PD-1 cis-targeted IL-2v in combination with radiotherapy inhibits lung cancer growth and remodels the immune microenvironment.

Background: More efficient therapeutic options for non-small cell lung cancer (NSCLC) are needed as the survival at 5 years of metastatic disease is near zero. In this regard, we used a preclinical model of metastatic lung adenocarcinoma (SV2-OVA) to assess the safety and efficacy of novel radio-immunotherapy combining hypofractionated radiotherapy (HRT) with muPD1-IL2v immunocytokine and muFAP-CD40 bispecific antibody.

Methods: We evaluated the changes in the lung immune microenvironment at multiple timepoints following combination therapies and investigated their underlying antitumor mechanisms.

In vivo measurements of change in tissue oxygen level during irradiation reveal novel dose rate dependence.

Background And Purpose: This study aimed to investigate the radiochemical oxygen depletion (ROD) in vivo by directly measuring oxygen levels in various mouse tissues during ultra-high dose rate (UHDR) irradiation at clinically relevant doses and dose rates.

Materials And Methods: Mice bearing subcutaneous human glioblastoma (U-87 MG) tumors were used for tumor and normal tissue (skin, muscle, brain) measurements. An oxygen-sensitive phosphorescent probe (Oxyphor PtG4) was injected into the tissues, and oxygen levels were monitored using a fiberoptic phosphorometer during UHDR irradiation with a 6 MeV electron linear accelerator (LINAC).

A multi-institutional study to investigate the sparing effect after whole brain electron FLASH in mice: Reproducibility and temporal evolution of functional, electrophysiological, and neurogenic endpoints.

Background And Purpose: Ultra-high dose-rate radiotherapy (FLASH) has been shown to mitigate normal tissue toxicities associated with conventional dose rate radiotherapy (CONV) without compromising tumor killing in preclinical models. A prominent challenge in preclinical radiation research, including FLASH, is validating both the physical dosimetry and the biological effects across multiple institutions.

Materials And Methods: We previously demonstrated dosimetric reproducibility of two different electron FLASH devices at separate institutions using standardized phantoms and dosimeters.

Structural plasticity of pyramidal cell neurons measured after FLASH and conventional dose-rate irradiation.

Evidence shows that ultra-high dose-rate FLASH-radiotherapy (FLASH-RT) protects against normal tissue complications and functional decrements in the irradiated brain. Past work has shown that radiation-induced cognitive impairment, neuroinflammation and reduced structural complexity of granule cell neurons were not observed to the same extent after FLASH-RT (> MGy/s) compared to conventional dose-rate (CONV, 0.1 Gy/s) delivery.

Navigating the Critical Translational Questions for Implementing FLASH in the Clinic.

The "FLASH effect" is an increased therapeutic index, that is, reduced normal tissue toxicity for a given degree of anti-cancer efficacy, produced by ultra-rapid irradiation delivered on time scales orders of magnitude shorter than currently conventional in the clinic for the same doses. This phenomenon has been observed in numerous preclinical in vivo tumor and normal tissue models. While the underlying biological mechanism(s) remain to be elucidated, a path to clinical implementation of FLASH can be paved by addressing several critical translational questions.