Combining Radiation and Immunotherapy in Patients With Bladder Cancer

“I think this is an exciting time in the treatment of bladder cancer and really oncology in general, because we’re learning to harness the body’s immune system against malignancies,” said Abhishek Solanki, assistant professor, radiation oncology, MD, MS, Loyola University of Chicago, during a session at the 2018 Genitourinary Cancers Symposium.

While discussing the role of immunotherapy in patients undergoing radiation therapy for bladder cancer, Solanki emphasized that it’s also an exciting time because there’s a lot of preclinical data that has led to us evaluating this approach.

Radiation is a local therapy, delivered for local purposes, like treating a primary tumor and in a bladder preservation case, said Solanki. It’s also known that immune invasion is a critical hallmark of cancer, and the main mechanisms by which tumors grow, progress, and metastasize.

According to Solanki, there’s emerging evidence that suggests that part of the effective radiation is immune driven. Cytotoxicity related to radiation releases tumor antigens, which leads to activation of Antigen Presenting Cells and migration to the lymph nodes, and in turn priming of T-cells. There’s also a release of cytokines that lead to T-cell trafficking back to the tumor and an increased expression of MHC1 within tumor cells. All of these things together lead to cell-mediated death, said Solanki.

However, radiation itself rarely leads to long-term immune memory, and the ability to prevent late recurrences. Additionally, there’s emerging data that suggests that radiation itself can lead to upregulation of PD-1/PD-L1 as well as regulatory T-cell infiltration into the tumor cell, suggesting that there may be some immunosuppressant effect of radiation.

“This brings us to the hypothesis that we can combine radiation immunotherapy to improve local control through radiosensitization by bypassing those resistance mechanisms,” said Solanki. “Potentially by combining these modalities, we can improve systemic response and potentially we can have long-lasting immune memory when we combine these agents”.

Solanki cited what he said is one of the only studies of bladder cancer specifically looking at the question of the combination of radiation immunotherapy. Investigators implanted mice with bladder cancer tumors and separated them into 2 groups: one treated with radiation alone and the other treated with radiation and anti—PD-L1 antibody. With radiation, there was a decrease in the size of the tumor, but it started growing again relatively shortly after. In the combination group, there was more durable and more significant tumor control.

"This leaves us with 2 clinical questions," said Solanki. "The first is with our traditional paradigms of bladder preservation and definitive chemoradiation therapy. Can we use immunotherapy to improve the outcomes? On the flipside, for patients who have metastatic disease who are being treated with checkpoint inhibitors and for palliation, can we use local radiation to augment that effect and give them more mileage with the available therapies?"

While there is not a lot of data available for bladder cancer, Soalnki said that we can turn to some non—small cell lung cancer (NSCLC) studies that can provide leads on benefits observed.

In the PACIFIC trial, stage 3 NSCLC patients receiving definitive chemoradiation with cisplatinum-based chemotherapy were randomized to be administered either placebo or up to 12 months of durvalumab. Investigators found that there was a clear difference in progression-free survival (PFS) that favored the durvalumab group. In the metastatic setting, in the KEYNOTE-001 study, UCLA investigators assessed their NSCLC cohort and found that radiation prior to pembrolizumab was associated with PFS and overall survival.

“Bringing things back to bladder cancer, one of the reasons why it's hypothesized that immunotherapy’s so successful in NSCLC is because of the high somatic tumor mutation burden, and bladder cancer is right up there,” said Solanki. “And, we already have a track record of success with immunotherapy in bladder cancer with BCG for non-muscle invasive disease and checkpoint inhibitors for metastatic disease, so I’d argue that bladder cancer is the ideal setting to investigate the combination of radiation immunotherapy.”

Solanki explained that while there is a lot of clinical and preclinical rationale to combining immunotherapy and radiation for bladder cancer, there’s a lot we don’t know, and the unknown at this time is bigger than the known. He concluded: “I think it’s up to us as a community to find out exactly how best to combine radiation with immunotherapy to augment the effects of both modalities.”