129 - Time-Synchronized Immune-Guided Partial Tumor Irradiation: Proof-of-Principle Trial (NCT04168320)

S. Tubin¹, M. M. Ahmed², C. Guha³, M. Ashdown⁴, B. Celedin⁵, G. Salerno⁶, and W. Raunik⁷; ¹Medaustron - the Center for Ion Therapy and Research, Wiener Neustadt, Austria, ²Albert Einstein College of Medicine, Bronx, NY, ³Montefiore Einstein Comprehensive Cancer Center, Bronx, NY, ⁴University of Melbourne, Melbourne, VIC, Australia, ⁵Institute of Radiation Oncology, Klinikum Klagenfurt am Wörthersee, Klagenfurt, Austria, ⁶Sant Andrea Hospital, Rome, Italy, ⁷General Hospital Klagenfurt, Klagenfurt, Austria

Purpose/Objective(s): Partial tumor irradiation (PTI) is a novel immunomodulatory concept which adds to the direct cell-killing radiation effects an additional component of immune-mediated tumor cell-killing. PTI consists of 3 key principles: 1) neutralizing the immunosuppressive, central hypovascularized, and hypometabolic tumor segment, 2) preserving the peritumoral immune microenvironment (PIM) as OAR, and 3) delivering the treatment at precisely planned times, individually tailored for each patient based on homeostatic oscillations of immune activity (time-synchronized immune-guided radiotherapy). We hypothesized that PTI would generate radio-immunogenic effects thereby enhancing patient prognosis. The primary endpoint: bystander and abscopal responses rate. Materials/

Methods: This is a mono-centric, prospective, two-arm, phase 1 proof of principle trial including 22 patients with complex unresectable bulky tumors and at least 1 untreated metastatic site, deemed unsuitable for standard radiotherapy experiencing disease progression despite systemic therapies. Hypovascularized and hypometabolic tumor segment, delineated using the c.e. CT and FDG-PET-CT, was targeted with 10Gy x 3 at 70% sparing the PIM. 2 weeks prior PTI, each patient had 7 serial blood draws assessing CRP, LDH and lymphocyte/monocyte ratio to determine each patient´s idiosyncratic immune activity cycle. First 11 patients (arm1) PTI was delivered at an estimated “less reactive day" and to last 11 patients (arm2) at “most reactive day“. In selected patients, residual tumors, radiation-spared PIM and unirradiated abscopal tumor sites were surgically removed for immunohistochemistry (IHC) and cell-death inducing genes (CDIG) analysis.
Results: PTI exhibited significant radio-immunogenic effect (Tab. 1). Arm 2 demonstrated superior outcomes across nearly all treatment aspects. A higher proportion of long-term survivors were from arm 2 (55%, median follow-up of 54 months) compared to arm 1 (27%, median follow-up of 43 months). IHC and CDIG revealed significant anti-tumor-directed-activation of the immune system.
Conclusion: PTI was safe and effective. This study highlights the profound impact PTI can have on a highly palliative patient cohort previously deemed beyond therapeutic hope. It revealed the critical impact of treatment timing on clinical outcomes, with significant implications for optimizing individualized cancer treatment.

Table 1

22 patients	ARM1: 11 patients “worst timing”	ARM2: 11 patients “best timing”
Median Follow Up 29 months (1-69)	15 months (1-61)	47 months (6-69)
LC 1 year 50% (11/22)	27% (3/11)	73% (8/11)
LC 2 years 45% (10/22)	18% (2/11)	73% (8/11)
OS 1 year 73% (16/22)	73% (8/11)	73% (8/11)
OS 2 years 54% (12/22)	45% (5/11)	64% (7/11)
PFS 1 year 23% (5/22)	9% (1/11)	36% (4/11)
CSS 1 year 77% (17/22)	73% (8/11)	82% (9/11)
ABSCOPAL RESPONSE 41% (9/22)	27% (3/11)	55% (6/11)
BYSTANDER RESPONSE 77% (17/22)	73% (8/11)	82% (9/11)
TUMOR-VOLUME REDUCTION median 74% (0-94%)	46% (0-94%)	77% (15-84%)