AUA 2019: Budding Biotechnologies of Bladder Cancer

Chicago, IL ( At the SBUR session at AUA 2019, Dr. Brant Inman from Duke University discussed new and budding biotechnologies on the horizon for bladder cancer. Dr. Inman starts by highlighting that there is no shortage of lay media press discussing the most recent BCG shortage for patients with high risk non-muscle invasive bladder cancer. From a global health perspective, the BCG shortage also affects tuberculosis treatment, specifically putting baby’s lives at risk in Africa. Dr. Inman dispels the myth that we do not know how BCG works – in fact we do, via a complex immunotherapy pathway:

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Dr. Inman also notes that it is not true that several BCG strains share similar efficacy. Furthermore, Dr. Inman excellently described the definition of BCG unresponsiveness. What it is not is BCG intolerance which is described as too many side effects or a small bladder that cannot hold treatment. BCG unresponsiveness requires that adequate BCG be given (5 + 2 rule), which means that at least 5 of 6 induction doses and at least 2 of 3 maintenance disease are given. It is the time of the tumor after BCG that matters:

  • Refractory: High-grade recurrence <6 months after starting BCG, or stage or grade progression < 3 months after starting BCG
  • Relapsing: Recurrence > 6 months after starting BCG
  • Unresponsive: refractory + relapsing within 6 months of last BCG exposure
Over the last several years we have seen several new immunotherapeutic agents for NMIBC:

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Imiquimod (TMX-101, Vesimune) is a TLR7 agonist used topically for skin cancer warts. It is instilled intravesically with 200 mg in 50 mL and is well tolerated with AEs <= grade 2; it has been tested in the phase 2 setting in CIS patients. ALT-803 (IL-15 superagonist) activates CD8 T cells and NK cells and is currently under investigation in phase 2 QUIILT-3.032 trial. Coxsackie A21 (CAVATAK) vaccine is an oncolytic virus targeting ICAM-1 and is being used in combination with intravesical mitomycin. Oportuzumab monatox (VB4-845, Vicinium) is an antibody-drug conjugate that targets the anti-EpCAM single-chain variable fragment (scFv). In BCG-unresponsive CIS it has a 44% complete response rate and 16% durable complete response. MAGE-A3 vaccine is a cancer-testis antigen that is expressed in male germ cells (normal) and its function is unclear. Vaccination (IM) is every 3 weeks for 5 rounds of therapy and is currently being combined with BCG. PANVAC (CV-301) vaccine is a viral vaccine that has two parts including antigens (CEA, MUC-1) and costimulatory factors (B7.1, ICAM-1, LFA-3); it is being tested in combination with BCG in a phase 2 study.

There are several aspects of heating intravesical therapies that are important:
  • Improves drug delivery to the bladder
  • Makes urothelial cancer more sensitive to the drug
  • May stimulate an immune response
  • Can damage tumors directly (if hot enough)
  • May allow for heat-targeting of systemic drugs
A recently published trial using this methodology is the HYMN trial. This trial was designed to compare DFS time between radiofrequency-induced thermo-chemotherapy effect (RITE) and institutional standard second-line therapy (control) in NMIBC patients with recurrence following BCG.1 Patients were randomly assigned (1:1) to RITE (60min, 40mg mitomycin-C, 42±2°C) or control following stratification for CIS status (present/absent), therapy history (failure of previous induction/maintenance BCG), and treatment center. There were 104 patients randomized (48 RITE: 56 control). The median follow-up for the 31 patients without a DFS event was 36 months, and there was no significant difference in DFS between treatment arms (HR 1.33, 95%CI 0.84-2.10, p=0.23) or in 3-month CR rate in CIS patients (n=71; RITE: 30% vs control: 47%, p=0.15). Similarly, there was no significant difference in DFS between treatment arms in non-CIS patients (n=33; RITE: 53% vs control: 24% at 24 months, HR 0.50, 95%CI 0.22-1.17, p=0.11). DFS was significantly lower in RITE than in control in CIS with/without papillary patients (n=71; HR 2.06, 95% CI 1.17-3.62, p=0.01). One of the conclusions by the authors was that HYMN highlights the importance of the control arm when evaluating novel therapies.

New technologies also include (i) nanoparticles in bladder cancer lead to an alternating magnetic field and subsequent generation of magnetic hyperthermia; (ii) the Taris pretzel (GemRIS), which is an osmotic pump that elutes drug for 1-3 weeks; (iii) Gel polymers (Mitogel, VesiGel®), which are reverse phase polymers that include mitomycin C (0.4% for Mitogel; 0.18% for Vesigel) and dissolve over 4-6 hours.

Presented by: Brant Inman, MD, Surgical Oncologist, Associate Professor of Surgery, Duke University School of Medicine, Durham, North Carolina

Written by: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University - Medical College of Georgia, Twitter: @zklaassen_md