Trials explore immune checkpoint blockade in NMIBC

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.

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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.

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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, “The promise of PD-1 ligand pathway in treating bladder cancer.”)

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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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