Rilzabrutinib, an Oral BTK Inhibitor, in Immune Thrombocytopenia.

Background: Rilzabrutinib, an oral, reversible covalent inhibitor of Bruton's tyrosine kinase, may increase platelet counts in patients with immune thrombocytopenia by means of dual mechanisms of action: decreased macrophage (Fcγ receptor)-mediated platelet destruction and reduced production of pathogenic autoantibodies.

Methods: In an international, adaptive, open-label, dose-finding, phase 1-2 clinical trial, we evaluated rilzabrutinib therapy in previously treated patients with immune thrombocytopenia. We used intrapatient dose escalation of oral rilzabrutinib over a period of 24 weeks; the lowest starting dose was 200 mg once daily, with higher starting doses of 400 mg once daily, 300 mg twice daily, and 400 mg twice daily.

A thorough QTc study to evaluate the effects of oral rilzabrutinib administered alone and with ritonavir in healthy subjects.

This study aimed to define the clinically relevant supratherapeutic dose of rilzabrutinib, an oral Bruton tyrosine kinase (BTK) inhibitor, and evaluate potential effects of therapeutic and supratherapeutic exposures on cardiac repolarization in healthy subjects. This was a two-part phase I study (anzctr.org.

A phase I pharmacokinetics trial comparing PF-05280586 (a potential biosimilar) and rituximab in patients with active rheumatoid arthritis.

Aims: Pharmacokinetic (PK) similarity was assessed among PF-05280586 (a proposed biosimilar) vs. rituximab sourced from the European Union (rituximab-EU) and the United States (rituximab-US). Pharmacodynamics (PD), overall safety and immunogenicity were also evaluated.

Development of biosimilars in an era of oncologic drug shortages.

Acute and chronic shortages of various pharmaceuticals and particularly of sterile injectable products are being reported on a global scale, prompting evaluation of more effective strategies to manage current shortages and development of new, high-quality pharmaceutical products to mitigate the risk of potential future shortages. Oncology drugs such as liposomal doxorubicin and 5-fluorouracil represent examples of first-choice drugs critically affected by shortages. Survey results indicate that the majority of hospitals and practicing oncologists have experienced drug shortages, which may have compromised patient safety and clinical outcomes, and increased health care costs, due to delays or changes in treatment regimens.

Clinical considerations for the development of biosimilars in oncology.

Despite availability of biologic therapies, limited patient access to many of the most-effective cancer treatments affects overall health outcomes. To address this issue, many governments have enacted legislation for the approval of biosimilars. The term "biosimilar" refers to a biologic product that is developed to be highly similar, as opposed to identical, to a licensed biologic product (the reference or innovator product), such that, per US Food and Drug administration draft guidelines, "no clinically meaningful differences [exist] between the biological product and the reference product in terms of safety, purity, and potency.

Improvement in renal function in kidney transplant recipients switched from cyclosporine or tacrolimus to belatacept: 2-year results from the long-term extension of a phase II study.

Kidney transplant recipients who switched from a calcineurin inhibitor (CNI) to belatacept demonstrated higher calculated glomerular filtration rates (cGFRs) at 1 year in a Phase II study. This report addresses whether improvement was sustained at 2 years in the long-term extension (LTE). Patients receiving cyclosporine or tacrolimus were randomized to switch to belatacept or continue CNI.

Summary of roundtable discussion meeting: non-human primates to assess risk for EBV-related lymphomas in humans.

Epstein-Barr virus (EBV)-associated lymphomas are a known risk for immunosuppressed individuals. Non-clinical methods to determine the potential of new immunomodulatory compounds to produce EBV-associated lymphomas (hazard identification) have not been developed. Since lymphocryptovirus (LCV) in non-human primates (NHP) has similar characteristics to EBV in humans, a Roundtable meeting was held in October 2010 to explore how the potential for EBV-related lymphomas in humans can be assessed by using surrogate biomarkers for lymphoma risk in NHP toxicity studies.

Lymphoproliferative disorders after adult kidney transplant: epidemiology and comparison of registry report with claims-based diagnoses.

Background: Posttransplant lymphoproliferative disorder (PTLD) is a major complication of kidney transplant.

Study Design: Retrospective cohort study comparing PTLD incidence rates using US Medicare claims and Organ Procurement and Transplantation Network (OPTN) data, examining risk factors for PTLD in OPTN data, and studying recipient and graft survival after PTLD diagnosis.

Setting & Participants: All adult first-transplant patients who underwent deceased or living donor kidney-only transplants in 2000-2006 (n = 89,485) followed up through 3 years posttransplant.

Belatacept-versus cyclosporine-based immunosuppression in renal transplant recipients with pre-existing diabetes.

Background And Objectives: Renal transplant recipients with pre-existing diabetes (PD) have reduced graft survival and increased risk of mortality and ischemic heart disease compared with nondiabetic transplant recipients. To assess the effect of belatacept in this high-risk group, we evaluated outcomes of the subpopulation with PD from previously published BENEFIT and BENEFIT-EXT trials.

Design, Setting, Participants, & Measurements: A post hoc analysis evaluated pooled data from BENEFIT (living donors or standard criteria donors) and BENEFIT-EXT (extended criteria donors).

An integrated safety profile analysis of belatacept in kidney transplant recipients.

Background: Belatacept is associated with better renal function and an improved cardiovascular/metabolic risk profile versus cyclosporine in kidney transplant recipients. The current analysis examined pooled safety data for belatacept versus cyclosporine used in combination with basiliximab, mycophenolate mofetil, and steroids.

Methods: Patients enrolled in three core studies in de novo kidney transplantation were randomized to a more intensive (MI) or less intensive (LI) regimen of belatacept or cyclosporine.

Switching from calcineurin inhibitor-based regimens to a belatacept-based regimen in renal transplant recipients: a randomized phase II study.

Background And Objectives: Prolonged use of calcineurin inhibitors (CNIs) in kidney transplant recipients is associated with renal and nonrenal toxicity and an increase in cardiovascular risk factors. Belatacept-based regimens may provide a treatment option for patients who switch from CNI-based maintenance immunosuppression.

Design, Setting, Participants, & Measurements: This is a randomized, open-label Phase II trial in renal transplant patients with stable graft function and receiving a CNI-based regimen.

Tonsilar NK cells restrict B cell transformation by the Epstein-Barr virus via IFN-gamma.

Cells of the innate immune system act in synergy to provide a first line of defense against pathogens. Here we describe that dendritic cells (DCs), matured with viral products or mimics thereof, including Epstein-Barr virus (EBV), activated natural killer (NK) cells more efficiently than other mature DC preparations. CD56(bright)CD16(-) NK cells, which are enriched in human secondary lymphoid tissues, responded primarily to this DC activation.

DEC-205/CD205+ dendritic cells are abundant in the white pulp of the human spleen, including the border region between the red and white pulp.

The distribution of dendritic cells (DCs) and macrophages in the human spleen has received less attention than that of lymphocytes. Here we have addressed this problem with the human DEC-205/CD205 marker ('DEC'), which is an endocytic receptor on DCs that mediates efficient presentation of antigens. DEC was abundant on dendritic profiles in the white pulp but absent from the red pulp, the latter defined with antibodies to two antigens, mannose receptor/CD206 on sinusoidal lining cells, and macrosialin/CD68 on macrophages.

Hyperexpression of Foxp3 and IDO during acute rejection of islet allografts.

Background: We investigated the hypothesis that Foxp3+ cells are an integral component of antiallograft immunity but are dominated by pathogenic effectors.

Methods: Wild-type H-2b C57BL/6 (B6) mice or B6 mice with a targeted disruption of c-Rel gene (c-Rel-/-) were used as recipients of islet grafts from allogeneic DBA/2 (H-2d) mice or syngeneic B6 mice. We developed kinetic quantitative polymerase chain reaction assays and measured intragraft expression of mRNA for Foxp3, IDO, cytolytic molecules, proinflammatory cytokines, and chemokines/receptors.

Mitochondrial targeting with antioxidant peptide SS-31 prevents mitochondrial depolarization, reduces islet cell apoptosis, increases islet cell yield, and improves posttransplantation function.

Apoptotic cell death is a defined pathway for islet cell demise, and mitochondrial dysfunction contributes to islet cell apoptosis. The hypothesis that the novel peptide D-Arg-2', 6'-dimethyltyrosine-Lys-Phe-NH2 (SS-31), previously shown to target inner mitochondrial membrane and prevent oxidative damage of neuronal cells and other cell types, optimizes pancreatic islet isolation and improves posttransplantation function in recipients with diabetes was investigated. Herein is demonstrated that SS-31 readily penetrates intact mouse islets, preserves mitochondrial polarization, reduces islet cell apoptosis, and increases islet cell yield.

Systemic transforming growth factor-beta1 gene therapy induces Foxp3+ regulatory cells, restores self-tolerance, and facilitates regeneration of beta cell function in overtly diabetic nonobese diabetic mice.

Background: Type 1 diabetes results from auto-aggressive T-cell-mediated destruction of beta cells of the pancreas. Recent data suggest that restoration of self-tolerance may facilitate islet-cell regeneration/recovery. In view of the immunoregulatory activity of transforming growth factor (TGF)-beta1, we investigated whether systemic TGF-beta1 gene therapy blocks islet destructive autoimmunity and facilitates regeneration of beta-cell function in overtly diabetic nonobese diabetic (NOD) mice.

Measurement of apoptosis of intact human islets by confocal optical sectioning and stereologic analysis of YO-PRO-1-stained islets.

Apoptosis is an established pathway for islet cell demise. Current protocols for assessment of islet cell apoptosis are time-consuming (as with terminal deoxynucleotide transferase-mediated dUTP nick-end labeling reaction) and involve disruption of the islet architecture (as with flow cytometry) or destruction of cell integrity (as with enzyme-linked immunosorbent assay). The membranes of apoptotic cells, but not those of live cells, are permeant to the DNA-intercalant dye YO-PRO-1.

Distinct roles of IL-12 and IL-15 in human natural killer cell activation by dendritic cells from secondary lymphoid organs.

Dendritic cells (DCs) are known to induce the growth and function of natural killer (NK) cells. Here, we address the capacity of DCs to interact with NK cells in human lymphoid organs and identify the role of specific DC-derived cytokines. We demonstrate that DCs colocalize with NK cells in the T cell areas of lymph nodes.

The abundant NK cells in human secondary lymphoid tissues require activation to express killer cell Ig-like receptors and become cytolytic.

Natural killer cells are important cytolytic cells in innate immunity. We have characterized human NK cells of spleen, lymph nodes, and tonsils. More than 95% of peripheral blood and 85% of spleen NK cells are CD56(dim)CD16(+) and express perforin, the natural cytotoxicity receptors (NCRs) NKp30 and NKp46, as well as in part killer cell Ig-like receptors (KIRs).

Rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer.

Purpose: Lung cancer has a dismal prognosis and comprises 5.5% of post-transplant malignancies. We explored whether rapamycin inhibits the growth and metastatic progression of non-small cell lung cancer (NSCLC).

Optimal modes and targets of gene therapy in transplantation.

Genetic modification strategies have the potential to improve outcome following cell/organ transplantation. A unique opportunity in transplantation is that gene therapies need not be restricted to in vivo approaches and that ex vivo genetic modification of cell and/or organs can be of value. Improvements in vector design, production, and delivery should enhance transfection efficiency and optimize gene expression.

Proapoptotic Bax is hyperexpressed in isolated human islets compared with antiapoptotic Bcl-2.

Background: Apoptosis is a well-documented pathway for islet cell death. One potential mechanism is overexpression of death-promoting Bax compared with antiapoptotic Bcl-2 in islets.

Methods: We isolated islets from 10 human pancreata and measured the expression of Bax mRNA and Bcl-2 mRNA by real-time quantitative polymerase chain reaction; islet and pancreas expression of Bax, Bcl-2, activated caspase-3, and cleaved poly (ADP-ribose) polymerase were also assessed by immunohistochemistry.

Enforced c-REL deficiency prolongs survival of islet allografts1.

Background: The NF-kappaB/Rel family of transcription factors regulates biologic processes ranging from apoptosis to inflammation and innate immunity. Whether c-Rel, a lymphoid-predominant member of the NF-kappaB/Rel family, is essential for transplantation immunity is not known.

Methods: We explored the role of c-Rel in the anti-allograft repertory using mice with targeted disruption of the c-Rel gene (c-Rel-/-) as recipients of H-2 mismatched islet allografts.