Vactosertib, a novel TGF-ß1 type I receptor kinase inhibitor, improves T-cell fitness: a single-arm, phase 1b trial in relapsed/refractory multiple myeloma.

Functional blockade of the transforming growth factor-beta (TGF-ß) signaling pathway improves the efficacy of cytotoxic and immunotherapies. We conducted a phase 1b study to determine the safety, efficacy, and maximal tolerated dose (200 mg po bid) of the potent, orally-available TGF-ß type I receptor kinase inhibitor vactosertib in relapsed and/or refractory multiple myeloma patients who had received ≥2 lines of chemoimmunotherapy. Vactosertib combined with pomalidomide was well-tolerated at all doses, had a manageable adverse event profile and induced durable responses with 80% progression-free survival (PFS-6) at 6 months, while pomalidomide alone historically achieved 20% PFS-6. Following treatment, the immunosuppressive marker PD-1 expression was reduced on patient CD8+ T-cells. Following ex vivo treatment, vactosertib decreased PD-1 expression on patient CD138+ cells, reduced PD-L1/PD-L2 on patient CD138+ cells and enhanced the anti-myeloma activity of autologous T-cells. Taken together, vactosertib is a safe immunotherapy that modulates the T-cell immunophenotype to reinvigorate T-cell fitness. Multiple myeloma (MM) is a genetically heterogeneous hematologic malignancy characterized by the excessive proliferation of clonal plasma cells (1, 2). MM remains mostly incurable but a small group of patients can achieve long-term remission (3). Treatment of MM presents unique challenges due to the complex molecular pathophysiology and genetic heterogeneity (4, 5). Given that MM is the second most common blood cancer characterized by cycles of remission and relapse, the development of new therapeutic modalities is crucial (6, 7). The prognosis for MM patients has improved substantially over the past two decades with the development of more effective therapeutics, e.g., proteasome inhibitors, and regimens that demonstrate greater anti-tumor activity (8-10). The management of RRMM represents a vital aspect of the overall care for patients with disease and a critical area of ongoing scientific and clinical research (10-12).

Label-free CMOS bio sensor with on-chip noise reduction scheme for real-time quantitative monitoring of biomolecules.

We present a label-free CMOS field-effect transistor sensing array to detect the surface potential change affected by the negative charge in DNA molecules for real-time monitoring and quantification. The proposed CMOS bio sensor includes a new sensing pixel architecture implemented with correlated double sampling for reducing offset fixed pattern noise and 1/f noise of the sensing devices. We incorporated non-surface binding detection which allows real-time continuous monitoring of DNA concentrations without immobilizing them on the sensing surface. Various concentrations of 19-bp oligonucleotides solution can be discriminated using the prototype device fabricated in 1- µm double-poly double-metal standard CMOS process. The detection limit was measured as 1.1 ng/µl with a dynamic range of 40 dB and the transient response time was measured less than 20 seconds.