CUOS 2019: Immune-Checkpoint Inhibition with Radiation in Bladder Cancer: In Situ and Abscopal Effects

Toronto, Ontario (UroToday.com) Urothelial cell carcinoma is radiosensitive cancer. Bladder-sparing approaches are rising in practice in the western world. However, response optimization in this specific therapy is still being studied. 20-30% of patients treated with trimodal therapy will require salvage cystectomy, and 40-50% of muscle-invasive bladder cancer patients will develop metastases.

Radiotherapy also induces bladder tumor cells to express PD-L1. A study demonstrated that 72 muscle-invasive bladder cancer patients treated with bladder preservation trimodal therapy (TURBT + radiotherapy + chemotherapy) demonstrated that enhanced PD-L1 expression was associated with lower complete response rates and higher rates of disease failure.1

In the presented study, the objective was to see if it is possible to augment an abscopal effect in urothelial cell carcinoma by combining radiation with an immune checkpoint inhibitor. For this study, murine bladder cell line (MB49) was injected with both flanks of immunocompetent C57BL/6 male mice:

  1. Right flank tumor was labeled “primary tumor.”
  2. Left flank tumor was labeled “distant tumor.”
Randomization was performed into four arms with eight mice per group with the following groups:

1.Sham group
2.anti-PD-L1 only group
3.sham and radiotherapy group
4.Anti-PD-L1 and radiotherapy group

The results demonstrated the lowest tumor growth kinetics in the group that received both anti-PD-L1 and radiotherapy treatments (figure 1). Kaplan Meier survival curve demonstrated that this group also had improved survival rates compared to all other groups (Figure 2).

Figure 1 – Tumor Growth Kinetic Among the Four Study Groups:
 UroToday CUOS19 Tumor Growth Kinetic

Figure 2 – Kaplan – Meier Survival Curve of the Four Groups:
UroToday CUOS19 Figure 2 Kaplan Meier Survival Curve of the Four Groups

In a follow-up experiment, the authors will evaluate whether combining therapy augments immune memory. In this follow-up study, tumors will be implanted in the flank of mice, and then the mice will be randomized again to four arms. Later the tumors will be excised, and one month later, the same mice would be re-challenged with the same cancer cells orthotopically.

Based on the preliminary results of the first trial described, the authors plan an investigator-initiated trial of trimodal therapy with concurrent and adjuvant atezolizumab in patients with muscle-invasive bladder cancer. This will be a single arm multicenter study consisting of 25 patients, taking place in McGill University, University of Toronto, and McMasters University. The primary objective will be the safety and toxicity of combined therapy, and to determine the locoregional control rate.

Another planned trial is the randomized phase two trial assessing trimodal therapy with or without adjuvant Durvalumab to treat patients with muscle-invasive bladder cancer.


Presented by: Wassim Kassouf, MD, Scientist, RI-MUHC, Glen site, Cancer Research Program, Program Director, McGill Urology ResidencyMcGill University
 
Written by: Hanan Goldberg, MD, Urologic Oncology Fellow (SUO), University of Toronto, Princess Margaret Cancer Centre, Twitter: @GoldbergHanan at the CUOS – Canadian Uro-Oncology Summit 2019, #CUOS19 January 10-12, 2019 Westin Harbour Castle, Toronto, Ontario, Canada

References:
1. Wu et al. Science Rep 2016
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