ABSTRACT
We report on manufacturing outcomes for 41 autologous polyclonal regulatory T cell (PolyTreg) products for 7 different Phase 1 clinical trials over a 10-year period (2011-2020). Data on patient characteristics, manufacturing parameters, and manufacturing outcomes were collected from manufacturing batch records and entered into a secure database. Overall, 88% (36/41) of PolyTreg products met release criteria and 83% (34/41) of products were successfully infused into patients. Of the 7 not infused, 5 failed release criteria, and 2 were not infused because the patient became ineligible due to a change in clinical status. The median fold expansion over the 14-day manufacturing process was 434.8 -fold (range 29.8-2,232), resulting in a median post-expansion cell count of 1,841 x 106 (range 56.9-16,179 x 106). The main correlate of post-expansion cell number was starting cell number, which positively correlates with absolute circulating Treg cell count. Other parameters, including date of PolyTreg production, patient sex, and patient age did not significantly correlate with fold expansion of Treg during product manufacturing. In conclusion, PolyTreg manufacturing outcomes are consistent across trials and dates of production.
Subject(s)
Biological Products , Cell- and Tissue-Based Therapy , Consumer Product Safety , T-Lymphocytes, Regulatory , Biological Products/standards , Cell- and Tissue-Based Therapy/methods , Cell- and Tissue-Based Therapy/standards , Consumer Product Safety/standards , Humans , Transplantation, Autologous/methods , Transplantation, Autologous/standardsABSTRACT
BACKGROUNDA previous phase I study showed that the infusion of autologous Tregs expanded ex vivo into patients with recent-onset type 1 diabetes (T1D) had an excellent safety profile. However, the majority of the infused Tregs were undetectable in the peripheral blood 3 months postinfusion (Treg-T1D trial). Therefore, we conducted a phase I study (TILT trial) combining polyclonal Tregs and low-dose IL-2, shown to enhance Treg survival and expansion, and assessed the impact over time on Treg populations and other immune cells.METHODSPatients with T1D were treated with a single infusion of autologous polyclonal Tregs followed by one or two 5-day courses of recombinant human low-dose IL-2 (ld-IL-2). Flow cytometry, cytometry by time of flight, and 10x Genomics single-cell RNA-Seq were used to follow the distinct immune cell populations' phenotypes over time.RESULTSMultiparametric analysis revealed that the combination therapy led to an increase in the number of infused and endogenous Tregs but also resulted in a substantial increase from baseline in a subset of activated NK, mucosal associated invariant T, and clonal CD8+ T cell populations.CONCLUSIONThese data support the hypothesis that ld-IL-2 expands exogenously administered Tregs but also can expand cytotoxic cells. These results have important implications for the use of a combination of ld-IL-2 and Tregs for the treatment of autoimmune diseases with preexisting active immunity.TRIAL REGISTRATIONClinicalTrials.gov NCT01210664 (Treg-T1D trial), NCT02772679 (TILT trial).FUNDINGSean N. Parker Autoimmune Research Laboratory Fund, National Center for Research Resources.
Subject(s)
Diabetes Mellitus, Type 1/blood , Diabetes Mellitus, Type 1/therapy , Immunotherapy, Adoptive , Interleukin-2/administration & dosage , T-Lymphocytes, Regulatory/transplantation , Adult , C-Peptide/blood , CD8-Positive T-Lymphocytes , Cell Survival , Combined Modality Therapy , Diabetes Mellitus, Type 1/immunology , Female , Glycated Hemoglobin/metabolism , Humans , Hypoglycemic Agents/therapeutic use , Insulin/therapeutic use , Interleukin-2/adverse effects , Lymphocyte Count , Male , Natural Killer T-Cells , Recombinant Proteins/administration & dosage , Time Factors , Transcriptome , Young AdultABSTRACT
BACKGROUND AND OBJECTIVES: A growing body of research suggests that nicotine withdrawal and cigarette craving may vary across the menstrual cycle and that the luteal phase of the cycle may be associated with increases in each. This potential relationship suggests that careful timing of quit attempts during the menstrual cycle may improve initial success at abstinence, although there are no direct tests of this approach yet published. Our objectives were to preliminarily test the effect of timing of quit attempts for smoking cessation relative to menstrual cycle and to identify methodological procedures that could guide subsequent, larger clinical trials. METHODS: In this pilot study, we randomized female smokers aged 18-40 who were not currently using hormonal contraception to quit smoking during either the follicular (n = 25) or luteal phase (n = 19) of their menstrual cycle. Participants were provided with two sessions of smoking cessation counseling (90 minutes total). All participants were provided with a transdermal nicotine patch contingent on maintenance of abstinence throughout the course of the 6-week study. RESULTS: Among participants who initiated treatment, received the patch, and made a quit attempt (n = 35), carbon monoxide-verified repeated point prevalence abstinence 2 weeks after the target quit date was higher in the follicular than the luteal group (32% vs. 19%, respectively; OR = 2.0, 95% CI = 0.4-9.8). Within the overall study population, this difference was slightly lower (24% vs. 16%; OR = 1.7, 95% CI = 0.4-7.8). CONCLUSIONS: Timing quit attempts based on menstrual phase is feasible. Insights gained from this study and the recommendations made herein may inform future research on this important clinical question.
