Vaxinia, oncolytic viruses and oncology
Given the fact Imugene’s flagship candidate Vaxinia is a prioritised drug when it comes to their product development, it is always good to revisit where the oncolytic virus (OV) stands in the larger scheme of things, by reviewing past and present happenings in the OV arena. Keeping in mind that after more than 70 years of clinical trials around the world, only T-VEC, a modified herpes simplex virus type 1 (HSV1) that targets advanced melanoma, has performed well enough to receive the Food and Drug Administration’s (FDA) go-ahead.
The FDA has followed the path of many OV clinical trial participants when it comes to the Vaxinia (MAST) Trial, by placing restrictions on Imugene when it comes to dosage rates in their Phase 1 dose escalation trial for the drug. In essence the FDA required Imugene to “dose down’ the drug in the initial phases of the current and ongoing trial, to ensure patients safety. Virologist Mary Hitt of the University of Alberta cites low dosage rates as being one reason for clinical trial failures in the past. At first, “Everyone was afraid oncolytic viruses wouldn’t be safe,” she notes. As a result, she says, many trials used weakened viruses that were too feeble to do much good.
Aside from low dosage rates in the embryonic stages of the Vaxinia (MAST) Trial Imugene has had to contend with extremely sick patients, who have already failed on several previous treatment lines. It has now been clinically proven oncolytic viruses rile the immune system, triggering inflammation and attracting anticancer warriors such as T cells, and they help break down the defences that shield tumors. Though virologist Grant McFadden of Arizona State University notes that historically speaking when it comes to “in human” trials participants typically had already undergone several rounds of therapies that could inhibit their immune systems. Therefore, because the patients couldn’t muster an immune response, the trials “were doomed,” he has said. These factors clearly make it even more difficult for Vaxinia to succeed.
Yet low dosage levels and advanced stage cancer patients may not ultimately stand in the way of Vaxinia’s success if recent oncolytic viral studies are anything to go by. In a recent Phase 3 study into bladder cancer doctors assessed the participants every 3 months after the treatment began. In 76% of the patients, tumours were undetectable at one or more of these checkups. And in 74% of that group, the tumors did not return for at least 6 months. Yet unlike the Vaxinia study the aforementioned CG Oncology study was focussed on one specific cancer, that being cancer of the bladder, whereas Imugene's Vaxinia study is being trialled across multiple cancer indications. As virologist McFadden notes, when speaking of the CG Oncology trial “when you do everything well, you can get good clinical outcomes,” he says. The company chose a type of cancer that is easy to target. The modified virus powerfully stimulated the immune system. And the enrolled patients had not undergone previous chemotherapy that would prevent their immune systems from responding to their treatment.
One positive for Imugene in the Vaxinia study is that despite the trial participants having extremely suppressed immune systems, those with a higher level of T cell diversity in peripheral blood (pre-treatment) have been shown to respond better to Vaxinia therapy. This outcome isconsistent with the known mechanism of action of oncolytic virotherapies and their ability to promote an anti-tumour T cell response. Vaxinia’s ability to change the tumour microenvironment, and turn solid tumours from cold to hot, definitely lends itself to further investigation for potential use in the checkpoint therapy refractory setting, which is seeing a growing and unmet need in oncology.
At latest count Vaxinia had resulted in one complete response within a cholangiocarcinoma patient and two partial responses in melanoma patients.A further 17 of the 20 evaluable patients on the trial were in a state of disease stabilisation as at April 20, 2024.Therefore the fight continues, now at higher dosage levels, to eradicate solid tumours within those remaining on the trial. The FDA has loosened their initial stance somewhat by granting Imugene a fast track designation in the bile duct cancer indication, enabling them to enrol a further 10 patients with cholangiocarcimomas in the study. These patients, being treated via IV and IT administration, shall be evaluated in the coming months with a view to returning to the FDA later this year in search of a registration trial designation for Vaxinia within the bile duct indication.
In December 2023 science.org noted in an article assessing the merits of oncolytic viruses another avenue to improve oncolytic viruses is pairing them with other immune therapies or with chemotherapy and radiation. Checkpoint inhibitors are obvious partners because they stymie tumors’ mechanisms for shutting down T cells. As but one example the aforementioned CG Oncology oncolytic virus has been shown to perform well with pembrolizumab, asa phase 2 study for the drug illustrated in 2022. A year after the treatment, tumors still hadn’t returned in 68% of bladder cancer patients participating in the trial. Hence Imugene’s eagerness to see what difference the addition of pembroluzimab makes to patient outcomes in their current and ongoing Vaxinia (MAST) Trial. Is Merck’s pembroluzimab set to improve patient health over and above Vaxinia as a monotherapy? Let's wait and see.
It’s probably worth noting for those interested in financial analysis, in addition to medical outcomes, that CG Oncology (NASDAQ: CGON) listed on the Nasdaq earlier this year and currently has a market capitalisation of 1.9 billion USD. Imugene (IMU - ASX) is not listed on the Nasdaq and has a current market capitalisation of approximately 362 million USD.
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