First Measurement: Proactive Immune Cell Sparing in Radiation Therapy

Radiation Therapy (RT) can modulate the immune system and generate anti-tumor T cells. However, this anti-tumor-activity is countered by radiation-induced immunosuppression (RIIS). Clinical advantages of proactively sparing RT dose to immune rich organs have not previously been evaluated.

We conducted a phase II randomized trial from 2020 to 2023, enrolling 51 early-stage lung cancer patients treated with SBRT, to evaluate the effect of dose reduction to immune rich organs on RIIS. Two groups were: RIIS-optimized-treatment (lowering the dose to blood, bone-marrow and lymph-node-stations) and standard-treatment. All treatments followed national protocol guidelines. Peripheral blood was collected at baseline, immediately, 4-weeks and 6-months post-treatment.

ALC changes from baseline immediately, 4-weeks and 6-months post-SBRT are: optimized-arm: -16%, -22%, -16%, standard-arm: -31%, -34%, -26%, leading to an overall-all-time-point improvement in ALC reduction in the optimized-arm compared to the standard-arm of 13.4 (5.3) % (95% CI, 2.8 to 24.0; p = 0.01). Central tumors had the largest improvement in ALC from baseline: optimized-arm: - 8%, -18%, -14%, standard-arm: -39%, -43%, -47%, leading to an overall-all-time-point improvement in ALC reduction in the optimized-arm compared to the standard-arm of 29.5 (9.6) % (95% CI, 10.1 to 48.9; p = 0.004). Grade 3 lymphopenia occurred in 15.4% of standard arm patients but was absent in the optimized arm. Additionally, 2.8 times more patients in the optimized arm experienced an ALC increase post-SBRT. Dose to organs such as the heart, great vessels, thoracic spine, and lymph nodes significantly correlated with RIIS. A trend towards increased Event-Free-Survival (two-year: 75.0% (SE = 10.8%) versus 59.8% (SE = 11.2%), p =0·10) and Overall Survival (two-year: 93.4% (SE=6.1%) versus 69.4% (SE=10.5%), p =0·14) was observed with optimized-planning compared to standard-planning in treatment naïve patients.

Reducing RT dose to immune rich organs significantly reduces RIIS compared to standard-of-care. This has implications in enhancing immune system mediated anti-tumor-activity. (Funded by National Cancer Institute and others. ClinicalTrials.gov number, NCT04273893 ).