Non muscular invasive bladder cancer (NMIBC) accounts for about 75% of all bladder malignant tumors. For NMIBC with high recurrence risk, its recurrence rate is high, about 15% -78%. The rate of progression to muscular invasion and metastasis is between 1% -45%. The long-term outcome shows that about 20% -25% of these patients will die of bladder cancer. Since the beginning of the 21st century, after obtaining positive results in many clinical trials, various oncolytic viruses have been approved for marketing both domestically and internationally.
Oncolytic viruses (including Recombinant Human Adenovirus Type 5 Injection, T-VEC, Teserpatulev, etc.) have been proven to be a promising approach for cancer treatment. The ORR of patients receiving Ankoray+chemotherapy reached 72.7%, compared to 40.3% for patients receiving chemotherapy alone. T-VEC has been used for the treatment of melanoma in Europe, the United States, and other regions. Patients receiving T-VEC have an ORR of 16.3% and a median OS of 23.3 months, while those receiving GM-CSF have an ORR of only 2.1% and a median OS of 18.9 months. Teserpaturev is based on the HSV skeleton and is used in Japan to treat glioblastoma, with a median PFS of 4.7 months and a median OS of 20.2 months, greatly changing the current treatment status.
Whether NMIBC patients can be treated with other therapies such as oncolytic virus instead of BCG has always been a hot topic in clinical research. In a phase I clinical trial consisting of 35 NMIBC patients with recurrent intravesical BCG, patients were sequentially treated with 0.1% DDM (n-dodecyl - β - D-maltoside, which can be used as a transduction enhancer) in the bladder, followed by CG0070. The CR rate was 48.6%, and the median CR time was 10.4 months. In an exploratory analysis, 81.8% of patients with critical or high Rb phosphorylation responded to treatment. The results of a subsequent phase II clinical trial (NCT02365818) showed a 6-month CR rate of 45% (95% CI 32-62%). Based on good preliminary results, the researchers initiated a phase III clinical trial (NCT04452591). The mid-term analysis data showed that the CR rate of BCG unresponsive NMIBC patients receiving CG0070 monotherapy was 75.7% (n=50/66), and the most common treatment-related adverse events in the trial included transient grade 1-2 local urogenital symptoms, with no related grade 3 or above adverse events observed. In addition, there are currently multiple NMIBC clinical trials underway for the treatment of BCG non responsiveness with oncolytic viruses.
Recombinant Human Adenovirus Type 5 Injection is an oncolytic adenovirus antitumor drug. In short, it mainly exerts anti-tumor effects through the following mechanisms: when adenovirus is infected, the E1a gene of the virus is immediately expressed to regulate the expression of other genes of the virus and promote the host cell to enter the S phase. The host cell responds by activating p53 induced apoptosis, thereby inhibiting the continued replication of the virus. At the same time, the E1b55k gene also exists in adenovirus, which can prevent E1a induced p53 effect through at least three mechanisms. Firstly, E1b55k binds to the amino terminus of p53, thereby inhibiting p53 transactivation; Secondly, E1b55k collaborates with Ad E4orf6 to hydrolyze and degrade p53 protein; Thirdly, using E1b55k alone can act as an E3 SUMO1-p53 ligase, ultimately leading to p53 polyubiquitination and proteasomal degradation. Therefore, E1b55k can counteract E1a induced p53 dependent cell apoptosis and prevent premature cell death, thereby effectively replicating the virus in normal cells. Without E1b55k, adenovirus may not be able to counteract E1a induced p53 accumulation, and therefore cannot replicate in cells with functional p53 protein. Due to the deletion or mutation of the p53 gene, p53 deficiency is common in many types of human cancers. Recombinant human adenovirus type 5 can selectively replicate in certain tumor cells by deleting fragments of E1b55k and E3 genes through gene editing, thereby achieving the effect of killing tumor cells.
