Injecting an immune checkpoint inhibitor for treatment of non-metastatic cancer shows promising results.
Immune checkpoint inhibitors have turned oncology upside down, but not for patients with early stage bladder cancer. Now, Western Australian researchers have succeeded in using a different mode of administration to bring the benefits a step closer, with fewer side-effects.
The Phase 1b trial, funded by the independent Australian and New Zealand Urogenital and Prostate Cancer Trials Group and the Spinnaker Health Research Foundation, showed that administering a target dose of durvalumab, a human monoclonal anti-PD-L1 antibody, via sub-urothelium injection to patients with localised bladder cancer was both safe and promising in terms of efficacy.
“The pharmaceutical industry has been very focussed on checkpoint inhibitors in metastatic disease. But these drugs may be very effective earlier on in the disease, when there’s much greater benefit to patients. You can cure their cancer before it spreads or before they need their bladder removed,” the study chair, Professor Dickon Hayne from the University of Western Australia, told OR.
Immune checkpoint inhibitors are already used to treat metastatic bladder cancer. However, 75% of patients have non-muscle invasive bladder cancer (NMIBC) at diagnosis which then often recurs and progresses to muscle-invasive bladder cancer.
The trial involved 11 patients (10 male) who had high grade (Ta/T1) non-metastatic muscle-invasive bladder cancer or non-metastatic muscle-invasive bladder cancer, with no prior chemotherapy or immunotherapy (except Bacillus Calmette-Guerin treatment), and who were scheduled to have a radical cystectomy.
Two weeks before bladder removal, patients had a cystoscopy and bladder biopsies, followed by treatment with durvalumab via a sub-urothelial injection – a first – rather than systemically or through intravesical deliver. Just before bladder removal, they had another cystoscopy and more tumour biopsies.
Professor Hayne said it was “humbling” to see the altruism that drove participants to volunteer for the study when they were not personally going to benefit.
“They chose to have an extra cystoscopy, another procedure that they didn’t need to have, and an experimental treatment. They chose to take part, knowing that we might find something to help people in the future, and I think that’s pretty special,” he said.
The trial group decided that only 10% of the systemic dose was needed with sub-urothelial injection, with the first group given 25mg, the second 75mg and the last group given the target dose of 150mg.
“These drugs have a lot of immune-related side effects when they’re given systemically. In this study, we’ve physically looked inside the bladder with a camera and injected the drug around the bladder,” said Professor Hayne.
“The bladder is something like 1% of the total tissue volume of the body. We figured that if we could safely reach 10% of the systemic dose, that would be an order of magnitude more than would be getting to the bladder via a vein.”
The participants reported mainly grade 1 adverse events – nausea, dysuria, cough, pruritis and diarrhoea; and one grade 2 event – fatigue.
“None of them had any serious side effects or any immune-related adverse events,” said Professor Hayne.
While the study was not designed to find a direct effect on tumours, relative changes to immune cell populations were seen after the injections were given, specifically for CD163 (M2 macrophages).
“This is only a single administration of the drug, and we’ve already seen immune changes occurring with a much lower dose than the patient would have into a vein,” said Professor Hayne.
“The reason this was such an important first step is because we just didn’t know if it was safe, if you could do it, and whether there was any immune related effect at all. And we have, in this relatively small study, shown all of those things.”
The usual treatment for non-muscle invasive bladder cancer patients would be transurethral tumour resection and postoperative chemotherapy, followed by BCG treatment for high-grade tumours or carcinoma in situ. Those unresponsive to BCG are left with bladder removal.
Where an immune checkpoint inhibitor has been tried in NMIBC BCG-unresponsive patients, response has been short term and two-thirds had treatment-related adverse events. Toxicity has been lower in some small studies of intravesical delivery of immune checkpoint inhibitors, but efficacy has been lacking.
Injecting the drug into the bladder was “a very pragmatic approach,” and while other methods, like using a catheter, were being trialled, sub-urothelial injection was more likely to succeed, said Professor Hayne.
Checkpoint inhibitors have large molecules which may not penetrate the urothelium, which is after all there to prevent absorption, and that’s where sub-urothelial injection has the advantage, Professor Hayne explained.
In addition, the injection can be done under local anaesthetic, using the same skills currently required to inject Botox for overactive bladder.
There are two further trials planned. One, expected to open this year, is to see how well the drug is distributed around the bladder and whether it escapes the bladder. Once funding is secured, another will look at whether this treatment could help patients whose cancer recurred despite BCG treatment.
“There is a whole class of drugs that can be used that are effective against urothelial cancer, which may have a role,” said Professor Hayne.
“It really comes down to whether the pharmaceutical industry is going to grasp the nettle at this point.”
