Smooth muscle cell-derived Cxcl12 directs macrophage accrual and sympathetic innervation to control thermogenic adipose tissue.

Sympathetic innervation of brown adipose tissue (BAT) controls mammalian adaptative thermogenesis. However, the cellular and molecular underpinnings contributing to BAT innervation remain poorly defined. Here, we show that smooth muscle cells (SMCs) support BAT growth, lipid utilization, and thermogenic plasticity. Moreover, we find that BAT SMCs express and control the bioavailability of Cxcl12. SMC deletion of Cxcl12 fosters brown adipocyte lipid accumulation, reduces energy expenditure, and increases susceptibility to diet-induced metabolic dysfunction. Mechanistically, we find that Cxcl12 stimulates CD301+ macrophage recruitment and supports sympathetic neuronal maintenance. Administering recombinant Cxcl12 to obese mice or leptin-deficient (Ob/Ob) mice is sufficient to boost macrophage presence and drive sympathetic innervation to restore BAT morphology and thermogenic responses. Altogether, our data reveal an SMC chemokine-dependent pathway linking immunological infiltration and sympathetic innervation as a rheostat for BAT maintenance and thermogenesis.

Real-world evidence of obinutuzumab and venetoclax in previously treated patients with chronic lymphocytic leukemia or small lymphocytic lymphoma.

Venetoclax-obinutuzumab (Ven-O) is frequently administered off-label in relapsed/refractory (r/r) CLL/SLL where venetoclax-rituximab is the approved regimen. We conducted this retrospective, real-world study to evaluate Ven-O in r/r CLL/SLL. Between 7/2019 and 6/2022, 40 patients with r/r CLL/SLL on Ven-O were included. The median age was 72, 28.2% had TP53 mutation and/or 17p deletion, median number of prior therapies was 1 (range, 1-6), and 55% had prior BTK inhibitor exposure. The overall response rate was 90% (complete response [CR] or CR with incomplete marrow recovery in 27.5% and partial response in 62.5%) of patients, and the 2-year progression-free survival was 81.2% (95% CI, 69.5-94.8). Therapy was well tolerated. No laboratory or clinical TLS occurred with venetoclax (Howard criteria). One (3%) patient experienced laboratory TLS with obinutuzumab initiation. In summary, this retrospective cohort study demonstrated that Ven-O achieves frequent, durable responses and can be safely administered in r/r CLL/SLL.

KLRG1 Cell Depletion as a Novel Therapeutic Strategy in Patients with Mature T-Cell Lymphoma Subtypes.

PURPOSE: Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms. EXPERIMENTAL DESIGN: Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation. RESULTS: Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3-/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL), respectively, expressed surface KLRG1. The humanized afucosylated anti-KLRG1 monoclonal antibody (mAb208) optimized for mouse in vivo use depleted KLRG1+ TCL cells by mechanisms of ADCC, ADCP, and CDC rather than apoptosis. mAb208 induced ADCC and ADCP of T-LGLL patient-derived CD8+/CD57+ cells ex vivo. mAb208 effected ADCC of subsets of healthy donor-derived KLRG1+ NK, CD4+, CD8+ Tem, and TemRA cells while sparing KLRG1- naïve and CD8+ Tcm cells. Treatment of cell line and TCL patient-derived xenografts with mAb208 or anti-CD47 mAb alone and in combination with the PI3K-δ/γ inhibitor duvelisib extended survival. The depletion of macrophages in vivo antagonized mAb208 efficacy. CONCLUSIONS: Our findings suggest the potential benefit of a broader treatment strategy combining therapeutic antibodies with PI3Ki for the treatment of patients with mature T-cell and NK-cell neoplasms. See related commentary by Varma and Diefenbach, p. 2300.

Combined analysis of the impact of second-generation BTK inhibitors on patient outcomes.

BTK inhibitors (BTKi) are highly effective in B-cell malignancies. Acalabrutinib and zanubrutinib have exhibited favorable safety profiles when compared with ibrutinib. We identified all published/presented randomized trials comparing a second-generation BTKi with ibrutinib and reconstructed individual patient-level, censored time-to-event data for adverse events to evaluate the impact of second-generation BTKi on safety outcomes including atrial fibrillation/flutter [AF], hypertension, bleeding, diarrhea, and infection. 1386 pts from ELEVATE-RR (n = 533), ALPINE (n = 652), and ASPEN (n = 201) trials were included in the analyses. Acalabrutinib or zanubrutinib were associated with significant reductions in cumulative event rates of AF (HR 0.28, 95% CI 0.18-0.42, p < 0.001), bleeding (HR 0.65, 95% CI 0.52-0.81, p < 0.001), diarrhea (HR 0.61, 95% CI 0.47-0.78, p < 0.001), hypertension (HR 0.40, 95% CI 0.27-0.61, p < 0.001), and infections (HR 0.83, 95% CI 0.70-0.98, p = 0.032). In summary, zanubrutinib and acalabrutinib have a favorable safety profile among pts with r/r B-cell malignancies. These data support use of acalabrutinib or zanubrutinib as preferred BTK inhibitors for approved indications.

Treatment of latent tuberculosis infection in contacts of new tuberculosis cases in the United States.

BACKGROUND: Few data are available describing treatment completion rates among recently infected contacts of tuberculosis (TB) cases, a group at high risk for development of active TB. METHODS: Health department records were reviewed for all contacts of 360 culture-positive pulmonary TB cases reported from five health departments in the United States in 1996. RESULTS: Of 2,267 contacts who completed screening, 630 (28%) had newly documented positive skin tests (121 with skin test conversion). Treatment of latent TB infection was documented to have been recommended for 447 (71%). Among these, treatment was documented to be initiated for 398 (89%). Of these, 203 (51%) were documented to have completed a 6-month course of treatment, and 78 (20%) received directly observed treatment. Treatment was recommended more often for contacts < 15 years of age, skin test converters, close contacts, and contacts of smear-positive cases. Treatment completion rates were higher for skin test converters. CONCLUSIONS: In this study, fewer than one third of all persons with newly documented positive skin tests detected during contact investigations were proven to have completed treatment. Achieving high rates of completion of therapy for latent TB infection in recently infected contacts of active cases of pulmonary TB is essential to maximize public health prevention efforts aimed at eliminating TB.

Evaluation of investigations conducted to detect and prevent transmission of tuberculosis.

CONTEXT: Contact investigations are routinely conducted by health departments throughout the United States for all cases of active pulmonary tuberculosis (TB) to identify secondary cases of active TB and latent TB infection and to initiate therapy as needed in these contacts. Little is known about the actual procedures followed, or the results. OBJECTIVES: To evaluate contact investigations conducted by US health departments and the outcomes of these investigations. DESIGN, SETTING, AND SUBJECTS: Review of health department records for all contacts of 349 patients with culture-positive pulmonary TB aged 15 years or older reported from 5 study areas in the United States during 1996. MAIN OUTCOME MEASURES: Number of contacts identified, fully screened, and infected per TB patient; rates of TB infection and disease among contacts of TB patients; and type and completeness of data collected during contact investigations. RESULTS: A total of 3824 contacts were identified for 349 patients with active pulmonary TB. Of the TB patients, 45 (13%) had no contacts identified. Of the contacts, 55% completed screening, 27% had an initial but no postexposure tuberculin skin test, 12% were not screened, and 6% had a history of prior TB or prior positive tuberculin skin test. Of 2095 contacts who completed screening, 68% had negative skin test results, 24% had initial positive results with no prior test result available, 7% had documented skin test conversions, and 1% had active TB at the time of investigation. Close contacts younger than 15 years (76% screened vs 65% for older age groups; P<.001) or exposed to a TB patient with a positive smear (74% screened vs 59% for those with a negative smear; P<.001) were more likely to be fully screened. Close contacts exposed to TB patients with both a positive smear and a cavitary chest radiograph were more likely to have TB infection or disease (62% vs 33% for positive smear only vs 44% for cavitary radiograph only vs 37% for neither characteristic; P<.001). A number of factors associated with TB patient infectiousness, contact susceptibility to infection, contact risk of progression to active TB, and amount of contact exposure to the TB patient were not routinely recorded in health department records. CONCLUSIONS: Improvement is needed in the complex, multistep process of contact investigations to ensure that contacts of patients with active pulmonary TB are identified and appropriately screened.