Nonactivated and IL-7 cultured CD19-specific CAR T cells are enriched in stem cell phenotypes and functionally superior.

ABSTRACT: CD19-specific chimeric antigen receptor (CAR) T cells have demonstrated impressive responses in patients with relapsed and refractory B cell malignancies. However, many patients relapse or fail to respond to CD19 CAR T cells, demonstrating the need to improve its efficacy and durability. Current protocols for generating CAR T cells involve T cell activation through CD3 stimulation to facilitate efficient CAR transfer followed by ex vivo expansion with exogenous cytokines to obtain adequate cell numbers for treatment. Both T cell activation and expansion inevitably lead to terminal differentiation and replicative senescence, which are suboptimal for therapy. Interleukin-7 (IL-7) was previously shown to allow for lentiviral transduction of T cells in the absence of activation. In these studies, we used IL-7 to generate CD19 CAR T cells without stimulating CD3. Nonactivated and IL-7 cultured (NICE) CD19 CAR T cells were enriched with the T memory stem cell population, retained novel markers of stemness, had lower expression of exhaustion markers, and increased proliferative potential. Furthermore, our findings are consistent with engraftment of NICE CD19 CAR T cells and demonstrate a superior therapeutic response in both intraperitoneal and subcutaneous in vivo B cell lymphoma models. These results suggest that NICE CD19 CAR T cells may improve outcomes for B cell malignancies and warrant clinical evaluation.

Genetic Modification of T Cells for the Immunotherapy of Cancer.

Immunotherapy is a beneficial treatment approach for multiple cancers, however, current therapies are effective only in a small subset of patients. Adoptive cell transfer (ACT) is a facet of immunotherapy where T cells targeting the tumor cells are transferred to the patient with several primary forms, utilizing unmodified or modified T cells: tumor-infiltrating lymphocytes (TIL), genetically modified T cell receptor transduced T cells, and chimeric antigen receptor (CAR) transduced T cells. Many clinical trials are underway investigating the efficacy and safety of these different subsets of ACT, as well as trials that combine one of these subsets with another type of immunotherapy. The main challenges existing with ACT are improving clinical responses and decreasing adverse events. Current research focuses on identifying novel tumor targeting T cell receptors, improving safety and efficacy, and investigating ACT in combination with other immunotherapies.

Making Partnerships Work: Proposing a Model to Support Parent-Practitioner Partnerships in the Early Years.

Building on Froebelian principles that highlight the importance of family and community, this study explored the importance of collaboration and communication as part of a two-way dialogue. The aim was to identify the key characteristics of a model that would encourage interest and commitment to partnerships from both parents and practitioners. The idea of such partnerships has a solid theoretical background and is supported both rhetorically and by legislation by the Department of Education. However, research has shown that practice often falls short of the ideal, due to reasons such as the managerial discourse that constructs parents as potential consumers and the challenges faced when performance is prioritised over creativity. As part of the study, we employed a mixed methods approach and encouraged parents and practitioners to work together by participating at two sessions with families and children. The sessions provided parents and practitioners with space and time to explore the issue of working in 'partnership'. After careful consideration of ethical issues, data were collected using pre and post-session questionnaires with all participants, as well as face to face interviews with some of them. Findings indicate that both parties need to invest time and recognise that 'effective partnership' is a two way process which requires engagement and dialogue to be able to develop meaningful relationships of trust. The findings were used to develop the 'CAFE' partnership model which incorporates those elements considered important to facilitate the development of partnerships between practitioners and parents. The CAFE model addresses the gap in the literature in terms of unpicking the key features of a partnership approach, as captured through the lived experience of both parents and practitioners. It also contributes to deepening the understanding of the applications of Froebelian principles in contemporary contexts and the ways in which they can encourage high quality early childhood development and education. Future research should explore how this model could be used to evaluate existing practice and guide the development of current partnership policies and approaches.

Octreotide long-acting repeatable in the treatment of neuroendocrine tumors: patient selection and perspectives.

Over the past three decades, the incidence and prevalence of neuroendocrine tumors have gradually increased. Due to the slow-growing nature of these tumors, most cases are diagnosed at advanced stages. Prognosis and survival are associated with location of primary lesion, biochemical functional status, differentiation, initial staging, and response to therapy. Octreotide, the first synthetic somatostatin analog, was initially used for the management of gastrointestinal symptoms associated with functional carcinoid tumors. Its commercial development over time led to long-acting repeatable octreotide acetate, a long-acting version that provided greater administration convenience. Recent research demonstrates that octreotide's efficacy has evolved beyond symptomatic management to targeted therapy with antitumoral effects. This review examines the history and development of octreotide, provides a synopsis on the classification, grading, and staging of neuroendocrine tumors, and reviews the evidence of long-acting repeatable octreotide acetate as monotherapy and in combination with other treatment modalities in the management of non-pituitary neuroendocrine tumors with special attention to recent high-quality Phase III trials.

Safety and effectiveness of U-500 insulin therapy in patients with insulin-resistant type 2 diabetes mellitus.

STUDY OBJECTIVE: To assess the safety and effectiveness of highly concentrated U-500 regular insulin in patients with insulin-resistant type 2 diabetes mellitus who were switched from U-100 insulin. DESIGN: Retrospective cohort study. SETTING: Outpatient diabetes management clinic. PATIENTS: Twenty-one adults with poorly controlled type 2 diabetes and insulin resistance who were referred to the clinic between July 1, 2007, and June 30, 2008, and whose therapy was changed from large doses of U-100 insulin to U-500 insulin. MEASUREMENTS AND MAIN RESULTS: Demographic and clinical data were collected through a computerized medical record system. Insulin resistance was defined as a requirement of more than 200 units/day of insulin and more than 100 units/injection. The primary outcome was the change in hemoglobin A(1c) (A1C) after switching from any type of U-100 insulin to stabilization with U-500 highly concentrated regular insulin. Secondary outcomes were the changes in number of daily insulin injections, daily insulin dose, and body weight. With use of U-500 insulin, patients were able to achieve an average reduction in A1C of 1.7% (p<0.001). The mean number of daily injections decreased from 4.3 with U-100 insulin to 2.7 after using U-500 insulin (p<0.001), but changes in body weight after the change in insulin were not statistically significant (279.8 vs 279.2 lbs, p=0.429). No patient discontinued U-500 insulin during the study, and none experienced hypoglycemia severe enough to require the assistance of another individual. CONCLUSION: In patients with insulin-resistant diabetes who have requirements of more than 200 units/day or 100 units/injection, use of U-500 regular insulin provided the same or better glucose control compared with U-100 insulin, with fewer daily injections and reduced injection volume. Although this drug represents an excellent treatment option, its safe use requires an experienced physician, a motivated and cooperative patient, and a dynamic diabetes management team.