Combinatorial Delivery of Low-Dose Radiotherapy and Immunotherapy to Patients with Immune-Excluded Tumors Enhances CD8+ T-cell Functionality
Year: 2026
Type: article
Study design: Clinical Trial
Abstract: PURPOSE: Immune-checkpoint blockade (ICB) has demonstrated efficacy across tumor types. However, "cold" tumors characterized by low intraepithelial T-cell infiltration exhibit poor responsiveness. We investigated whether low-dose radiotherapy (LDRT) could enhance ICB efficacy in patients with multimetastatic immune-excluded solid tumors. PATIENTS AND METHODS: We conducted a multicohort phase I clinical trial (RACIN) involving 25 patients treated with escalating doses of LDRT in combination with a backbone regimen of nivolumab, ipilimumab, aspirin, or celecoxib and low-dose cyclophosphamide. The primary endpoints were safety and tolerability; secondary endpoints included disease control rate (DCR), progression-free survival, and overall survival. Exploratory endpoint analyses used paired pre- and post-LDRT tumor biopsies for single-cell profiling of the tumor microenvironment (TME). RESULTS: The combination therapy showed a manageable safety profile, with grade ≥3 adverse events in 12% to 21% of patients. The overall DCR was 42%, with one patient with ovarian cancer maintaining a complete response at 3 years. In responders, enhanced CD8+ tumor-infiltrating lymphocyte (TIL) functionality was associated with increased DNA damage response signatures and the presence of PD-1+CD8+ TILs at baseline. In contrast, nonresponders exhibited heightened immune regulatory innate lymphocytes such as CD8 Mucosal-Associated Invariant T (MAIT) and regulatory natural killer (NK) cells at baseline, accompanied by a lack of immunostimulatory myeloid cells in the TME and increased TIL radiosensitivity after LDRT. CONCLUSIONS: These findings suggest that LDRT combined with ICB is safe and may contribute to immunomodulatory activity in immune-excluded tumors. CD8+ TIL dynamics, DNA repair responsiveness, and TME composition may predict response and merit further validation in controlled larger studies.
Source: Clinical Cancer Research
Authors: Maria Ochoa-de-Olza, Nicolas Rayroux, Martina Imbimbo, Angela Orcurto, Noémie Fahr, Fabrizio Benedetti, Julien Dagher, Giulia Spagnol, David Barras, Eleonora Ghisoni, Blanca Navarro, Arthur Mulvey, Dominik Berthold, Apostolos Sarivalasis, Khalil Zaman, Athina Stravodimou, Antonia Digklia, Rafael Duran, Clarisse Dromain, John O. Prior, Niklaus Schaefer, Stefan Zimmermann, Michel Obeid, Nikos Chalkidis, Tsourti Zoi, Bettina Bisig, Lionel Trueb, Doga C. Gulhan, Christine Sempoux, Urania Dafni, Stephanie Tissot, George Coukos, Fernanda G. Herrera, Denarda Dangaj Laniti
Institutions: Centre Hospitalier Universitaire Vaudois, Ludwig Cancer Research, University of Lausanne, University of Padua, Azienda Ospedale - Università Padova, Harvard University, Massachusetts General Hospital, Massachusetts Institute of Technology, National and Kapodistrian University of Athens
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Awards: G4775471903, G661661167
OpenAlex ID: W7154699235