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Immune mechanisms of FLASH radiotherapy: a new paradigm for lung cancer cure

Institution: Stanford University
Investigator(s): Billy Loo,
Award Cycle: 2019 (Cycle 29) Grant #: T29IP0443 Award: $628,421
Subject Area: Cancer
Award Type: High Impact Pilot Award

Initial Award Abstract
Lung cancer is not only the most common tobacco-related cancer, it is by far the leading cause of cancer deaths worldwide. Radiation therapy plays a crucial role for most patients who have the potential of being cured of lung cancer, and is increasingly used with the goal of cure in selected patients with lung cancer from early to metastatic stages. Immunotherapy has recently become an important treatment for incurable metastatic lung cancer, and is just starting to play a role in potentially curable lung cancer. Radiation therapy can increase the effectiveness of immunotherapy. Used together even metastatic lung cancer can sometimes be cured, but we do not yet know how to do so reliably. Furthermore, the side effects of radiation therapy and immunotherapy limit their ability to achieve cures safely. Increasing the curative effect on lung cancer while decreasing collateral damage to normal organs is the key to the success of any cancer therapy.

Ultra-fast FLASH radiation therapy (completed in under one second compared to several minutes conventionally) promises to be a breakthrough in curative radiation therapy for lung cancer. FLASH would solve the problem of precisely treating moving targets like lung tumors by freezing the motion, allowing more intense treatment to the tumor while reducing unnecessary radiation to the surrounding normal organs. Remarkably, preliminary experiments of biological effects of FLASH in mice have shown that it produces better killing of lung cancer cells but dramatically less damage to the lungs. These effects appear to involve different immune responses in tumors and normal tissues compared to those produced by conventional speed radiation.

We propose to study the immune signature produced by FLASH in order to understand how to maximize its beneficial effects, and how it might interact with immunotherapy to achieve more reliable cures with minimal injury to normal organs. If these biological results translate to humans, FLASH would transform curative lung cancer treatment. Importantly, Stanford and SLAC National Accelerator Lab are collaborating on a parallel research program to develop a next-generation medical linear accelerator capable of delivering FLASH to humans, providing a direct path to clinical realization of the biological benefits of FLASH in addition to its advantages in precision targeting.