Max Biopharma (United States)

6047 Background: Nasopharyngeal carcinoma (NPC) refraction and metastasis is common, but therapeutics are limited. As adoptive immunotherapy has emerged as effective against other cancers, engineered T cells bearing a transgenic Epstein-Barr virus (EBV)-specific TCR (TCR-T) represent a viable approach to treat EBV-associated NPC. Given PD-1/PD-L1 induced T cell hypofunction, we herein report preliminary findings of a phase I trial of EBV-targeting TCR-T cells armored with secreted PD-1 blockade for patients who failed in two or more lines of standard therapies. Methods: Patients with advanced NPCs were consented and screened for EBV serotype and HLA haplotype. EBV+/HLA-A*02+ patients were enrolled in a rapid titration setting to escalate the single infusion dose from 5x106 to 1.0x107 and 5.0x107 /kg TCR-T cells. After safety evaluation, the 5.0X107 /kg cohort was expanded for further investigation of combining with IL-2 administration. Fludarabine/cyclophosphamide were administered prior to TCR-T cell transfer as pre-conditioning. Patient monitoring and peripheral blood analysis occurred weekly over the first month and then monthly until disease progression or patient withdrawal. The primary objective was to determine safety and a recommended phase 2 dose (RP2D), while the secondary objective was investigator assessed ORR (RECIST v1.1). Results: One patient per TCR-T dose was treated, and, as no dose-limiting toxicity (DLT) has been observed, dose level 3 (5.0x107 /kg) was expanded with IL-2 administration upon TCR-T cell infusion. As of January 2023, six patients have been treated. One patient (16.7%) exhibited grade 1 CRS (n=6). No grade 4 treatment-related adverse events (TRAEs) have been observed, with leukopenia and fever being the most common AEs. Two patients (33.3%) were assessed as partial response (PR), with one reaching a response duration of 9 months to date. Three patients (50%) were assessed as stable disease (SD). For all patients, pharmacokinetic analysis revealed that levels of TCR-T cells in peripheral blood peak between 3- and 14-days post-infusion, with a maximum duration of 180 days. Conclusions: EBV-targeting TCR-T cells armored with PD-1 blockade are well tolerated. Initial results from this ongoing study indicate that EBV proteins may be safe and effective TCR-T targets to achieve superior outcomes in advanced EBV-positive NPC patients. Clinical trial information: NCT04139057 . [Table: see text]

Oxy210, a semi-synthetic oxysterol derivative, displays cell-selective inhibition of Hedgehog (Hh) and transforming growth factor beta (TGF-β) signaling in epithelial cells, fibroblasts, and macrophages as well as antifibrotic and anti-inflammatory efficacy in models of liver fibrosis. In the present report, we examine the effects of Oxy210 in cellular models of lung and kidney fibrosis, such as human lung fibroblast cell lines IMR-90, derived from healthy lung tissue, and LL97A, derived from an idiopathic pulmonary fibrosis (IPF) patient. In addition, we examine the effects of Oxy210 in primary human renal fibroblasts, pericytes, mesangial cells, and renal tubular epithelial cells, known for their involvement in chronic kidney disease (CKD) and kidney fibrosis. We demonstrate in fibroblasts that the expression of several profibrotic TGF-β target genes, including fibronectin (FN), collagen 1A1 (COL1A1), and connective tissue growth factor (CTGF) are inhibited by Oxy210, both at the basal level and following TGF-β stimulation in a statistically significant manner. The inhibition of COL1A1 gene expression translated directly to significantly reduced COL1A1 protein expression. In human primary small airway epithelial cells (HSAECs) and renal tubular epithelial cells, Oxy210 significantly inhibited TGF-β target gene expression associated with epithelial-mesenchymal transition (EMT). Oxy210 also inhibited the proliferation of fibroblasts, pericytes, and mesangial cells in a dose-dependent and statistically significant manner.

Non-Small Cell Lung Cancer (NSCLC) is a common malignancy and leading cause of death by cancer. Metastasis and drug resistance are serious clinical problems encountered in NSCLC therapy. Aberrant activation of the Transforming Growth Factor beta (TGFβ) and Hedgehog (Hh) signal transduction cascades often associate with poor prognosis and aggressive disease progression in NSCLC, as these signals can drive cell proliferation, angiogenesis, metastasis, immune evasion and emergence of drug resistance. Therefore, simultaneous inhibition of TGFβ and Hh signaling, by a single agent, or in combination with other drugs, could yield therapeutic benefits in NSCLC and other cancers. In the current study, we report on the biological and pharmacological evaluation of Oxy210, an oxysterol-based dual inhibitor of TGFβ and Hh signaling. In NSCLC cells, Oxy210 inhibits proliferation, epithelial-mesenchymal transition (EMT) and invasive activity. Combining Oxy210 with Carboplatin (CP) increases the anti-proliferative response to CP and inhibits TGFβ-induced resistance to CP in A549 NSCLC cells. In addition, Oxy210 displays encouraging drug-like properties, including chemical scalability, metabolic stability and oral bioavailability in mice. Unlike other known inhibitors, Oxy210 antagonizes TGFβ and Hh signaling independently of TGFβ receptor kinase inhibition and downstream of Smoothened, respectively.

Prescription of implant treatments is very widespread at present, mainly due to the low rate of annual loss and, to date, few studies have assessed their survival in the routine clinical practice of dentistry. The purpose of this observational study was to evaluate the effectiveness of dental implants with a calcium-phosphate surface in the daily practice of dental clinics. A multicenter, prospective, non-interventional, observational study was performed, in which three experienced practitioners (one maxillofacial and two oral surgeons) inserted implants using standard external and internal hexagon connections in adult patients requiring ≥1 osseointegrated implants to replace missing teeth. Follow-up was performed for 24 months after implant loading. Two hundred and twelve subjects were included (51.5% men), with a mean age of 51.2 ± 11.90 years, in whom 544 implants were inserted. 87.2% of the patients received 1–4 implants. The preferred connection system was internal hexagon (73.5%). There were nine failures, with an interval survival rate (ISR) at 24 months of 100% and a cumulative survival rate (CSR) of 98.3%. In conclusion, implants with a modified calcium-phosphate surface are associated with a high rate of survival and may be considered a method of choice in clinical practice.