Professor Dickon Hayne

Direct injection of immune checkpoint inhibitor therapy into the bladder wall may be a feasible alternative approach to radical cystectomy for treating bladder cancer, according to a first-in-human trial led by the University of WA.

A small study involving 11 patients with non-malignant bladder cancer found that sub-urothelial injection of anti-PD-L1 monoclonal antibody durvalumab was feasible and safe and the treatment produced local immunological responses.

The novel approach also showed that direct injection of immunotherapy did not results in immune related adverse events, according to a team of clinicians led by Professor Dickon Hayne, from UWA Medical School and head of urology for the South Metropolitan Health Service in Perth.

In a paper published in the BJU International, (link here) Professor Hayne said there was a high unmet need for new treatment options for non-muscle-invasive bladder cancer (NMIBC) because there are currently few effective therapy options beyond intravesical BCG and management has hardly changed in three decades.

He noted that patients experience high rates of disease recurrence and progression to muscle-invasive bladder cancer (MIBC), and for high grade tumours radical cystectomy is the preferred treatment but has a high morbidity and may overtreat many patients.

Use of systemic immune checkpoint inhibitors (ICIs) has had limited success in treating NMIBC, and the team at UWA postulated that sub-urothelial administration of ICIs would increase effectiveness by achieving maximal urothelial penetrance and ‘vastly increased’ local tissue concentrations.

Direct injections of ICI into the bladder wall should also be safer than systemic delivery with less immune-related AEs (IRAEs) and it may be effective in BCG-unresponsive bladder cancer, they suggested.

In the 11 patients who underwent the sub-urothelial durvalumab injection there were no significant adverse events or toxicities reported based on AUA Symptom Scores, O’Leary Interstitial Cystitis Scale or biochemical or haematological measures.

Of the 14 adverse events reported all but one were mild and none considered immune-related. All the patients subsequently underwent radical cystectomy.

Analysis of tissue immune populations showed changes suggestive of local immune responses following durvalumab injection, with a significant increase in M2-macrophages (CD163) particularly in basal/mixed cancers compared to luminal cancers.

There were no significant alterations in circulating monocytes, neutrophils, or lymphocytes after durvalumab injection.

The study investigators said that the favourable overall toxicity profile observed in the patient group supported the hypothesis that sub-urothelial durvalumab was safe in bladder cancer.

“The absence of IRAEs likely arises from confinement of drug exposure to the bladder, an organ generally regarded to harbour a favourable immunological milieu,” they wrote.

“The confinement of disease to the bladder, which obviates the need for systemic exposure in NMIBC introduces the hope that lasting therapeutic benefit might also be achieved without the serious IRAEs associated with systemic ICIs,” they added.

“This new method of treatment may have a role for high-risk non-muscle-invasive bladder cancer patients as a strategy to avoid the need for cystectomy.”

The trial was developed through the Australian and New Zealand Urogenital and Prostate Cancer Trials Group (ANZUP) and funded by an ANZUP Below the Belt grant and the Spinnaker Foundation.