Translational development of a novel BAFF-R CAR-T therapy targeting B-cell lymphoid malignancies.

Several CD19-targeting CAR-T cells are used to treat leukemias and lymphomas; however, relapsed and/or refractory (R/R) disease is still observed in a significant number of patients. Additionally, the success of CD19-CAR-T cell therapies is not uniform across hematological malignancies, particularly in chronic lymphocytic leukemia (CLL). In this study, we present the development of a novel CAR-T cell therapy targeting B-cell activating factor receptor (BAFF-R), a key regulator of B-cell proliferation and maturation. A new monoclonal antibody against BAFF-R was generated from a hybridoma clone and used to create a novel MC10029 CAR construct. Through a series of in vitro and in vivo models using the Nalm-6 cell line for leukemia and the Z138 cell line for lymphoma, we demonstrated the antigen-specific cytotoxicity of MC10029 CAR-T cells against tumor cells. Additionally, MC10029 CAR-T cells exhibited potent antitumor effects against CD19 knockout tumor cells, mimicking CD19-negative R/R disease. MC10029 CAR-T cells were specifically targeted to CLL, in which BAFF-R is nearly always expressed. The cytotoxicity of MC10029 CAR-T cells was first shown in the MEC-1 CLL cell line, before we turned our efforts to subject-derived samples. Using healthy donor-engineered MC10029 CAR-T cells against enriched primary tumor cells, followed by subject-derived MC10029 CAR-T cells against autologous tumor cells, we showed the efficacy of MC10029 CAR-T cells against CLL subject samples. With these robust data, we have advanced to the production of MC10029 CAR-T cells, using GMP lentivirus, and obtained an IND approval in preparation for a Phase 1 clinical trial.

Targeting chronic lymphocytic leukemia with B-cell activating factor receptor CAR T cells.

The challenge of disease relapsed/refractory (R/R) remains a therapeutic hurdle in chimeric antigen receptor (CAR) T-cell therapy, especially for hematological diseases, with chronic lymphocytic leukemia (CLL) being particularly resistant to CD19 CAR T cells. Currently, there is no approved CAR T-cell therapy for CLL patients. In this study, we aimed to address this unmet medical need by choosing the B-cell activating factor receptor (BAFF-R) as a promising target for CAR design against CLL. BAFF-R is essential for B-cell survival and is consistently expressed on CLL tumors. Our research discovered that BAFF-R CAR T-cell therapy exerted the cytotoxic effects on both CLL cell lines and primary B cells derived from CLL patients. In addition, the CAR T cells exhibited cytotoxicity against CD19-knockout CLL cells that are resistant to CD19 CAR T therapy. Furthermore, we were able to generate BAFF-R CAR T cells from small blood samples collected from CLL patients and then demonstrated the cytotoxic effects of these patient-derived CAR T cells against autologous tumor cells. Given these promising results, BAFF-R CAR T-cell therapy has the potential to meet the long-standing need for an effective treatment on CLL patients.

Nocturnal heart rate variability moderates the association between sleep-wake regularity and mood in young adults.

STUDY OBJECTIVES: Sleep-wake regularity (SWR) is often disrupted in college students and mood disorders are rife at this age. Disrupted SWR can cause repetitive and long-term misalignment between environmental and behavioral cycles and the circadian system which may then have psychological and physical health consequences. We tested whether SWR was independently associated with mood and autonomic function in a healthy adult cohort. METHODS: We studied 42 college students over a 3 week period using daily sleep-wake diaries and continuous electrocardiogram recordings. Weekly SWR was quantified by the interdaily stability of sleep-wake times (ISSW) and mood was assessed weekly using the Beck Depression Inventory-II. To assess autonomic function, we quantified the high-frequency (HF) power of heart rate variability (HRV). Linear mixed effects models were used to assess the relationship between repeated weekly measures of mood, SWR, and HF. RESULTS: Low weekly ISSW predicted subsequent poor mood and worsening mood independently of age, sex, race, sleep duration, and physical activity. Although no association was found between ISSW and HF, the ISSW-mood association was significantly moderated by nocturnal HF, i.e. reported mood was lowest after a week with low ISSW and high HF. Prior week mood scores did not significantly predict the subsequent week's ISSW. CONCLUSIONS: Irregular sleep-wake timing appears to precede poor mood in young adults. Further work is needed to understand the implications of high nocturnal HRV in those with low mood and irregular sleep-wake cycles.

Fractal Regulation in Temporal Activity Fluctuations: A Biomarker for Circadian Control and Beyond.

Motor activity in humans and other animals possesses fractal temporal fluctuations that co-exists with circadian or daily activity rhythms. The perturbations in fractal activity patterns are often accompanied by altered circadian/daily rhythms. The goal of this study is to test whether fractal regulation in motor activity provides physiological information independent from 24-h/circadian rhythmicity. To achieve the goal, we studied locomotor activity recordings of rats with the lesion of the suprachiasmatic nucleus (SCN) that are known to have diminished circadian/daily activity rhythms and perturbed fractal regulation. By restricting feeding time (i.e., food was only availability in the dark period of the 12h: 12h light-dark cycles), we found that mean activity levels in these animals displayed significant 24-h rhythms. In contrast, the restricted feeding had no influences on the perturbed fractal regulation in these SCN-lesioned animals, i.e., activity fluctuations in these animals remained random over a wide range of time scales from 2-20h. Our results indicate that 24-h rhythm of food availability can restore/improve circadian/daily rhythms in the SCN-lesioned animals but not necessarily improve the disrupted fractal activity regulation in these animals. This study provides clear and direct evidence that fractal activity patterns offer complementary information about motor activity regulation at multiple time scales that is beyond 24-h rhythm control.