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Updated: Dec 12, 2025

Induction of Invasive Transitional Cell Bladder Carcinoma in Immune Intact Human MUC1 Transgenic Mice: A Model for Immunotherapy Development
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Immunotherapy-based combination strategies for advanced urothelial cancer: A long quest

Ali Raza Khaki1,2, Neeraj Agarwal3, Sumanta K Pal4

  • 1Division of Oncology, Department of Medicine, University of Washington, Seattle, Washington.

Cancer
|August 7, 2020
PubMed
Abstract

Insights

Combining pembrolizumab with acalabrutinib did not improve outcomes for metastatic urothelial carcinoma patients. Further research is needed to enhance immunotherapy efficacy in this lethal cancer.

Area of Science:

  • Oncology
  • Immunotherapy
  • Urothelial Carcinoma Research

Background:

  • Metastatic urothelial carcinoma (mUC) has a poor prognosis despite advances in immune checkpoint inhibitors (ICIs).
  • Programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) inhibitors offer survival benefits but do not provide a cure for mUC.
  • There is a critical need to improve the efficacy of current immunotherapies for mUC.

Discussion:

  • A phase 2 trial investigated the combination of pembrolizumab (a PD-1 inhibitor) and acalabrutinib (an enzyme inhibitor targeting immunotherapy resistance).
  • The combination therapy was evaluated based on a strong scientific rationale suggesting potential synergy.
  • The study did not demonstrate a significant clinical benefit of the combination compared to pembrolizumab monotherapy.

Key Insights:

  • The combination of pembrolizumab and acalabrutinib did not show improved clinical benefit over pembrolizumab alone in metastatic urothelial carcinoma.
  • Acalabrutinib, despite its rationale for overcoming immunotherapy resistance, did not enhance the efficacy of PD-1 inhibition in this trial.
  • These findings highlight the complexity of overcoming resistance mechanisms in urothelial carcinoma immunotherapy.

Outlook:

  • Future clinical trials should explore novel rational combinations to improve ICI efficacy in mUC.
  • Biomarker-driven patient selection may be crucial for optimizing treatment benefit in future immunotherapy trials.
  • Personalized therapeutic strategies are essential in the ongoing effort to improve outcomes for patients with metastatic urothelial carcinoma.
Keywords:
bladder cancerclinical trialimmunotherapymyeloid-derived suppressor cellstranslational researchurothelial carcinoma

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