Promising Developments in the Theralase® Project of Intravesical Photodynamic Therapy for BCG Unresponsive Bladder Cancer - Girish Kulkarni

May 18, 2023

In a discussion, Ashish Kamat and Girish Kulkarni delve into the Theralase ® project of intravesical photodynamic therapy for non-muscle invasive bladder cancer. This study, led by Dr. Kulkarni, employs photo-dynamic therapy in a phase two trial for BCG unresponsive bladder cancer, with promising early results. The procedure uses a ruthenium-based photosensitizer and a laser light that creates oxygen singlets to destroy cancer cells. Despite a learning curve, the procedure is straightforward, and patients experience lower urinary tract symptoms that typically resolve after a month or two. Unlike previous therapies, this method offers urologist-led, localized treatment with minimal systemic side effects. Kulkarni notes that its use as a single treatment with a six-month maintenance dose can be a more practical option for patients living in remote areas. The conversation wraps up with insights into the therapy's specificity to bladder cancer cells and its advanced control features that further enhance its clinical potential.


Girish Kulkarni, MD, Ph.D., FRCSC, Urologic Surgeon, Department of Surgery, University of Toronto

Ashish Kamat, MD, MBBS, Professor, Department of Urology, Division of Surgery, University of Texas MD Anderson Cancer Center, President, International Bladder Cancer Group (IBCG), Houston, Texas

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Ashish Kamat: Hello, it's a great pleasure to have you here with us today, Girish, to talk about several things that you're doing at the AUA. But first off, let me ask you about the Theralase project that you're working on. You're a PI of the study. We're all eagerly awaiting what you have to say about the results of the patients. So enlighten us.

Girish Kulkarni: Yeah, so the Theralase study is a phase two trial for BCG unresponsive bladder cancer. It's photo-dynamic therapy, with a ruthenium based photosensitizer placed within the bladder an hour before a general anesthetic. And the time of the GA, the general anesthetic, we place a 520 nanometer laser light that's green in the bladder, that activates the drug, and it creates oxygen singlets, free radicals to kill any kind of CIS. So it's in the CIS based population. The phase 1B was published already in European Urology open science, and demonstrated excellent safety.

So now we're on phase two. We have interim results, at the AUA. 56 patients have been enrolled of 125, so we're about halfway there, and the early results are quite promising. So 54% three month CR, which is quite good, particularly when you look at what has been published to date. We don't have as much long-term data right now, and it is a quite safe and tolerated procedure. Patients do get lower urinary tract symptoms for a short period of time, but they almost all resolve to baseline after a month or two.

Ashish Kamat: And in your experience, how easy or difficult is it to actually do the instillation? The whole drug, and then the laser application.

Girish Kulkarni: So there is a learning curve to it. Right now the drug is instilled to 80% of bladder volume. So we do get a voiding diary. A three day voiding diary. The issue sometimes is patients have trouble holding the capacity, 80%. So we do have to drain the bladder at points, prior to bringing them to the OR. So that's one aspect that makes it a bit more challenging. The idea is to have a full bladder so that all the rugae and folds within the bladder are stretched out. So there's optimal contact with the photo sensitizer.

Then when the patient's brought into the OR, at that point, it's pretty straightforward. Setting up the laser and placing it within the center of the bladder with an ultrasound takes a short amount of time. Only about 10 minutes. Obviously, with any new procedure, it will take some time to learn that. But now we've got it down to a fine art to do that.

The time is variable. So that's the one amount of heterogeneity. So the actual illumination is anywhere from 50 to 100 ... Sorry, 50 to about 70 or 80 minutes. And that's based on the surface area of the bladder.

Ashish Kamat: Now again, you're involved in a lot of studies when it comes to muscle invasive and non-muscle invasive bladder cancer. So if you could just share with us, assuming that these data hold out and it pans out, and let's assume it gets approved, where would you fit this into the whole armamentarium or sequencing of therapies for patients in this particular disease space?

Girish Kulkarni: Yeah, so I think one of the advantages here is it is a urologist run therapy. Urologists are comfortable going to the OR and treating patients cystoscopically or endoscopically. It's a single treatment. So that's very appealing. And if patients are doing well, there's a maintenance treatment at six months. If they don't have progressive disease, they're also eligible in the trial for a six month treatment. So basically it's two treatments and you're done. So that's the appealing part of the study. So patients who are coming from a distance in large states, for example, Texas, large countries like mine, Canada, where patients have to travel five or six hours to get their treatments, is far more practical than an intravesical therapy, and it doesn't have any of the systemic side effects of immune checkpoint inhibitors.

Ashish Kamat: Yeah. Speaking of systemic side effects, I remember the previous times of photo-sensitizers, where patients had to literally cover themselves from head to toe and go about. And you don't have to do that with this one. If you could just enlighten the audience a little bit on the mechanistic as to why is this new agent so much different from the older ones? Because some of them might be remembering the old data, and might be a little gun shy. So a little bit there

Girish Kulkarni: For sure. The old data, we had a lot of bladder fibrosis. So here the idea is that the compound is specific just to bladder cancer cells. It's a transfer and mediated uptake into the bladder cancer cell. So it's supposed to spare the non-bladder cancer cell because of the lower expression of transfer on the normal urothelium. So that's one component. The green laser light doesn't penetrate as much as older light modalities, so that decreases the fibrosis as well. And the device actually has detectors for the illumination.

So when the green light is shone in the center of the bladder, what happens is it can pick up the light that is emanating from the actual probe, but also the light that may be bouncing around within the bladder. So there's a bit more control as to providing a dose, and the dose is 90 jewels per centimeter squared. We as urologists don't have to calculate that, which is good, because I don't know how to calculate it. It's done through the proprietary machine created by Theralase.

Ashish Kamat: Right. And then just to emphasize, this is the next generation of photodynamic therapy, not what we used to have back in the late '90s or early 2000s. And obviously, the results that you're presenting are encouraging, and we hope that it pans out for our patient's sake. So Girish, thanks again for taking the time during your busy AUA schedule and sharing this with us.

Girish Kulkarni: Oh, it's my pleasure. Thank you so much for having me.