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

Abstract

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. 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). 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. 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.