Immune features are associated with response to neoadjuvant chemo-immunotherapy for muscle-invasive bladder cancer

Nat Commun. 2024 May 24;15(1):4448. doi: 10.1038/s41467-024-48480-1.

Abstract

Neoadjuvant cisplatin-based chemotherapy is standard of care for muscle-invasive bladder cancer (MIBC). Immune checkpoint inhibition (ICI) alone, and ICI in combination with chemotherapy, have demonstrated promising pathologic response (<pT2) in the neoadjuvant setting. In LCCC1520 (NCT02690558), a phase 2 single-arm trial of neoadjuvant chemo-immunotherapy (gemcitabine and cisplatin plus pembrolizumab; NAC-ICI) for MIBC, 22/39 patients responded (pathologic downstaging as primary outcome), as previously described. Here, we report post-hoc correlative analyses. Treatment was associated with changes in tumor mutational profile, immune gene signatures, and RNA subtype switching. Clinical response was associated with an increase in plasma IL-9 from pre-treatment to initiation of cycle 2 of therapy. Tumors harbored diverse predicted antigen landscapes that change across treatment and are associated with APOBEC, tobacco, and other etiologies. Higher pre-treatment tumor PD-L1 and TIGIT RNA expression were associated with complete response. IL-8 signature and Stroma-rich subtype were associated with improved response to NAC-ICI versus neoadjuvant ICI (ABACUS trial, NCT02662309). Plasma IL-9 represents a potential predictive biomarker of NAC-ICI response, while tumor IL-8 signature and stroma-rich subtype represent potential predictive biomarkers of response benefit of NAC-ICI over neoadjuvant ICI. Future efforts must include additional independent biomarker discovery and validation, ultimately to improve the selection of patients for ICI-related treatments.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Aged
  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • B7-H1 Antigen / metabolism
  • Biomarkers, Tumor / blood
  • Cisplatin / administration & dosage
  • Cisplatin / therapeutic use
  • Deoxycytidine* / administration & dosage
  • Deoxycytidine* / analogs & derivatives
  • Deoxycytidine* / therapeutic use
  • Female
  • Gemcitabine*
  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use
  • Immunotherapy* / methods
  • Interleukin-9 / metabolism
  • Male
  • Middle Aged
  • Neoadjuvant Therapy* / methods
  • Neoplasm Invasiveness
  • Treatment Outcome
  • Urinary Bladder Neoplasms* / drug therapy
  • Urinary Bladder Neoplasms* / immunology
  • Urinary Bladder Neoplasms* / pathology
  • Urinary Bladder Neoplasms* / therapy

Substances

  • Deoxycytidine
  • Gemcitabine
  • pembrolizumab
  • Cisplatin
  • Antibodies, Monoclonal, Humanized
  • Immune Checkpoint Inhibitors
  • Interleukin-9
  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human