Can Rational Combination of Ultra-high Dose Rate FLASH Radiotherapy with Immunotherapy Provide a Novel Approach to Cancer Treatment?

Zhang, Y.; Ding, Zeyang; Perentesis, John P.; Khuntia, Deepak; Pfister, Stefan; Sharma, Ricky A.

doi:10.1016/j.clon.2021.09.003

Cited by 33 publications

(21 citation statements)

References 64 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 162 ), and combination with drugs that enhances the effect (Ref. 163 ). Preclinical assays, such as the ones described above, will be essential tools in identifying the radiobiological mechanisms behind the effect and finally being able to fully exploit the benefits associated with FLASH-RT.…”

Section: Concluding Remarks/translational Implicationsmentioning

confidence: 99%

In vitroassays for investigating the FLASH effect

Adrian

Ruan

Paillas

et al. 2022

Expert Rev. Mol. Med.

View full text Add to dashboard Cite

FLASH radiotherapy is a novel technique that has been shown in numerous preclinical in vivo studies to have the potential to be the next important improvement in cancer treatment. However, the biological mechanisms responsible for the selective FLASH sparing effect of normal tissues are not yet known. An optimal translation of FLASH radiotherapy into the clinic would require a good understanding of the specific beam parameters that induces a FLASH effect, environmental conditions affecting the response, and the radiobiological mechanisms involved. Even though the FLASH effect has generally been considered as an in vivo effect, studies finding these answers would be difficult and ethically challenging to carry out solely in animals. Hence, suitable in vitro studies aimed towards finding these answers are needed. In this review, we describe and summarise several in vitro assays that have been used or could be used to finally elucidate the mechanisms behind the FLASH effect.

show abstract

Section: Concluding Remarks/translational Implicationsmentioning

confidence: 99%

In vitroassays for investigating the FLASH effect

Adrian

Ruan

Paillas

et al. 2022

Expert Rev. Mol. Med.

View full text Add to dashboard Cite

show abstract

“…To date, the biological mechanisms under FLASH-RT remain elusive. Several mechanisms have been proposed in the literature, namely, the lower creation of oxygen reactive species depending on tissue hypoxia level or a different immune activation through the systemic immune cells or inflammatory response in the tissue ( 20 , 24 , 78 – 81 ). However, there is currently a lack of substantial biological data to support this hypothesis, and, for the moment, only few evaluations were performed.…”

Section: Discussionmentioning

confidence: 99%

Practice-oriented solutions integrating intraoperative electron irradiation and personalized proton therapy for recurrent or unresectable cancers: Proof of concept and potential for dual FLASH effect

Ayestaran¹,

Serrano²,

Cambeiro³

et al. 2022

Front. Oncol.

View full text Add to dashboard Cite

BackgroundOligo-recurrent disease has a consolidated evidence of long-term surviving patients due to the use of intense local cancer therapy. The latter combines real-time surgical exploration/resection with high-energy electron beam single dose of irradiation. This results in a very precise radiation dose deposit, which is an essential element of contemporary multidisciplinary individualized oncology.MethodsPatient candidates to proton therapy were evaluated in Multidisciplinary Tumor Board to consider improved treatment options based on the institutional resources and expertise. Proton therapy was delivered by a synchrotron-based pencil beam scanning technology with energy levels from 70.2 to 228.7 MeV, whereas intraoperative electrons were generated in a miniaturized linear accelerator with dose rates ranging from 22 to 36 Gy/min (at Dmax) and energies from 6 to 12 MeV.ResultsIn a period of 24 months, 327 patients were treated with proton therapy: 218 were adults, 97 had recurrent cancer, and 54 required re-irradiation. The specific radiation modalities selected in five cases included an integral strategy to optimize the local disease management by the combination of surgery, intraoperative electron boost, and external pencil beam proton therapy as components of the radiotherapy management. Recurrent cancer was present in four cases (cervix, sarcoma, melanoma, and rectum), and one patient had a primary unresectable locally advanced pancreatic adenocarcinoma. In re-irradiated patients (cervix and rectum), a tentative radical total dose was achieved by integrating beams of electrons (ranging from 10- to 20-Gy single dose) and protons (30 to 54-Gy Relative Biological Effectiveness (RBE), in 10–25 fractions).ConclusionsIndividual case solution strategies combining intraoperative electron radiation therapy and proton therapy for patients with oligo-recurrent or unresectable localized cancer are feasible. The potential of this combination can be clinically explored with electron and proton FLASH beams.

show abstract

“…In the in vivo setting, the reduced mitochondrial damage might also result from the potential sparing of circulating immune cells by ultra-high dose rate irradiation. Additionally, if FLASH RT could preserve the function of T cells and their mitochondria, its combination with immunotherapy, which often depends on functioning T cells, could be a promising strategy to enhance anti-tumor immunity [ 127 ].…”

Section: Mechanisms For the Flash Effectmentioning

confidence: 99%

Potential Molecular Mechanisms behind the Ultra-High Dose Rate “FLASH” Effect

Bogaerts

Macaeva

Isebaert

et al. 2022

IJMS

View full text Add to dashboard Cite

FLASH radiotherapy, or the delivery of a dose at an ultra-high dose rate (>40 Gy/s), has recently emerged as a promising tool to enhance the therapeutic index in cancer treatment. The remarkable sparing of normal tissues and equivalent tumor control by FLASH irradiation compared to conventional dose rate irradiation—the FLASH effect—has already been demonstrated in several preclinical models and even in a first patient with T-cell cutaneous lymphoma. However, the biological mechanisms responsible for the differential effect produced by FLASH irradiation in normal and cancer cells remain to be elucidated. This is of great importance because a good understanding of the underlying radiobiological mechanisms and characterization of the specific beam parameters is required for a successful clinical translation of FLASH radiotherapy. In this review, we summarize the FLASH investigations performed so far and critically evaluate the current hypotheses explaining the FLASH effect, including oxygen depletion, the production of reactive oxygen species, and an altered immune response. We also propose a new theory that assumes an important role of mitochondria in mediating the normal tissue and tumor response to FLASH dose rates.

show abstract

Can Rational Combination of Ultra-high Dose Rate FLASH Radiotherapy with Immunotherapy Provide a Novel Approach to Cancer Treatment?

Cited by 33 publications

References 64 publications

In vitroassays for investigating the FLASH effect

In vitroassays for investigating the FLASH effect

Practice-oriented solutions integrating intraoperative electron irradiation and personalized proton therapy for recurrent or unresectable cancers: Proof of concept and potential for dual FLASH effect

Potential Molecular Mechanisms behind the Ultra-High Dose Rate “FLASH” Effect

Contact Info

Product

Resources

About