
Introduction There have been substantial gains in the range and efficacy of technologies available for HIV prevention, with voluntary medical male circumcision (VMMC), treatment as prevention, and pre‐exposure prophylaxis (PrEP) being added to the existing toolbox of condoms, lubricant, behaviour change, harm reduction, structural interventions and advocacy programmes. There has been relatively little recent work measuring patterns of risk in young women, but in Southern and East Africa the risks include transactional sex (broadly defined), age‐disparate partnerships, multiple sex partners, alcohol use, being or having partners uncircumcised, partners who travel, and for young women risk seems to increase with time after sexual debut and be associated with marriage . Social epidemiological framework The prevention cascade can be used alongside a social epidemiological framework which highlights the influence of structural factors, such as laws, policies, regulations, relational factors, such as family, relationship status, economic situation and more immediate factors, such as setting and privacy, intimate partner violence, alcohol and drug use . The paper summarizes lessons from PrEP implementation projects and concludes that these are feasible interventions, but identified significant challenges; like Gomez they identify the need for appropriate and targeted messages for demand creation; the need for youth friendly and integrated services that address wider concerns such as sexually transmitted infections and contraception; the need for novel approaches to supporting adherence.
Journal Article
Developing national cancer survivorship standards to inform quality of care in the United States using a consensus approach
PurposeTo develop United States (US) standards for survivorship care that informs (1) essential health system policy and process components and (2) evaluation of the quality of survivorship care.MethodsThe National Cancer Institute and the Department of Veterans Affairs led a review to identify indicators of quality cancer survivorship care in the domains of health system policy, process, and evaluation/assessment. A series of three virtual consensus meetings with survivorship care and research experts and advocates was conducted to rate the importance of the indicators and refine the top indicators. The final set of standards was developed, including ten indicators in each domain.ResultsPrioritized items were survivor-focused, including processes to both assess and manage physical, psychological, and social issues, and evaluation of patient outcomes and experiences. Specific indicators focused on developing a business model for sustaining survivorship care and collecting relevant business metrics (e.g., healthcare utilization, downstream revenue) to show value of survivorship care to health systems.ConclusionsThe National Standards for Cancer Survivorship Care can be used by health systems to guide development of new survivorship care programs or services or to assess alignment and enhance services in existing survivorship programs. Given the variety of settings providing care to survivors, it is necessary for health systems to adapt these standards based on factors including age-specific needs, cancer types, treatments received, and health system resources.Implications for Cancer SurvivorsWith over 18 million cancer survivors in the United States, many of whom experience varied symptoms and unmet needs, it is essential for health systems to have a comprehensive strategy to provide ongoing care. The US National Standards for Survivorship Care should serve as a blueprint for what survivors and their families can anticipate after a cancer diagnosis to address their needs.
Journal Article
Compost Application Enhances Soil Health and Maintains Crop Yield: Insights From 56 Farmer‐Managed Arable Fields
Introduction Improving soil health while maintaining crop yield is a key challenge for farmers. So far, only a few studies assessed the effects of compost and solid digestate application on soil health and plant yield under practical on‐farm conditions across both organic and conventional cropping systems. Materials and Methods This study examined 56 arable fields in Switzerland, managed either conventionally (n = 39) or organically (n = 17) by individual farmers. Fields were categorised based on their fertilisation history: standard fertilisation (n = 21), including livestock manure, slurry, and mineral fertilisers (reference), or with additional compost (n = 26) or solid digestate (n = 9) amendments. Soil health was assessed based on eight chemical, biological, and physical soil health indicators. Results Compost use, but not solid digestate use, was associated with enhanced average soil health ( + 31% over reference fields), driven by increases in basal respiration ( + 45%), cation exchange capacity ( + 42%), fungal richness ( + 18%), and marginally higher soil organic carbon stocks ( + 28%). These differences were consistent across management systems, despite site variability. Clay content and extended periods of crop cover also positively influenced soil health. Wheat yields were 21% lower under organic management but unaffected by compost or digestate use. Conclusion These findings suggest that using compost alongside practices like extended periods of crop cover can effectively promote soil health while maintaining yields in practical farming scenarios, offering a means to balance multiple sustainability goals simultaneously.
Journal Article
N-acetyl cysteine protects anti-melanoma cytotoxic T cells from exhaustion induced by rapid expansion via the downmodulation of Foxo1 in an Akt-dependent manner
Therapeutic outcomes for adoptive cell transfer (ACT) therapy are constrained by the quality of the infused T cells. The rapid expansion necessary to obtain large numbers of cells results in a more terminally differentiated phenotype with decreased durability and functionality. N-acetyl cysteine (NAC) protects against activation-induced cell death (AICD) and improves anti-tumor efficacy of Pmel-1 T cells in vivo. Here, we show that these benefits of NAC can be extended to engineered T cells and significantly increases T-cell survival within the tumor microenvironment. The addition of NAC to the expansion protocol of human TIL13838I TCR-transduced T cells that are under evaluation in a Phase I clinical trial, demonstrated that findings in murine cells extend to human cells. Expansion of TIL13838I TCR-transduced T cells in NAC also increased their ability to kill target cells in vitro. Interestingly, NAC did not affect memory subsets, but diminished up-regulation of senescence (CD57) and exhaustion (PD-1) markers and significantly decreased expression of the transcription factors EOMES and Foxo1. Pharmacological inhibition of the PI3K/Akt pathway ablates the decrease in Foxo1 induced by NAC treatment of activated T cells. This suggests a model in which NAC through PI3K/Akt activation suppresses Foxo1 expression, thereby impacting its transcriptional targets EOMES, PD-1, and granzyme B. Taken together, our results indicate that NAC exerts pleiotropic effects that impact the quality of TCR-transduced T cells and suggest that the addition of NAC to current clinical protocols should be considered.
Journal Article
Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells
Malignant melanoma incidence has been increasing for over 30 years, and despite promising new therapies, metastatic disease remains difficult to treat. We describe preliminary results from a Phase I clinical trial (NCT01586403) of adoptive cell therapy in which three patients received autologous CD4+ and CD8+ T cells transduced with a lentivirus carrying a tyrosinase-specific TCR and a marker protein, truncated CD34 (CD34t). This unusual MHC Class I-restricted TCR produces functional responses in both CD4+ and CD8+ T cells. Parameters monitored on transduced T cells included activation (CD25, CD69), inhibitory (PD-1, TIM-3, CTLA-4), costimulatory (OX40), and memory (CCR7) markers. For the clinical trial, T cells were activated, transduced, selected for CD34t+ cells, then re-activated, and expanded in IL-2 and IL-15. After lymphodepleting chemotherapy, patients were given transduced T cells and IL-2, and were followed for clinical and biological responses. Transduced T cells were detected in the circulation of three treated patients for the duration of observation (42, 523, and 255 days). Patient 1 tolerated the infusion well but died from progressive disease after 6 weeks. Patient 2 had a partial response by RECIST criteria then progressed. After progressing, Patient 2 was given high-dose IL-2 and subsequently achieved complete remission, coinciding with the development of vitiligo. Patient 3 had a mixed response that did not meet RECIST criteria for a clinical response and developed vitiligo. In two of these three patients, adoptive transfer of tyrosinase-reactive TCR-transduced T cells into metastatic melanoma patients had clinical and/or biological activity without serious adverse events.
Journal Article