Background: The interaction between the host's immune system and the tumor appears to be dynamic with reports suggesting this interplay is homeostatically oscillating "on & off" in a repeating or cyclical fashion. We hypothesized that it would be possible to determine the periodicity of anti-tumor immune response in order to synchronize radiotherapy with its most excitable phase, and to overcome tumor tolerance locally and systemically. Our concept for maximization of the bystander/abscopal effects considered the accurate timing (immune-synchronization) of single (or limited) pulsed SBRT-PArtial Tumor irradiation directed at the HYpoxic tumor segment (SBRT-PATHY) while preserving adjacent tumor micro-environmental immune signalling.
Methods/ Trial Design: We serially monitored patients two weeks prior to the initiation of time-targeted SBRT using biomarkers Hs-CRP, LMR and LDH to detect the anti-tumor immune response oscillation and its periodicity, defining the “most favourable” and “least favourable” treatment time-positions in the immune cycle. Four patients were treated with SBRT-PATHY 10Gy x 3 to the 70%-isodose line on the “most favourable” while another four on the “least favourable” day.
Results: The median follow-up was 12 months (range: 4–22). Optimally synchronized SBRT-PATHY with the favourable immune cycle phase was associated with improved clinical outcomes (three complete responses plus significant abscopal effects in 3 patients). Four patients in total experienced fatigue grade 1. No patient reported any late toxicity.
Conclusion: Time-targeted/immune-synchronized delivery of SBRT-PATHY could provide a potent immune-modulating signal to reverse immune suppression and break tumor tolerance in a consistent manner. In addition, this effect appears possible with limited therapy and in the absence of other systemic agents and allows for the possibility of re-treatment. Larger prospective trial on time-synchronized immune-guided SBRT-PATHY is ongoing at our institute.