Novel Gene Tx Shows Early Promise in BCG-Unresponsive Bladder Cancer

Nearly three-fourths of patients with non-muscle-invasive bladder cancer (NMIBC) had a complete response to the novel gene therapy EG-70, according to preliminary data from the phase I/II LEGEND trial, which was presented at the recent ASCO Genitourinary Cancers Symposium.

In this exclusive video, lead study author Gary Steinberg, MD, of NYU Langone’s Perlmutter Cancer Center in New York City, discusses the study and its implications for clinical practice.

Following is a transcript of his remarks:

Our enGene trial was a phase I trial using EG-70, and EG-70 is a novel innovative construct. It uses a plasma delivery system, a chitosan, which is a very lipophilic construct. And this lipophilic construct readily is absorbed by any epithelial surface. So the bladder is lined by urothelium, which is an epithelial surface, same thing for the head and neck, colorectal, lung, any time there’s an epithelial surface.

And our particular construct includes two very important cytokines for bladder cancer. One, to turn on the innate immune system, which is RIG-I. And so there are two RNA plasmas for the RIG-I, and then also for the adaptive immune system, IL-12, which is a very important cytokine, IL-12, which is a DNA plasma, which has been put into the construct.

And so the concept is that we now have a non-viral gene delivery system that is readily absorbed by the cells that line, for example, the bladder, delivering their plasmas to the DNA and RNA to then be transected and then produce these very important cytokines.

The most common treatment that we’re using for non-muscle-based bladder cancer is something called bacillus Calmette-Guérin (BCG), which is a live-attenuated mycobacterium that was initially invented in the early 1920s by Louis Pasteur. It’s been genetically altered over the years, and it’s kind of what we call a dirty type of immunotherapy. Although it is very effective turning on the innate and adaptive immune system, but in a very non-specific way.

We know that there are potential side effects from BCG due to it being a live-attenuated mycobacterium. It has infectious disease concerns, and most importantly, is that it is difficult to manufacture. And in the United States, there’s only one company currently making the Tice BCG, which is FDA approved, and that is in short supply. And we’ve been in this short supply situation since about 2017, and probably not going to have any new production facilities in the United States until 2027 at the earliest.

So we desperately need to find alternatives. And I think that this is a very novel way to simulate the immune system.

One of the nice things about this construct is that we can also add other things into the construct. So one of the things we’re finding from ImmunityBio, which is using an IL-15 cytokine with BCG, that would potentially put an IL-15 plasmid into our construct. Even checkpoint inhibitors such as TIGIT, which is a checkpoint inhibitor for NK cells, natural killer cells, which are a very important asset or a component of immune cell killing in urothelial cancer.

The study was a phase I dose-escalation trial. We’re looking at something called the BCG-unresponsive space. So these are patients with high-grade, high-risk, non-muscle-invasive bladder cancer at high risk for progression to muscle invasion or metastasis that no longer respond to intravesical BCG. It started out with dose escalation. We’ve treated 19 patients. We reported on our first 17 patients that we’ve treated.

We think that we’ve found the proper dose already, and that we’re going to be giving these four installations. So we put a catheter in the patient’s bladder, put the medication in, and we’re going to be putting four installations over a 12-week period. BCG is once a week for 6 weeks. We’re going to do once a week for 2 weeks, and then a break, and then once a week for 2 weeks, two more times over a 12-week period.

The medication has been very well tolerated. We’ve been measuring interleukin-12 in the urine and see that we’ve got a nice dose-dependent response to IL-12, which is an important part of the transection. So we’re kind of assuring ourselves that we’re transecting what we say we are into the bladder and getting into the urine. And again, it’s small numbers, early data.

But what we are looking for in these BCG-unresponsive trials is response at 3 months. And most importantly, what the urologic community and the patient community wants is not just response to 3 months, but durability of response. So if you have a response of 3 months, they want to make sure that it’s durable at 12 months and beyond.

We clearly don’t have that data yet, but our complete response rate at 3 months is quite nice. It’s 12 out of 17 patients that had carcinoma in situ of the bladder, high-grade carcinoma in situ of the bladder, not responding to BCG, treated at an initial 3-month time point, 12 out of 17 patients had a complete response.

And so we’re very excited about this and very hopeful, but we need to continue onto our phase II. And I think that this data clearly demonstrates that we have enough of a signal that we should proceed to a phase II trial, which will be, again, looking at patients with high-risk, non-muscle-invasive bladder cancer. We’re also hoping to add some patients with papillary disease, not just carcinoma in situ, and treat these patients, looking at event-free survival and durability of our response.

One of the nice things, however, is since it’s not an infectious agent, it’s a non-viral delivery system, is that we can re-treat patients. So say that you have a patient that responds for a year or two, and then they recur, well then, potentially, you can re-treat these patients without any risk. One of the things about using, for example, an adenovirus vector as your vaccine, potentially patients after repeated installations can form antibodies to the adenovirus and diminish your efficacy.

So, again, I would love to be able to get this approved, and I would love it to actually replace BCG. It’s easy to make, it’s easier to use. It comes as a powder, a solution. It’s very easy to instill. It doesn’t need to be frozen and so forth. And so I think that this is a nice step forward. However, early on, early data and small numbers, we clearly need to expand this population that we’re studying.