Generation of functional human T cell development in NOD/SCID/IL2rγnull humanized mice without using fetal tissue: Application as a model of HIV infection and persistence.

Humanization of mice with functional T cells currently relies on co-implantation of hematopoietic stem cells from fetal liver and autologous fetal thymic tissue (so-called BLT mouse model). Here, we show that NOD/SCID/IL2rγnull mice humanized with cord blood- derived CD34+ cells and implanted with allogeneic pediatric thymic tissues excised during cardiac surgeries (CCST) represent an alternative to BLT mice. CCST mice displayed a strong immune reconstitution, with functional T cells originating from CD34+ progenitor cells. They were equally susceptible to mucosal or intraperitoneal HIV infection and had significantly higher HIV-specific T cell responses. Antiretroviral therapy (ART) robustly suppressed viremia and reduced the frequencies of cells carrying integrated HIV DNA. As in BLT mice, we observed a complete viral rebound following ART interruption, suggesting the presence of HIV reservoirs. In conclusion, CCST mice represent a practical alternative to BLT mice, broadening the use of humanized mice for research.

Pharmacokinetic Analysis of Weekly Versus Biweekly IgPro20 Dosing in Patients With Primary Immunodeficiency.

Flexible dosing of IgPro20 (Hizentra®, CSL Behring, King of Prussia, Pennsylvania) maintains normal serum immunoglobulin G (IgG) levels in patients with primary immunodeficiencies (PID). Until now, clinical trials testing the pharmacokinetic (PK) characteristics of serum IgG of weekly and biweekly subcutaneous IgG therapy were not published. This is the first study assessing PK characteristics following weekly and biweekly IgPro20 in patients with PID. The PK study was conducted in 2 parts: weekly dosing (12 weeks) and biweekly dosing (up to 12 months). Serum IgG concentration-time data were analyzed using noncompartmental methods to generate PK parameters. Fifteen patients provided PK samples for both dosing regimens. For weekly and biweekly regimens, mean doses per infusion were 109 and 213 mg/kg, respectively, and median tmax was 2.0 and 3.02 days, respectively. The mean Ctrough values were similar in weekly and biweekly regimens (10.21 and 10.13 g/dL, respectively). The geometric mean ratios (GMRs) with 90% confidence intervals of biweekly to weekly Cmax and Ctrough were 1.10 (1.06-1.13) and 0.98 (0.95-1.01), respectively. The GMR of dAUC was 1.07 (1.03-1.10). This PK analysis demonstrated similar systemic IgG exposure after weekly and biweekly IgPro20 dosing with an equivalent monthly dose in patients with PID.

Efficient and Robust NK-Cell Transduction With Baboon Envelope Pseudotyped Lentivector.

NK-cell resistance to transduction is a major technical hurdle for developing NK-cell immunotherapy. By using Baboon envelope pseudotyped lentiviral vectors (BaEV-LVs) encoding eGFP, we obtained a transduction rate of 23.0 ± 6.6% (mean ± SD) in freshly-isolated human NK-cells (FI-NK) and 83.4 ± 10.1% (mean ± SD) in NK-cells obtained from the NK-cell Activation and Expansion System (NKAES), with a sustained transgene expression for at least 21 days. BaEV-LVs outperformed Vesicular Stomatitis Virus type-G (VSV-G)-, RD114- and Measles Virus (MV)- pseudotyped LVs (p < 0.0001). mRNA expression of both BaEV receptors, ASCT1 and ASCT2, was detected in FI-NK and NKAES, with higher expression in NKAES. Transduction with BaEV-LVs encoding for CAR-CD22 resulted in robust CAR-expression on 38.3 ± 23.8% (mean ± SD) of NKAES cells, leading to specific killing of NK-resistant pre-B-ALL-RS4;11 cell line. Using a larger vector encoding a dual CD19/CD22-CAR, we were able to transduce and re-expand dual-CAR-expressing NKAES, even with lower viral titer. These dual-CAR-NK efficiently killed both CD19KO- and CD22KO-RS4;11 cells. Our results suggest that BaEV-LVs may efficiently enable NK-cell biological studies and translation of NK-cell-based immunotherapy to the clinic.

Quality of Life, Treatment Beliefs, and Treatment Satisfaction in Children Treated for Primary Immunodeficiency with SCIg.

Despite the development of subcutaneous treatment, children and adolescents with primary immunodeficiency (PID) are vulnerable to a lower quality of life (QoL) than non-clinical participants. Comparisons have been offered in rare reports with limited sample sizes. No description is available of treatment beliefs and treatment satisfaction with standard tools. The objective of this study was to describe a large sample of patients with pediatric PID on QoL, treatment beliefs and satisfaction, and identify perceived benefits and issues of treatment both in children and parents. A mail-back survey was conducted in 60 patients with PID treated with subcutaneous Ig and their parents from a clinic in Montreal (QC, Canada). We used the standardized tools to assess for QoL levels, beliefs of necessity and concerns with treatment, and dimensions of satisfaction. We collected and coded perceived benefits and issues through open-ended questions. We found lower QoL in children with PID than in healthy non-clinical participants (median d = 0.40) and similar QoL levels to children with cancer (median d = 0.12). Participants considered their treatment as less necessary and able to control the illness and less convenient than patients with other conditions. Children were more prone to consider the treatment as convenient (69 vs. 47% p = .028) but reported more discomfort (24 vs. 10% p = .043) than parents. Results suggest a lower-than-expected QoL in pediatric PID. Aspects of the illness and treatment are probably unclear to patients and their families, as necessity beliefs were lower than expected. Educational strategies should be developed and assessed to address this issue.