Recurrent or Refractory High-Grade Gliomas Treated by Convection-Enhanced Delivery of a TGFß2-Targeting RNA Therapeutic: A Post-Hoc Analysis with Long-Term Follow-Up.

Background. OT101 is a first-in-class RNA therapeutic designed to abrogate the immunosuppressive actions of transforming growth factor beta 2 (TGFß2). Here, we report our post-hoc analysis of the single-agent activity of OT101 in adult patients with recurrent and/or refractory (R/R) high-grade gliomas. Methods. In a Phase 2 clinical trial (ClinicalTrials.gov, NCT00431561), OT101 was administered to 89 R/R high-grade glioma (HGG) (anaplastic astrocytoma/AA: 27; glioblastoma multiforme/GBM: 62) patients with an intratumoral catheter using a convection enhanced delivery (CED) system. Seventy-seven patients (efficacy population; GBM: 51; AA: 26) received at least the intended minimum number of four OT101 treatment cycles. Response determinations were based on central review of magnetic resonance imaging (MRI) scans according to the McDonald criteria. Standard statistical methods were applied for the analysis of data. Findings. Nineteen patients had a complete response (CR) or partial response (PR) following a slow but robust size reduction of their target lesions (median time for 90% reduction of the baseline tumor volume = 11.7 months, range: 4.9-57.7 months). The mean log reduction of the tumor volume was 2.2 ± 0.4 (median = 1.4: range: 0.4-4.5) logs. In addition, seven patients had a stable disease (SD) lasting ≥6 months. For the combined group of 26 AA/GBM patients with favorable responses, the median progression-free survival (PFS) of 1109 days and overall survival (OS) of 1280 days were significantly better than the median PFS (p < 0.00001) and OS (p < 0.00001) of the non-responders among the 89 patients or the 77-patient efficacy population. Conclusion. Intratumorally administered OT101 exhibits clinically meaningful single-agent activity and induces durable CR/PR/SD in R/R HGG patients.

Impact of targeting transforming growth factor ß-2 with antisense OT-101 on the cytokine and chemokine profile in patients with advanced pancreatic cancer.

BACKGROUND: Overexpression of the cytokine - transforming growth factor-beta 2 (TGF-ß2) - has been implicated in the malignant progression of pancreatic cancer (PAC). OT-101 (trabedersen) is an antisense oligodeoxynucleotide designed to target the human TGF-ß2 mRNA. In a Phase I/II study, OT-101 treatment with subsequent chemotherapy was characterized by outstanding overall survival (OS) in patients with PAC. OBJECTIVE: This study sought to identify 1) co-regulated sets of cyto-/chemokines; 2) potential mechanisms that link TGF-ß receptor type 2 receptor inhibition that may result in the induction of a cytokine storm; and 3) predictive biomarkers for OS outcome in OT-101-treated patients with PAC. MATERIALS AND METHODS: Plasma levels of 31 cyto-/chemokines were tracked over three cycles of OT-101 therapy (140 mg/m2/day) in 12 PAC patients. Samples were acquired before onset of OT-101 therapy and at eight selected time points during therapy. A mixed ANCOVA model was developed for 19 cyto-/chemokines with median expression >1 following OT-101 therapy. Regression and hierarchical clustering analyses were performed to identify correlated expressions in each patient across cyto-/chemokines or in each cyto-/chemokine across patients. Plasma cyto-/chemokine levels were compared with OS with and without subsequent chemotherapy. RESULTS: Three highly correlated subsets of cyto-/chemokines (Cluster 1: EGF, MIP-1α, MIP-1ß; Cluster 2: FGF-2, MIG, IP-10, IL-15, IFN-α, IL-12; and Cluster 3: HGF, IL-6, IL-8) were identified following OT-101 therapy. Suppression of TGF-ß signaling by OT-101 led to upregulation of IL-8, IL-15, IP-10, and HGF. Protein-protein interaction networks constructed using STRING10 algorithm identified a relationship between IL-8, IL-15, and TGF-ß receptor type 2 inhibition. The mixed analysis of covariance model that examined the levels of 19 cyto-/chemokines with OS as the covariate at each of the time points resulted in IL-8 and IL-15 exhibiting a significant association with OS during Cycle 1 of therapy. In the whole-blood culture model, the cytokines with the most pronounced increase after OT-101 treatment were IL-1ß, IL-8, and MCP-1. CONCLUSION: No consistent responses in cyto-/chemokine levels were observed due to OT-101 treatment. Levels of IL-8 and IL-15 during Cycle 1 were positively associated with OS across 12 patients with PAC and served as potential biomarkers for treatment outcome following OT-101 therapy.

Improved effectiveness of nanoparticle albumin-bound (nab) paclitaxel versus polysorbate-based docetaxel in multiple xenografts as a function of HER2 and SPARC status.

Nanoparticle albumin-bound (nab)-paclitaxel (Abraxane) is an albumin-bound 130-nm particle form of paclitaxel that demonstrated higher efficacy and was well tolerated compared with solvent-based paclitaxel (Taxol) and docetaxel (Taxotere) in clinical trials for metastatic breast cancer. Nab-paclitaxel enhances tumor targeting through gp60 and caveolae-mediated endothelial transcytosis and the association with the albumin-binding protein SPARC (secreted protein, acidic and rich in cysteine) in the tumor microenvironment. The overexpression of human epidermal growth factor receptor-2 (HER2) in breast cancer has been shown to correlate with resistance to paclitaxel. To evaluate the importance of HER2 and SPARC status in determining the relative efficacy of nab-paclitaxel compared with polysorbate-based docetaxel, nude mice bearing six different human tumor xenografts were treated with nab-paclitaxel (MX-1: 15 mg/kg, once a week for 3 weeks; LX-1, MDA-MB-231/HER2+, PC3, and HT29: 50 and 120 mg/kg, every 4 days three times ; MDA-MB-231: 120 and 180 mg/kg, every 4 days three times) and polysorbate-based docetaxel (15 mg/kg). HER2 and SPARC status were analyzed by RT-PCR and immunohistochemical staining. MDA-MB-231 and MX-1 breast and LX-1 lung cancers were HER2 negative and low in SPARC expression. Nab-paclitaxel at submaximum-tolerated dosage was significantly more effective than polysorbate-based docetaxel at its maximum-tolerated dosage in these three HER2-negative tumors. The HER2-positive tumors had variable SPARC expression, with MDA-MB-231/HER2+