AUA 2018: Translational Research to Potentiate Immunotherapy in Urothelial Cancer

San Francisco, CA (UroToday.com) In this SBUR/SUO session, Chong-Xian Pan, MD, discussed an overview of immunotherapy for advanced urothelial cancers, focusing on strategies to improve therapy.  Multiple PD1/PD-L1 agents have been approved for use in the United States for metastatic urothelial cancers and have an approximate overall response rate of 20%.  The Keynote-045 trial stratified patients who had disease progression after platinum-based chemotherapy to dealer’s choice chemotherapy versus Pembrolizumab.  This study demonstrated an overall response to pembrolizumab of 21% compared to chemotherapy of 11%. 

Pan asked the hypothetical question, “What can we do to improve immunotherapy in urothelial cancers?” Pan told the audience we need to improve patient selection and develop more effective treatments.  Biomarkers need development to improve patient selection.  PD1/PDL1 immune score, gene expression profile, mutation load and response have not been reliable biomarkers to date to select potential responders for immunotherapy.

Potential strategies to potentiate immunotherapy include: 

  1. Tumor vaccine or neoantigen
  2. Radiation therapy
  3. Molecularly targeted therapy
  4. Conventional chemotherapy
  5. Photodynamic and photothermal therapies
  6. Cancer-specific nanoparticles
  7. Inhibitor of inhibitory pathways
  8. Activator of stimulatory pathways
Signaling pathway activation affect tumor immune escape via increased expression of PD-L1, CSK3B activation, increased lactate production, decreased CTL activation, and downregulation of MHC I and II.

Photodynamic therapy kills cancer cells and releases tumor antigen via the creation of reactive oxygen species which modify macromolecules and increase immunogenicity.  Photothermal therapy denatures macromolecules and makes them more immunogenic.  Photothermal therapy has been used in bladder cancer, but the photosensitizer has low efficiency, low potency, is nonspecific and high toxicity. 

Bladder cancer specific PLZ4 nanoporphyrin (PNP) has the potential of a synergistic benefit of targeted chemo and photodynamic therapy. Photothermal therapy with PCP raises the temperature to 55 degrees Celsius and is retained in tumors for up to two weeks allowing for flexible scheduling.  In mice models, PNP treatment converts non-immunogenic tumor to immunogenic, to help potentiate immunotherapy.

In summary, Pan stated that PD1/PDL1 inhibitors have been approved and have an overall response of approximately 20%.  To date, no biomarkers have been developed to assist with patient selection, prediction or response.  Genetic alterations in bladder cancers can potentially be targeted for cancer therapy and used to potentiate immunotherapy.  Cancer-specific chemotherapy/nanoparticles are less toxic and may be combined with immunotherapy.  Cancer-specific nanoporphyrin can also potentially enhance the efficacy of immunotherapy.


Presented by: Chong-Xian Pan, MD, PhD, MS University of California-Davis Cancer Center

Written by:  David B. Cahn, DO, MBS Fox Chase Cancer Center Philadelphia, PA @dbcahn at the 2018 AUA Annual Meeting - May 18 - 21, 2018 – San Francisco, CA USA
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