Immunotherapy Advances Offer New Hope in Bladder Cancer

Michael Poch, MD

With the recent FDA approval of atezolizumab (Tecentriq) coupled with the breakthrough therapy designation of nivolumab (Opdivo), the field of metastatic bladder cancer—an area that had long been stagnant—has quickly evolved with immunotherapy coming to the forefront.

The FDA granted atezolizumab an accelerated approval in May 2016 following encouraging phase II findings in the IMvigor 210 study. The indication is for patients with locally advanced or mUC whose disease progressed during or after platinum-based chemotherapy, or within 12 months of receiving platinum-containing chemotherapy, either before or after surgery.

Michael Poch, MD, urologist and assistant member at Moffitt Cancer Center, discussed immunotherapy in the landscape of bladder cancer during a lecture at the 2016 OncLive State of the Science Summit on Genitourinary Cancers.

OncLive: What are the key advancements we have made with immunotherapy in bladder cancer?

In an interview with OncLive during the meeting, Poch provided deeper insight into how immunotherapy has propelled the field of bladder cancer forward, as well as the research that still needs to be done.Poch: Over the past 15 years, we have had no new drugs that are FDA approved to treat bladder cancer. In the past 18 to 36 months, there has been almost an explosion of clinical trials looking at immune therapy for bladder cancer—both at the bladder level as well as in the metastatic or systemic disease space. That is very exciting.

Nivolumab was granted a priority review in this space, as well. What potential does this agent have?

We have had the first new FDA-approved medication for metastatic bladder cancer approved in May 2016. We are seeing strides and I think that we are seeing some meaningful changes in the space for treatment.What is exciting now for bladder cancer is this concept of checkpoint inhibition—on the tumor side as well as on the immune cell side. What we see are T cells, which provide some immunity against all kinds of cancers, being downregulated by the tumor cells with this interaction between some of the surface molecules called PD-1 and PD-L1. That interaction actually downregulates the T cell and, therefore, tumor cells can escape the immune response.

The idea of these checkpoint inhibitors is to block that downregulation of the immune cell, whether it’s nivolumab or pembrolizumab (Keytruda) on the PD-1 side, or whether it’s atezolizumab or durvalumab on the PD-L1 side. Those are some of new and exciting things that are going on.

You mentioned PD-L1 staining. In 5 to 10 years, do you think we will have a biomarker for selecting patients? Is that kind of the next step to further tailor therapy?

We have seen significant responses that we weren’t seeing, particularly in patients who have failed cisplatin-based chemotherapy. Some of that is based upon the inherent immunohistochemistry of the tumors themselves, meaning that we have been seeing some better responses in those patients who have PD-L1 staining on their tumors. However, that is kind of where this space is going, which is exciting.The next step to further tailor therapy is to use some of this information to help guide therapy. Five to 10 years seems like a very good window for that. Right now, if you look at the ability to stain some of the tissue, it’s much better for our patients who are undergoing radical cystectomy in terms of having enough tissue to stain.

What other ongoing research are you excited about?

There is also some element of tumor heterogeneity. Ideally, we would see some genetic breakdown of these things, as well. On a genetic and a mutational load level, we should be able to refine some of those answers.I am excited about what we are doing. At Moffitt Cancer Center, what we are doing right now is actually some work that Moffitt Cancer Center has already done for melanoma— looking at tumor-infiltrating lymphocytes (TILs). We are trying to harvest some TILs from bladder cancer specimens, grow them in a lab, and clonally expand them. Then, we test them against the tumor with the concept of reinfusing them—after lymphodepletion—back into patients with metastatic disease.

This approach sounds similar to chimeric antigen receptor T-cell therapy. Is it?

What other steps need to be taken in bladder cancer?

We are basically harvesting these TILs; then, they should be able to fight the patient’s own tumor downstream when they develop metastatic disease, or possibly in an adjuvant setting.In a way, yes we are. We are essentially identifying those cells that are most active against tumor cells, clonally expanding them, and reinfusing them.The other thing is that we are not where we necessarily need to be with intravesical therapy. There are some clinical trials that are accruing for intravesical therapy, both in the immune space as well as harvesting some of what we know already about bacillus Calmette-Guérin (BCG) therapy. There is certainly opportunity from that end to treat patients with BCG-refractory disease or even move some of these therapies into the pre-BCG setting.

Nivolumab was granted the designation in June 2016 as a potential treatment of patients with unresectable locally advanced or metastatic urothelial carcinoma (mUC) after the failure of a platinum-containing regimen, primarily based on findings from the phase II CA209-275 trial.