955 CORE1: phase 2, single arm study of CG0070 combined with pembrolizumab in patients with non muscle invasive bladder cancer (NMIBC) unresponsive to bacillus calmette-guerin (BCG)

BackgroundCG0070, an oncolytic vaccine available as an intravesical therapy, is a serotype 5 adenovirus engineered to express GM-CSF and replicate in tumor cells with mutated or deficient RB (which results in increased of the transcription factor E2F). The CG0070 mechanism of action includes direct cell lysis in conjunction with immunogenic cell death which is enhanced in the presence of GM-CSF. In an initial phase 1 study as well as a subsequent phase 2 study, an overall CR rate of ~62% and a CR at 12 months (m) of 29% have been observed in patients with high risk NMIBC previously treated with BCG. Intravenous Pembrolizumab was recently approved by the FDA for patients with BCG-unresponsive CIS (with or without papillary tumors) with an overall complete RR of 41% and a 12m CR rate of ~20%. This phase 2 study (NCT04387461) will assess the potential synergy of the two agents in the treatment of BCG-unresponsive NMIBC.Methods35 patients with BCG-unresponsive CIS with or without concurrent Ta or T1 disease will be treated with intravesical (IVE) CG0070 at a dose of 1x10e12 vp in combination with pembrolizumab at a dose of 400 mg IV q6 weeks. CG0070 will be administered weekly x 6 as induction followed by weekly x 3 maintenance instillations at 3, 6, 9, 12, and 18m. Patients with persistent CIS or HG Ta at 3 m may receive re-induction with weekly x 6 CG0070. Pembrolizumab will be administered up to 24m. Assessment of response will include q 3m cystoscopy with biopsy, urine cytology, CTU/MRU, and mandatory bladder mapping biopsies at 12m.ResultsThe primary endpoint is CR at 12 m. Secondary endpoints will include CR at any time, progression free survival, duration of response, cystectomy free survival and the safety of the combination. Correlate assessments will include changes in the TME, systemic immune induction, viral replication and transgene expression. Baseline expression of PD-L1, coxsackie adenovirus receptor, E2F transcription factor as well as anti-adenovirus antibody titer will be correlated with tumor response. At this time the first 5 patients demonstrates 100% 3 m CR. Treatment related AE have been limited to transient grade 1-2 urinary frequency (3 patients) and grade 1 bladder spasm, hematuria, painful urination, thyroiditis, and flu-like symptoms (one patient/each). No grade 3, 4, 5 AE or SAE were observed.ConclusionsThe study is currently enrolling. Preliminary safety and efficacy data on 8 patients will be available by November 2021Trial RegistrationNCT04387461Ethics ApprovalIRB: CG2003C

Advantages of Using Paclitaxel in Combination with Oncolytic Adenovirus Utilizing RNA Destabilization Mechanism

Oncolytic virotherapy is a novel approach to cancer therapy. Ad-fosARE is a conditionally replicative adenovirus engineered by inserting AU-rich elements (ARE) in the 3’-untranslated region of the E1A gene. In this study, we examined the oncolytic activity of Ad-fosARE and used it in a synergistic combination with the chemotherapeutic agent paclitaxel (PTX) for treating cancer cells. The expression of E1A was high in cancer cells due to stabilized E1A-ARE mRNA. As a result, the efficiency of its replication and cytolytic activity in cancer cells was higher than in normal cells. PTX treatment increased the cytoplasmic HuR relocalization in cancer cells, enhanced viral replication through elevated E1A expression, and upregulated CAR (Coxsackie-adenovirus receptor) required for viral uptake. Furthermore, PTX altered the instability of microtubules by acetylation and detyrosination, which is essential for viral internalization and trafficking to the nucleus. These results indicate that PTX can provide multiple advantages to the efficacy of Ad-fosARE both in vitro and in vivo, and provides a basis for designing novel clinical trials. Thus, this virus has a lot of benefits that are not found in other oncolytic viruses. The virus also has the potential for treating PXT-resistant cancers.

Protective Role of Coxsackie-Adenovirus Receptor in the Pathogenesis of Inflammatory Bowel Diseases

Aim. To investigate the role of Coxsackie-adenovirus receptor (CAR) in inflammatory bowel disease (IBD). Background. CAR, a type I transmembrane protein with functions in virus attachment, has been shown to be associated with epithelial tight junctions (TJs) and mediates cell adhesion, implying its potential roles in the pathogenesis of IBD. Methods and Materials. To determine the effect of CAR in IBD using QPCR and Western blotting to determine the expression of CAD in TNF-α induced NCM460 and SW480 cells and IBD tissues compared to control groups. Furthermore, TJs dysregulation, FITC-Dextran permeability assay, qRT-PCR, Western blot, and IF assessed the permeability in CAR overexpressed cells treated with TNF-α. HE, qRT-PCR, Western blot, and IHC assay were used to assess the CAR overexpressed cells whether they have the effect to cure DSS induced ulcerative colitis rat model in vivo. Result. We found CAR levels in human colon cell lines are significantly downregulated under the treatment of tumor necrosis factor-alpha (TNF-α). Furthermore, overexpression of CAR markedly prevented TNF-α induced inflammatory response, TJs dysregulation, and permeability disruption (FITC-Dextran permeability assay) in cells. Consistent with these findings in vitro, we found that CAR overexpression could suppress gut inflammation, attenuate the downregulation of TJ protein ZO-1 and Occludin, and limit the induction of barrier permeability in a DSS induced ulcerative colitis rat model in vivo. Together, our findings strongly suggest that CAR could protect tight junctions and has an anti-inflammatory effect during the pathogenesis of IBD. Thus CAR may serve as a therapeutic target for the diagnosis and treatment of IBD.