Combinatorial Delivery of Low-Dose Radiotherapy and Immunotherapy to Patients with Immune-Excluded Tumors Enhances CD8+ T-cell Functionality
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…
How strong is the evidence?
Evidence Hub reads this as a clinical trial, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 25 participants or records.
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