Abstract P014: Sparing blood and immune rich organs significantly reduces immune suppression during lung SBRT: Randomized, Phase 2 trial
Authors: Wijesooriya Krishni , Larner James , Read Paul , Nguyen Cam , Conaway Mark , Showalter Timothy 
Published: January 2025

Background: Radiation Therapy (RT) is known to modulate the immune system and contribute to the generation of anti-tumor T cells . However, this anti-tumor-activity is countered by radiation-induced immunosuppression (RIIS), which destroys highly radiosensitive existing and newly formed lymphocytes (80% T cells). Optimizing RT treatment planning by considering circulating blood and lymphatics as a critical organ at risk may mitigate RIIS and lead to the creation and preservation of cytotoxic T lymphocytes, potentially converting the tumor from immunologically cold to a hot environment thereby increasing the efficacy of immunotherapy. Methods: We conducted a phase 2 randomized trial from 2020 to 2023, enrolling 51 stage I lung cancer patients treated with SBRT alone, to evaluate whether reducing the dose to circulate blood, lymphatics, and bone marrow could lower RIIS. Patients with baseline absolute lymphocyte counts (ALC) below 0.5x10⁹ cells/L were excluded. Participants were randomized into two groups: an experimental arm with RIIS-optimized treatment (lowering the dose to blood and lymphatic-rich organs) and a standard SBRT arm. All treatment plans followed national protocol guidelines. Peripheral blood samples were collected at baseline, end of treatment, 4 weeks and 6 months post-treatment. Contrasts within repeated measures models were used to determine the statistical significance. Results: Post SBRT ALC changes from baseline immediately, 4 weeks and 24 weeks post SBRT are: optimized arm: -16%, -22%, -16%, standard arm: -31%, -34% and -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% confidence interval [CI], 2.8 to 24.0; p = 0.01. Central tumors had the largest improvements, with ALC changes from baseline in the optimized arm of only -8%, -18%, -14% , and -39%, -43%, -47% in the standard arm, 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% confidence interval [CI], 10.1 to 48.9; p = 0.004. In the standard arm, 15.4% of patients experienced post-SBRT grade- 3 lymphopenia, while none in the optimized arm were lymphopenic. Two and a half times as many patients in the optimized arm observed a post SBRT ALC increase compared to the standard arm. In a multivariate Cox regression analysis, a trend towards increased Event Free Survival (two-year: 75.0% (SE = 10.8%) versus 59.8% (SE = 11.2%), p=0·095) and Overall Survival (two-year: 93.4% (SE=6.1%) versus 69.4% (SE=10.5%), p=0·135) was observed with optimized planning compared to status quo in treatment naïve patients. Conclusion: Reducing RT dose to blood and immune rich organs provided a significant reduction in RIIS compared to standard of care. Observed increase in OS and EFS needs further confirmation from a phase 3 trial. This has implications in enhancing immune system mediated anti-tumor activity. (Funded by National Cancer Institute and others. ClinicalTrials.gov number, NCT04273893).

Citation Format: Krishni Wijesooriya, James Larner, Paul Read, Cam Nguyen, Mark Conaway, Timothy Showalter.Sparing blood and immune rich organs significantly reduces immune suppression during lung SBRT: Randomized, Phase 2 trial.[abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr P014