Novel gene Tx shows early promise in BCG-responsive bladder cancer

Nearly three-quarters of patients with non-muscle invasive bladder cancer (NMIBC) have a complete response to novel gene therapy EG-70, according to preliminary data from a recent Phase I/II Legendary trial presented at the ASCO Genitourinary Cancer Symposium.

In this exclusive video, the main character Study author Gary Steinberg, MD , of NYU Langone Perlmutter Cancer Center, discusses the study and its implications for clinical practice.

The following is a transcript of his speech:

Our enGene trial is a Phase I trial using EG-70, a novel innovative construct. It uses a plasma delivery system, chitosan, which is a very lipophilic structure. And this lipophilic structure is easily absorbed by any epithelial surface. So the bladder is lined with the urothelium, which is an epithelial surface, and it’s the same for the head and neck, the colorectum, and the lungs, as long as there is an epithelial surface.

Our specific construct includes two cytokines that are important for bladder cancer. First, turn on the innate immune system, or RIG-I. So there’s two RNA plasmas for RIG-I and then there’s the adaptive immune system IL-12 which is a very important cytokine and IL-12 which is a DNA plasma that’s been put into the structure .

So the concept is that we now have a non-viral gene delivery system that is readily taken up by cells, eg, the bladder, delivering their plasma to and then delivering the DNA and RNA Transect and then produce these very important cytokines.

The most common treatment we use for non-muscle bladder cancer is something called Bacillus Calmette-Guérin (BCG), which is a live attenuated mycobacterium , originally invented by Louis Pasteur in the early 1920s. It has been genetically altered over the years, which is what we call a dirty immunotherapy. While it turns on the innate and adaptive immune systems very effectively, it does so in a very non-specific way.

We know that BCG has potential side effects because it is a live attenuated mycobacterium. It has infectious disease problems and, most importantly, it is difficult to manufacture. In the United States, only one company currently manufactures FDA-approved Tice BCG, and demand exceeds supply. And we’ve been in this supply shortage since around 2017 and probably won’t have any new manufacturing facilities in the US until 2027 at the earliest.

So we desperately need to find a replacement. And I think it’s a very novel way of modeling the immune system.

One nice thing about this construct is that we can also add other things to the construct. So one of the things that we found out from ImmunityBio was using the IL-15 cytokine and BCG, which might put the IL-15 plasmid into our construct. Even checkpoint inhibitors like TIGIT, which is a checkpoint inhibitor of NK cells, natural killer cells, which are very important assets or components of immune cell killing in urothelial cancer.

This study is a phase I dose escalation trial. We’re working on something called BCG unresponsive spaces. Thus, these patients with high-grade, high-risk, non-muscle-invasive bladder cancer are at high risk for progression to muscle-invasive or metastatic disease and no longer respond to intravesical BCG. It starts with dose escalation. We have treated 19 patients. We report the first 17 patients we treated.

We think we’ve found the right dose, and we’re going to do these four installs. So we put a catheter in the patient’s bladder, put the drug in, and we Four installations will be performed over a 12-week period. BCG once a week for 6 weeks. We’re going to do it once a week for 2 weeks, then take a break, then do it once a week for 2 weeks, and do it twice over a 12 week period.

The drug was very well tolerated. We’ve been measuring interleukin 12 in urine and found that we have a very good dose-dependent response to IL-12, which is a significant portion of the cross-section. So we sort of reassure ourselves that we’re crosscutting what we’re talking about going into the bladder and going into the urine. Again, this is a small amount of early data.

But what we were looking for in these BCG non-response trials was response at 3 months. Most importantly, the urology community and the patient community want not just a 3-month response, but the durability of the response. So if you have a 3 month response, they want to make sure it’s durable for 12 months and beyond.

We obviously don’t have the data yet, but our response rate for the full 3 months is pretty good. Twelve of 17 patients with bladder carcinoma in situ, high-grade carcinoma in situ, who did not respond to BCG, were treated at the initial 3-month time point, and 12 of 17 patients had a complete response.

So we’re very excited about this and hopeful, but we need to move on to our second phase. I think these data clearly show that we have enough signal to proceed with a phase II trial that will again focus on patients with high-risk, non-muscle-invasive bladder cancer. We also want to add some patients with papillary disease, not just carcinoma in situ, and treat those patients, study event-free survival and the durability of our response.

One of the benefits, however, is that because it’s not an infectious source, it’s a non-viral delivery system, and we can re-treat patients. So say you have a patient who responds for a year or two, and then they relapse, well, you can re-treat those patients without any risk. For example, one of the things about using an adenovirus vector as a vaccine is that potential patients after repeated doses may develop antibodies against the adenovirus and reduce your efficacy.

So, again, I hope it gets approved and I hope it actually replaces BCG. It’s simple to make and even easier to use. It comes in the form of powder, solution. It’s easy to instill. It doesn’t need to be frozen etc. So I think it’s a big step forward. However, early, early data and small amounts of data, we clearly need to expand the population that we are studying.