{"title":"Time-Synchronized Immune-Guided Partial Tumor Irradiation: Proof-of-Principle Trial (NCT04168320)","authors":"","doi":"10.1016/j.ijrobp.2024.07.036","DOIUrl":null,"url":null,"abstract":"<div><h3>Purpose/Objective(s)</h3><div>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.</div></div><div><h3>Materials/Methods</h3><div>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 10 Gy 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 (arm 1) PTI was delivered at an estimated “less reactive day” and to last 11 patients (arm 2) 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.</div></div><div><h3>Results</h3><div>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.</div></div><div><h3>Conclusion</h3><div>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 which has significant implications for optimizing individualized cancer treatment.</div></div>","PeriodicalId":14215,"journal":{"name":"International Journal of Radiation Oncology Biology Physics","volume":null,"pages":null},"PeriodicalIF":6.4000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"International Journal of Radiation Oncology Biology Physics","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0360301624007983","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
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 10 Gy 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 (arm 1) PTI was delivered at an estimated “less reactive day” and to last 11 patients (arm 2) 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 which has significant implications for optimizing individualized cancer treatment.
期刊介绍:
International Journal of Radiation Oncology • Biology • Physics (IJROBP), known in the field as the Red Journal, publishes original laboratory and clinical investigations related to radiation oncology, radiation biology, medical physics, and both education and health policy as it relates to the field.
This journal has a particular interest in original contributions of the following types: prospective clinical trials, outcomes research, and large database interrogation. In addition, it seeks reports of high-impact innovations in single or combined modality treatment, tumor sensitization, normal tissue protection (including both precision avoidance and pharmacologic means), brachytherapy, particle irradiation, and cancer imaging. Technical advances related to dosimetry and conformal radiation treatment planning are of interest, as are basic science studies investigating tumor physiology and the molecular biology underlying cancer and normal tissue radiation response.