Improved Tumor Control Through T-cell Infiltration Modulated by Ultra-High Dose Rate Proton FLASH Using a Clinical Pencil Beam Scanning Proton System

Rama, Nihar; Saha, Tamoghna; Shukla, Sujit; Goda, Chinmayee; Milewski, David; Mascia, Anthony; Vatner, Ralph; Sengupta, Dilip K.; Katsis, Alexander; Abel, Eric; Girdhani, Swati; Miyazaki, Mitsue; Rodriguez, A.; Ku, Andrew; Dua, Rajiv; Parry, Renate; Kalin, Tanya V.

doi:10.1016/j.ijrobp.2019.06.187

Cited by 53 publications

(52 citation statements)

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“…This study reported that immune system wide activation and maturation was dampened in mice following FLASH-RT relative to CONV-RT. Also as mentioned above, the study by Rama et al showed an improved recruitment of T lymphocytes into the tumor microenvironment for tumors treated with FLASH-RT compared to CONV-RT, which gives merit to this hypothesis (36). In several studies, immunocompromised animals were used to compare treatment efficacy of FLASH-RT and CONV-RT with no observed difference in tumor response ( Table 2), which could be interpreted to further strengthen the hypothesis (7,8,10,35).…”

Section: Immune Hypothesismentioning

confidence: 72%

“…Surprisingly, the tumors of the mice treated with proton FLASH-RT were smaller than the tumors of the mice treated with proton CONV-RT. Moreover, immuno?uorescent staining on harvested tumor sections showed an improved recruitment of T lymphocytes into the tumor microenvironment for tumors treated with FLASH-RT compared to CONV-RT (36). Evidentially in some cases, the anti-tumor response to FLASH-RT might even be better than that of CONV-RT.…”

Section: Similar Anti-tumor Response With Flash-rt As Conv-rtmentioning

confidence: 95%

“…Using bioluminescence to assess the tumor burden, no significant difference could be seen between FLASH-RT and CONV-RT for any of the fractionation schemes (8). In a study by Rama et al Lewis Lung Carcinoma (LLC) cells were inoculated into the left lung of C57Bl/6J mice (36). Two weeks post-inoculation, the whole lungs of tumor-bearing mice were irradiated with a single fraction dose of 18 Gy, using a clinical pencil beam scanning proton system.…”

Section: Similar Anti-tumor Response With Flash-rt As Conv-rtmentioning

confidence: 99%

“…The FLASH effect has been predominantly observed following FLASH-RT using dedicated electron linear accelerators as the source of radiation (10,14,15,18,37). However, recent studies have expanded the FLASH field and include observations of a FLASH effect following proton (11,23,36) and X-ray (24) irradiation. Again, it must be noted that there have been a couple of studies that have been unable to induce a FLASH effect using proton and X-ray sources ( Table 1).…”

Section: What Factors Influence the Flash Effect?mentioning

confidence: 99%

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Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold?

et al. 2020

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Radiotherapy is a cornerstone of both curative and palliative cancer care. However, radiotherapy is severely limited by radiation-induced toxicities. If these toxicities could be reduced, a greater dose of radiation could be given therefore facilitating a better tumor response. Initial pre-clinical studies have shown that irradiation at dose rates far exceeding those currently used in clinical contexts reduce radiation-induced toxicities whilst maintaining an equivalent tumor response. This is known as the FLASH effect. To date, a single patient has been subjected to FLASH radiotherapy for the treatment of subcutaneous T-cell lymphoma resulting in complete response and minimal toxicities. The mechanism responsible for reduced tissue toxicity following FLASH radiotherapy is yet to be elucidated, but the most prominent hypothesis so far proposed is that acute oxygen depletion occurs within the irradiated tissue. This review examines the tissue response to FLASH radiotherapy, critically evaluates the evidence supporting hypotheses surrounding the biological basis of the FLASH effect, and considers the potential for FLASH radiotherapy to be translated into clinical contexts.

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Section: Immune Hypothesismentioning

confidence: 72%

Section: Similar Anti-tumor Response With Flash-rt As Conv-rtmentioning

confidence: 95%

Section: Similar Anti-tumor Response With Flash-rt As Conv-rtmentioning

confidence: 99%

Section: What Factors Influence the Flash Effect?mentioning

confidence: 99%

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Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold?

et al. 2020

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“…It has also been suggested that FLASH may offer an improved immune response due to the fast exposure time leading to less irradiation of circulating immune cells, although this effect may be reduced for fractionated FLASH radiotherapy [54]. Finally, it has been reported that proton irradiation of mice at FLASH dose rates showed an increased T-lymphocyte recruitment into the tumor microenvironment compared to conventional dose rates, further supporting the notation that changes in the immune response may contribute to the FLASH effect [29].…”

Section: Immune Responsementioning

confidence: 95%

FLASH Radiotherapy: Current Knowledge and Future Insights Using Proton-Beam Therapy

Hughes

Parsons

2020

IJMS

181

127

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FLASH radiotherapy is the delivery of ultra-high dose rate radiation several orders of magnitude higher than what is currently used in conventional clinical radiotherapy, and has the potential to revolutionize the future of cancer treatment. FLASH radiotherapy induces a phenomenon known as the FLASH effect, whereby the ultra-high dose rate radiation reduces the normal tissue toxicities commonly associated with conventional radiotherapy, while still maintaining local tumor control. The underlying mechanism(s) responsible for the FLASH effect are yet to be fully elucidated, but a prominent role for oxygen tension and reactive oxygen species production is the most current valid hypothesis. The FLASH effect has been confirmed in many studies in recent years, both in vitro and in vivo, with even the first patient with T-cell cutaneous lymphoma being treated using FLASH radiotherapy. However, most of the studies into FLASH radiotherapy have used electron beams that have low tissue penetration, which presents a limitation for translation into clinical practice. A promising alternate FLASH delivery method is via proton beam therapy, as the dose can be deposited deeper within the tissue. However, studies into FLASH protons are currently sparse. This review will summarize FLASH radiotherapy research conducted to date and the current theories explaining the FLASH effect, with an emphasis on the future potential for FLASH proton beam therapy.

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A potential revolution in cancer treatment: A topical review of FLASH radiotherapy

Gao

Liu

Chang

et al. 2022

J Applied Clin Med Phys

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FLASH radiotherapy (RT) is a novel technique in which the ultrahigh dose rate (UHDR) (≥40 Gy/s) is delivered to the entire treatment volume. Recent outcomes of in vivo studies show that the UHDR RT has the potential to spare normal tissue without sacrificing tumor control. There is a growing interest in the application of FLASH RT, and the ultrahigh dose irradiation delivery has been achieved by a few experimental and modified linear accelerators. The underlying mechanism of FLASH effect is yet to be fully understood, but the oxygen depletion in normal tissue providing extra protection during FLASH irradiation is a hypothesis that attracts most attention currently. Monte Carlo simulation is playing an important role in FLASH, enabling the understanding of its dosimetry calculations and hardware design. More advanced Monte Carlo simulation tools are under development to fulfill the challenge of reproducing the radiolysis and radiobiology processes in FLASH irradiation. FLASH RT may become one of standard treatment modalities for tumor treatment in the future. This paper presents the history and status of FLASH RT studies with a focus on FLASH irradiation delivery modalities, underlying mechanism of FLASH effect, in vivo and vitro experiments, and simulation studies. Existing challenges and prospects of this novel technique are discussed in this manuscript.

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Improved Tumor Control Through T-cell Infiltration Modulated by Ultra-High Dose Rate Proton FLASH Using a Clinical Pencil Beam Scanning Proton System

Cited by 53 publications

References 0 publications

Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold?

Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold?

FLASH Radiotherapy: Current Knowledge and Future Insights Using Proton-Beam Therapy

A potential revolution in cancer treatment: A topical review of FLASH radiotherapy

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