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 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.