Overexpression of Rorγt in CAR T Cells Improves Persistence and Reduces Exhaustion

Although T cells modified with a chimeric antigen receptor (CAR) are highly effective, durability of remissions may be limited by the poor persistence of adoptively transferred CAR T cells in patients. Growing evidence supports the idea that the pre-infusion phenotype of CAR T cells affects the efficacy of CAR T cell therapies, in part due to the increased ability of certain subsets of CAR T cells to persist long-term. Studies using conventional T cells have suggested that adoptive transfer of T cells programmed to have Th17/Tc17 effector functions can increase the anti-tumor efficacy and persistence of transferred cells when compared to adoptive transfer of non-Th17/Tc17 cells. However, standard CAR formats currently in clinical use that contain either a CD28 or 4-1BB costimulatory domain fail to generate substantial numbers of Th17/Tc17-like cells. Thus, few studies have investigated whether Th17/Tc17 CAR T cells could enhance the efficacy of CAR T cell therapies. We generated a multi-cistronic lentiviral construct encoding ROR-related Orphan Receptor gamma (RORγt), a key lineage-specifying transcription factor involved in Th17/Tc17 differentiation, followed by a murine CAR targeting CD19 that contains a CD28 costimulatory domain (1928z). RORγt expression did not hinder degranulation in response to CAR antigen upon co-culture with E2aPbx, a murine acute lymphoblastic leukemia cell line. Significantly higher numbers of RORγt-1928z CAR T cells produce IL-17 compared to 1928z CAR T cells (p<0.0001) suggesting that RORγt expression is sufficient to program type-17 effector functions in CAR T cells. To determine the impact of RORγt overexpression on CAR T cell phenotype and persistence in vivo, we adoptively transferred 1x10 6 1928z or RORγt-1928z CAR T cells into leukemia-bearing C57Bl6/J recipients and analyzed CAR T cells from the bone marrow at days 4, 11, and 31. As early as day 4 post-transfer, RORγt-1928z CAR T cells were present at significantly higher numbers than 1928z CAR T cells, and remained higher through Day 31 (0.16% of the bone marrow for 1928z CAR T cells vs 0.84% of the bone marrow for RORγt-1928z CARs; p= 0.0012, n=5 mice per group. The RORγt-1928z CAR T cells were enriched for an effector/effector memory phenotype (CD62L-) compared to 1928z CAR T cells, which were mostly of a central memory phenotype (CD62L+). Interestingly, the RORγt-1928z CAR T cells were enriched for IL-7Rα+ cells and expressed more IL7Rα than their 1928z CAR T cell counterparts (p=0.0012), suggesting an increased capacity for self-renewal in RORγt-1928z CAR T cells. Previous work from our lab has demonstrated that CAR T cells that persist after leukemia clearance have an exhausted phenotype, with increased expression of PD1 and a reduced functionality 1. After leukemia clearance, RORγt-1928z CAR T cells expressed lower levels of PD1 than their 1928z counterparts (p<0.0001). Finally, 1928z CAR T cells form a population of Eomes hiPD1 hi cells, associated with terminal exhaustion, that is absent in the RORγt-1928z CAR T cells. Taken together, our preliminary data demonstrates that overexpression of RORγt is sufficient to program type-17 effector functions in CAR T cells and suggests that RORγt overexpression can enhance the ability of CAR T cells to persist and self-renew, and prevent terminal exhaustion. RORγt overexpression may enhance persistence of CAR T cells and durability of remissions in hematologic malignancies. Furthermore, RORγt overexpression may also be a strategy to enhance CAR T cell efficacy against solid tumors, where an immunosuppressive microenvironment contributes to T cell dysfunction. Yinmeng Yang, Mark Eric Kohler, Terry J. Fry; Effect of Chronic Endogenous Antigen Stimulation on CAR T Cell Persistence and Memory Formation. Blood2017; 130 (Supplement 1): 166. doi: https://doi.org/10.1182/blood.V130.Suppl_1.166.16 Disclosures Fry: Sana Biotechnology: Current Employment, Current equity holder in publicly-traded company.

Internal medicine residents’ awareness on cancer survivorship care plan: A cross sectional study.

e23011 Background: Survivorship care plans (SCPs) is recommended as a tool for communication between oncologists and primary care physicians. According to the Institute of Medicine, it is necessary to lead a cultural shift to provide SCPs to all cancer survivors to improve the transition from the oncology clinic to primary care practices. Studies suggest residency training curriculums for internal medicine (IM) are lacking education about cancer survivorship and SCPs. We aimed to assess the awareness of trainees toward SCPs. Methods: A survey was distributed to IM trainees in an outpatient setting. We stratified the descriptive analyses by program type (transitional [TY] and categorical [CT] trainees) and year of training. Differences in the proportions were tested appropriately. Analyses were conducted in R v3.6.2. Results: 37 trainees were interviewed; 32.4% were TY and 67.6% CT trainees. A 54% were PGY-1, 21.6% PGY-2, and 24.3% PGY-3. None of the trainees reported following a SCP for cancer-free patients nor to use SCP as a source to obtain cancer-related information. 78.3% and 92.6% reported that they were not taught during residency or medical school about SCPs, respectively. 84.8% informed that cancer-related information was inaccessible during the encounter with patients; sources cancer diagnosis and treatment information included: patients/family members (97.3%), outside records (83.8%), and oncology notes (86.5%). By program type, there was a statistically significant difference between TY v. CT groups (p = 0.017) regarding how often cancer-related issues were discussed with patients; the TY group mainly reported ‘Not at all’ whether CT were more likely to engage in discussion about cancer. Differences in the trainees’ comfort level answering patients concerns about cancer recurrence were observed between TY v. CT trainees but was not statistically significant (p = 0.864). Most common barriers to discuss cancer history and/or SCP were insufficient information from patients (83.8%), perceived inaccuracy from patients’ information (81.1%), unclear if patient has a SCP (81.1%), lack of SCP in medical record (75.7%), and trainees’ low medical knowledge about side effects of cancer therapies (70.3%). Conclusions: The awareness of cancer SCP among the IM trainees is limited, and many have not accessed or received training in SCPs. Efforts intended to facilitate SCP use and educate residents about cancer survivorship may be effective to increase the comfort level of trainees managing the growing number of survivors and improve transition from oncology to primary care clinics.[Table: see text]

Sex Does Not Sell: Effects of Sexual Advertising Parameters on Women Viewers’ Implicit and Explicit Recall of Ads and Brands

This study investigated implicit and explicit memory effects of sexual and non-sexual advertisements embedded in either a sexual or non-sexual program among women viewers. We predicted that sexual appeals would facilitate implicit memory for the brand, and we explored whether program-type (sexual or non-sexual) and its associated congruity would impact or moderate recall of the surrounding advertisement among a small sample (n = 52) of exclusively women advertisement viewers. Sexual (versus non-sexual) advertising led to significantly worse implicit memory for the brand logo but better explicit recall for the advertisement scene itself. There was no effect of sexual appeals on explicit brand name recall, and no significant effect on advertisement recall of the program type. There was a significant interaction effect for program type and advertisement type for explicit recall of the advertisement scene, in which program-type moderated sexual advertisement recall. These results suggest that sexual advertising may increase memory for the advertisement at the expense of recalling the brand advertised. Limitations and implications of this study are discussed.

Delivering Person-Centered Care in Community Mental Health Programs

The aim of this study was to examine the extent of and variation in person-centered care across programs within community mental health clinics. Service plans ( N = 160) from programs within eight clinics were assessed for person-centered care planning using an objective fidelity measure. Univariate statistics calculated overall fidelity to person-centered care planning and mixed-effect regression models examined person-centered care planning by program type. Overall, providers demonstrated low levels of competency in person-centered care planning. There were significant differences according to program type, with providers from assertive community treatment programs demonstrating the highest level of competency. Providers need more training and support to implement person-centered care consistently across community mental health programs. Those program types with associated fidelity measures that include person-centered care had a higher level of competence confirming the value of fidelity measurement in promoting quality services.

Free exercise programs for the elderly: a systematic review on adherence and abandonment

The elderly population in Brazil is on the rise. As a consequence, there is an equal growth in the number of free public exercise programs directed to this group. Considering the benefits of exercising and the importance of adherence to this behavior so that the benefits can be perceived, we conducted a systematic review of the existing literature on the topic, aiming to identify the reasons that lead to adherence to free public exercise programs, as well as those that lead to abandoning the same programs. Searches were conducted on SciElo, SPORTdiscus and Pubmed databases, with search phrases in Portuguese and in English. After a triage, ten studies were analyzed regarding sample characteristics, program type, data collection method and the reasons behind the subjects’ adherence and abandonment. We verified that elderly people tend to enter the projects for health-related reasons, but they remain due to other factors, such as socialization and the perception of the benefits brought on by exercising. As for abandonment, it occurs due to health problems, muscle pain due to exercising, dislike for the classes and family business.

Nationwide use, challenges, facilitators, and impact of preceptors in prelicensure clinical nursing education

Background and objective: Preceptor-facilitated clinical nursing education prevalence information is dated. Information is most often limited to regional baccalaureate programs and provides sparse evidence of its education-related outcomes. The purpose of this study is to describe the nationwide use, structures, facilitators, and challenges of using preceptors in prelicensure clinical education; compare its use by program characteristics; and explore its impact on education-related outcomes.Methods: In this cross-sectional comparative study, prelicensure programs in randomly selected jurisdictions in all four regions of the US were identified and official pass rates obtained. Program administrators completed an online questionnaire about preceptor use, incentives used, challenges, facilitators, and perceived impact on program capacity.Results: Preceptors were used in 73% of the 366 responding programs. Prevalence rates ranged from 25% to 87% by program type and from 64% to 86% by region. Programs’ NCLEX-RN® pass rates and perceived impact on program capacity did not differ by use of preceptors. Most respondents indicated there was no impact although one-fifth perceived moderate to high impact. The top five challenges and facilitators to preceptor use were identified. Programs used a variety of preceptor incentives, ranging from 62% using informal recognition to 7% providing some type of financial compensation.Conclusions: Most programs use preceptors with differences by program type and region. Designating resources to enhance preceptor orientation and preceptor-student-faculty communications may be useful, as well as identifying the challenges and facilitators. While a variety of preceptor incentives are available, few offer direct monetary compensation. Regional preceptor incentive data provide useful benchmarks. With high rates of use in some sectors and yet no demonstrable influence on pass rates, closer scrutiny of the quality of preceptor-facilitated educational experiences and associated outcomes are warranted.

EU Funds Absorption: Case of Romania

Article studies the absorption of European funds in Romania for the two post-accession periods: 2007-2014 and 2014-2020 and highlight the situation in Romania regarding the amount and evolution of European funds received (in relation to its contribution to the EU budget), the structure of these funds, the evolution of the absorption during the two intervals by program type and Romanian areas of development as well as difficulties encountered and the solutions adopted to overcome them. The analysis is based on primary statistical data provided by the Romanian Government and the European Commission, as well as studies and reports on national particularities and problems of absorption of European fund in Romania. In addition, a qualitative analysis of legislative and institutional framework aims to point out weakness and causes that hindered the absorption of funds. Paper highlights the increase of funds absorption in the current financial framework compared to the previous and emphasizes weaknesses in the Romanian institutional framework. The fact that many of the difficulties manifested in the first stage after adhesion were counter through appropriate solutions, enable better management of funds, which places Romania to the EU average in terms of rate of absorption. These solutions concern the improvement of administrative capacity (information, transparency, implementation, relationship with beneficiaries).

Internal Medicine Residency Program Responses to the Increase of Residency Applications: Differences by Program Type and Characteristics

ABSTRACT Background Over the past decade, the number of residency applications has increased substantially, causing many residency programs to change their recruitment practices. Objective We determined how internal medicine (IM) residency programs have responded to increased applications by program type (community-based, community-based/university-affiliated, and university-based) and characteristics (percentage of international medical graduates, program size, and program director [PD] tenure). Methods The Association of Program Directors in Internal Medicine conducted a national survey of 363 IM PDs in 2017. Five questions assessed IM program responses to the increased number of residency applications in 3 areas: changes in recruitment strategies, impact on ability to perform holistic review, and interest in 5 potential solutions. We performed a subgroup analysis to measure differences by program type and characteristics. Results The response rate was 64% (233 of 363). There were no differences by program type or characteristics for experiencing an increase in the number of applicants, altering recruitment practices, or conducting holistic reviews. There were moderate differences in alterations of recruitment practices by program characteristics and moderate differences in interest in proposed solutions by program type. Community-based programs had the greatest interest in a program-specific statement (59%, P = .032) and the lowest percentage in a national database of matched applicants (44%, P = .034). Conclusions IM residency programs are experiencing an increasing number of applications and are accommodating by adjusting recruitment practices in a variety of ways. A majority of IM PDs supported 4 of the 5 solutions, although the level of interest differed by program type.