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

• Published in: Nature communications Vol. 15; no. 1; pp. 4448 - 14
• Main Authors: Beckabir, Wolfgang, Zhou, Mi, Lee, Jin Seok, Vensko, Steven P., Woodcock, Mark G., Wang, Hsing-Hui, Wobker, Sara E., Atassi, Gatphan, Wilkinson, Alec D., Fowler, Kenneth, Flick, Leah M., Damrauer, Jeffrey S., Harrison, Michael R., McKinnon, Karen P., Rose, Tracy L., Milowsky, Matthew I., Serody, Jonathan S., Kim, William Y., Vincent, Benjamin G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.05.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/21; 13/31; 14; 38; 45; 45/23; 45/91; 631/250/251; 631/67/580; 631/67/589/1336; 692/53/2423; Aged; Antibodies, Monoclonal, Humanized - therapeutic use; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; B7-H1 Antigen - metabolism; Biomarkers; Biomarkers, Tumor - blood; Bladder; Bladder cancer; Cancer; Cancer therapies; Chemotherapy; Cisplatin; Cisplatin - administration & dosage; Cisplatin - therapeutic use; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Female; Gemcitabine; Gene expression; Humanities and Social Sciences; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - therapeutic use; Immunotherapy; Immunotherapy - methods; Interleukin 8; Interleukin 9; Interleukin-9 - metabolism; Invasiveness; Male; Methyl isobutyl carbinol; Middle Aged; Monoclonal antibodies; multidisciplinary; Muscles; Neoadjuvant Therapy - methods; Neoplasm Invasiveness; Patients; PD-L1 protein; Pembrolizumab; Pretreatment; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Stroma; Tobacco; Treatment Outcome; Tumors; Urinary Bladder Neoplasms - drug therapy; Urinary Bladder Neoplasms - immunology; Urinary Bladder Neoplasms - pathology; Urinary Bladder Neoplasms - therapy
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48480-1

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. In the phase 2 study LCCC1520 (NCT02690558), clinical activity of pembrolizumab in combination with gemcitabine and cisplatin as neoadjuvant therapy in patients with muscle-invasive bladder cancer has been reported. Here the authors present molecular and immune cellular features associated with response to neoadjuvant chemo-immunotherapy.