Phase 2 trial of perioperative chemo-immunotherapy for gastro-esophageal adenocarcinoma: The role of M2 macrophage landscape in predicting response
We present the clinical results of a phase 2 trial combining neoadjuvant docetaxel, cisplatin, 5 Flourouracil, and the PD-L1 inhibitor avelumab in locally advanced gastro-esophageal adenocarcinoma (GEA). Fifty-one patients receive neoadjuvant therapy with 50 proceeding to surgery. Grade 3-4 adverse events occur in 40%; complete/major pathological response is found in 7/50 (14%) and 9/50 (18%), with 2-year disease-free survival of 67.5%. There is no correlation between tumor regression and PD-L1 or mismatch repair (MMR) status. Multiplex immunohistochemistry and longitudinal single-cell transcriptomic profiling reveal alterations in certain innate immune cell populations, particularly noting an M2-tumor-associated macrophage (M2-TAM) proliferation in non-responding tumors. These findings describe the effective nature of this treatment regimen for GEA and reveal associated features of the inflammatory milieux associated with response to chemo-immunotherapy. The specific character of the inflammatory environment in non-responders may, in the future, help personalize treatment. This study was registered at ClinicalTrials.gov (NCT03288350).
Authors
- Alan Spatz (ORCID: https://orcid.org/0000-0003-3020-1420)
- Mina Farag (ORCID: https://orcid.org/0000-0002-1579-1680)
- Sui Huang (ORCID: https://orcid.org/0000-0002-3545-4665)
- Veena Sangwan (ORCID: https://orcid.org/0000-0002-8229-4158)
- Nicholas Bertos (ORCID: https://orcid.org/0000-0001-5466-6076)
- Lorenzo Ferri (ORCID: https://orcid.org/0000-0003-3275-2584)
- Pierre Fiset (ORCID: https://orcid.org/0000-0002-4117-490X)
- Jonathan Cools‐Lartigue (ORCID: https://orcid.org/0000-0002-3607-6889)
- Touhid Opu
- Swneke D. Bailey (ORCID: https://orcid.org/0000-0003-3778-8391)
- Victoria Marcus (ORCID: https://orcid.org/0009-0005-0873-8506)
- Arielle Elkrief (ORCID: https://orcid.org/0000-0003-1981-1535)
- Ramy Saleh (ORCID: https://orcid.org/0000-0001-8265-9316)
- Gertruda Evaristo (ORCID: https://orcid.org/0000-0002-6750-9026)
- Michael Strasser (ORCID: https://orcid.org/0000-0001-8512-6814)
- Mehrnoush Dehghani
- James Tankel (ORCID: https://orcid.org/0000-0002-2044-2821)
- Giovanni Artho
- Thierry Alcindor (ORCID: https://orcid.org/0000-0002-6004-0405)
- Carmen Mueller (ORCID: https://orcid.org/0000-0001-6678-9129)
- Sanjima Pal (ORCID: https://orcid.org/0000-0002-1992-273X)
- Sophie Camilleri‐Broët (ORCID: https://orcid.org/0000-0002-3453-636X)
- Morag Park (ORCID: https://orcid.org/0000-0001-5400-606X)
- Marc Hickeson (ORCID: https://orcid.org/0000-0001-6116-2888)
- Dongmei Zuo (ORCID: https://orcid.org/0000-0002-5061-3310)
Institutions
- McGill University Health Centre (CA)
- Institute for Systems Biology (US)
Publication Details
- Journal
- Cell Reports Medicine
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1016/j.xcrm.2025.102045
- Citations
- 6
- Primary Topic
- Esophageal Cancer Research and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 12.04
Funders
- U.S. Department of Defense
- Fondation de l'Hôpital Général de Montréal
- EMD Serono