Combinatorial delivery of low-dose radiotherapy and immunotherapy to patients with immune-excluded tumors enhances CD8+ T cell functionality

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 multi-cohort 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 endpoint were safety and tolerability; secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Exploratory endpoints 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 12-21% of patients. The overall DCR was 42%, with one ovarian cancer patient maintaining a complete response at three years. In responders, enhanced CD8⁺ TIL functionality associated with increased DNA damage response signatures and the presence of PD1⁺CD8⁺ TILs at baseline. In contrast, non-responders exhibited heightened immune regulatory innate lymphocytes such as CD8 MAIT and regulatory NK cells at baseline, accompanied by a lack of immune-stimulatory myeloid cells in the TME and increased TIL radiosensitivity post LDRT. CONCLUSIONS: These findingssuggest 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.

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Publication Details

Journal
Clinical Cancer Research
Published
2026-04-17
DOI
https://doi.org/10.1158/1078-0432.ccr-25-2743
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
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article

Combinatorial delivery of low-dose radiotherapy and immunotherapy to patients with immune-excluded tumors enhances CD8+ T cell functionality

Giulia Spagnol, Fabrizio Benedetti, Athina Stravodimou, Stéphanie Tissot-Renaud et al.
Clinical Cancer Research
Cancer Immunotherapy and Biomarkers
article

Combinatorial delivery of low-dose radiotherapy and immunotherapy to patients with immune-excluded tumors enhances CD8+ T cell functionality

Giulia Spagnol, Fabrizio Benedetti, Athina Stravodimou, Stéphanie Tissot-Renaud, María Ochoa-de-Olza, John Olivier Prior, Michel Obéid, Noémie Fahr, Apostolos Sarivalasis, Martina Imbimbo, Rafael Durán, Arthur Mulvey, Khalil Zaman, Clarisse Dromain, Christine Sempoux, Fernanda Herrera, Bettina Bisig, Denarda Dangaj Laniti, Niklaus Schaefer, Julien Dagher, Antonia Digklia, Urania Dafni, David Barras, Lionel Trueb, Nicolas Rayroux, Dr Dominik Berthold, Nikos Chalkidis, G Coukos, Eleonora Ghisoni, Stefan Zimmermann, Doga C. Gulhan, Tsourti Zoi, Blanca Navarro
article en

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 multi-cohort 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 endpoint were safety and tolerability; secondary endpoints included disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Exploratory endpoints 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 12-21% of patients. The overall DCR was 42%, with one ovarian cancer patient maintaining a complete response at three years. In responders, enhanced CD8⁺ TIL functionality associated with increased DNA damage response signatures and the presence of PD1⁺CD8⁺ TILs at baseline. In contrast, non-responders exhibited heightened immune regulatory innate lymphocytes such as CD8 MAIT and regulatory NK cells at baseline, accompanied by a lack of immune-stimulatory myeloid cells in the TME and increased TIL radiosensitivity post LDRT. CONCLUSIONS: These findingssuggest 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.

Clinical Cancer Research
Harvard University (US), University of Padua (IT), National and Kapodistrian University of Athens (GR), Harvard University Press (US), Centre Hospitalier Universitaire Vaudois (CH), Space Hellas (Greece) (GR), Dana-Farber/Harvard Cancer Center (US), University of Lausanne (CH)
Openalex Percentile: Top 21%
Cancer Immunotherapy and Biomarkers
DOIOpen Access PDFOpenAlex
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