William Parker, MD

	Tumor immunology is rapidly becoming one of the hottest fields in medicine. Specifically, immune checkpoint inhibitors have emerged as a treatment route for numerous malignancies, genitourinary and otherwise.

	In his talk at the 2015 Society of Urologic Oncology annual meeting in Washington, Peter C. Black, MD, of the University of British Columbia, Vancouver reviewed the current state of immunotherapy-specifically, the role of immune checkpoint inhibition-in nonmuscle-invasive bladder cancer (NMIBC).

	“The rationale that we have currently is, first of all, we use immunotherapy already in this disease setting in the form of intravesical BCG [bacillus Calmette–Guérin (TheraCys, TICE BCG)]. Truly, we as urologists have been employing intravesical immunotherapy for decades; however, only recently have we begun to uncover the immune milieu of NMIBC while simultaneously broadening our understanding immune checkpoint molecules-CTLA-4, PD1, and PDL1,” Dr. Black said.

Study weighs impact of BCG shortage on outcomes

	Previous work at Mayo Clinic demonstrated the relationship between BCG treatment and immune checkpoint molecules in NMIBC. “We know that PD-L1 is expressed in nonmuscle-invasive bladder cancer previously treated with BCG,” Dr. Black said, but he added: “We cannot predict, with what we know now, how exactly the checkpoint molecules are related [to our understanding of immunology in NMIBC].”

Next: Current plans for phase I, II clinical trials

	After thoroughly reviewing the current state of our knowledge of the immune checkpoint molecules in NMIBC, Dr. Black outlined current plans for phase I and II clinical trials. Specifically, he discussed five proposed trials (three phase I and two phase II trials) in NMIBC using these molecules. The first is a phase I trial run by Shaheen Alanee, MD, at Southern Illinois University, Springfield, looking at the combination of pembrolizumab (anti-PD1 antibody) with BCG in high-risk NMIBC. The second proposed phase I trial is sponsored by Genentech and will evaluate atezolizumab (anti-PD-L1) in a similar population. (Also see, “

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	The third phase I trial he discussed is an interesting approach to trial design, looking at multiple combinations of therapy with BCG and various checkpoint inhibitors compared to a single control arm of BCG in NMIBC. He then went on to discuss two phase II trials: a SWOG-sponsored trial looking at intravesical anti-PD-L1 therapy in BCG-unresponsive NMIBC, and KEYNOTE-057, a trial assessing the role of pembrolizumab given every 3 weeks for up to 2 years in the same population.

	Where are we going with all of this? Dr. Black concluded by underscoring the importance of patient selection, the key to success with these treatments. As we gain understanding of the role of immune checkpoint blockade in human cancers, we are also gaining understanding about the role of tumor antigen and immunogenicity.

	Specifically, in order for these checkpoint inhibitors to function, the immune system must recognize the tumor. There has been exciting work in other cancers showing that the degree of mutational burden is directly proportional to the antigen load that a tumor represents. Harnessing our ability to categorize patients based on this immunogenicity may help us understand who can be treated with checkpoint blockade alone and who may require immune stimulation, either through BCG, radiation, or some other local ablative therapy.

	Certainly, this is an exciting time in the management of NMIBC. Hopefully, as data from these trials mature, we will begin to understand better the role of immune checkpoint blockade in this malignancy.

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Peter C. Black, MD, discusses the current state of immune checkpoint inhibition for bladder cancer in this article from Urology Times SUO internship program member William Parker, MD.

Trials explore immune checkpoint blockade in NMIBC

	Bacillus Calmette-Guérin (BCG [TheraCys, TICE BCG]) is the standard of care for high-grade nonmuscle-invasive bladder cancer, but due to various factors, the supply of BCG was greatly affected 4 years ago. At the 2015 Society for Urologic Oncology annual meeting in Washington, researchers from Columbia University Medical Center (CUMC), New York sought to evaluate the effect of the BCG shortage on patient treatment and outcomes.

	"Though the worldwide shortages of BCG began in the summers of 2012 and 2014, our outpatient urologic clinic at CUMC did not significantly feel the impact until October 2014. We wanted to systematically assess how the shortage was impacting our patients and establish protocol to prioritize BCG for those who needed it the most,” said lead author Jamie Pak, BA.

	Pak and senior author James McKiernan, MD, reviewed the records of patients who were eligible for BCG therapy-either induction or continued maintenance therapy-during the time period of the BCG shortage at their institution. They identified 105 patients who met criteria for BCG therapy, of whom 91 (87%) experienced a divergence from the standard of care and planned treatment course. Specifically, 28 patients never received indicated BCG, 40 experienced delayed or missed doses, 14 had incomplete therapy, and nine received an alternative regimen. Only 14 patients-13%-actually received planned BCG therapy without treatment alteration.

	When evaluating the effect of these altered treatment plans, 37.5% of the affected patients had recurrent disease at their first cystoscopic surveillance. Unsurprisingly, clinical stage and grade were predictive of recurrence for this patient population. However, and most importantly, also predictive of recurrence were indications for induction therapy and receipt of alternative regimens.

	“Recurrence rate was the highest in those patients who required induction BCG therapy and in those who were given alternative regimens of intravesical therapy,” Pak said.

	“While we hope that there are no future shortages, our data suggests that should this situation occur again, we should focus our efforts on preserving available BCG stocks for patients who need induction therapy, perhaps at the expense of longer-term maintenance therapy,” he added.

	“We hope this serves as a wake-up call not only to patients and providers but also to the pharmaceutical industry and the FDA, who may need to consider a change in policies and incentives to ensure patients are not negatively impacted by drug shortages in the future. Though we understand the unfortunate events that led to this shortage, we suspect that the complexity and cost of manufacturing BCG, along with its off-patent status, may have also contributed to the slow revamping of supply."

	So, will a similar supply shortage occur again? Certainly we hope it does not, but if it does, we now have evidence that alternative therapy does not mean equivalent therapy, particularly for our patients who require induction therapy.

Urology Times SUO internship program member William Parker, MD, discusses a retrospective review of more than 100 patients at Columbia University Medical Center in New York.