High-dose irradiation in combination with non-ablative low-dose radiation to treat metastatic disease after progression on immunotherapy: Results of a phase II trial

Patel, Roshal R.; He, Kewen; Barsoumian, Hampartsoum B.; Chang, Joe Y.; Tang, Chad; Verma, Vivek; Comeaux, Nathan; Chun, Stephen G.; Gandhi, Saumil; Truong, Mylene T.; Erasmus, Jeremy J.; Hong, David S.; Lee, Percy P.; Ning, Matthew S.; Nguyen, Quynh‐Nhu; Heymach, John V.; Altan, Mehmet; Blumenschein, George R.; Fossella, Frank V.; Sezen, Duygu; Chen, Fan; Carter, Brett W.; Davies, Michael A.; Glitza, Isabella C.; Diab, Adi; Ferrarotto, Renata; Cabanillas, Maria E.; Yuan, Ying; Shah, Shalin; Parra, Edwin R.; Sun, Baohua; Cortez, María Angélica; Welsh, James W.

doi:10.1016/j.radonc.2021.06.037

Cited by 55 publications

(45 citation statements)

References 69 publications

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“…The efficacy of this technique is illustrated in another preclinical study, wherein a single-dose of HDRT (22 Gy), followed by four daily LD fractions (4 × 0.5 Gy), so called “postablation modulation (PAM)”, improved both local tumor control and remote lung metastases by reducing Tregs and M2 macrophages, hence enabling the infiltration of effector T cells into lung and breast carcinomas ( 8 ). Of note, this novel non-ablative regimen is safe and comes at minimal additional cost to that incurred by HDRT ( 9 ). The safety and efficacy of RadScopal™ treatment has been further validated by our recently published phase II trial of HDRT – with or without LDRT – for metastatic disease after progression on immunotherapy ( 9 ).…”

Section: Low-dose Radiotherapy (Ldrt)mentioning

confidence: 99%

“…Thus, an NK cell-stimulating treatment such as IL-15 may further augment the antitumor effect of LDRT to liver metastases. Preliminary post-hoc analysis of our ongoing Phase-II trial (NCT02710253) ( 9 ), showed a lesion-specific response rate after LDRT that was higher for liver metastases (71%, n=7) compared to lung metastases (29% in lung, n=17).…”

Section: Low-dose Radiotherapy (Ldrt) For Liver Metastasesmentioning

confidence: 99%

“…Similar to immune-oncology agents, LDRT is capable of reprogramming the tumor microenvironment (TME), facilitating the infiltration of effector immune cells, and modulating the stroma in favor of tumor eradication. This has been borne out by a growing number of studies over the past decade, prompting much interest in the increasingly evident benefits of LDRT in the context of cancer immunotherapy (6)(7)(8)(9)(10)(11)24). Early evidence in a mouse model of localized neuroendocrine pancreatic tumors suggested that LDRT can remodel the TME in a variety of ways.…”

Section: Low-dose Radiotherapy (Ldrt)mentioning

confidence: 99%

“…Of note, this novel non-ablative regimen is safe and comes at minimal additional cost to that incurred by HDRT (9). The safety and efficacy of RadScopal ™ treatment has been further validated by our recently published phase II trial of HDRTwith or without LDRTfor metastatic disease after progression on immunotherapy (9). This study showed that RadScopal ™ therapy increased the response rate to 55%, compared to an 11% abscopal (HDRT alone) response rate, without added toxicity (3% RadScopal vs. 5% HDRT, grade ≥3 toxicity); while the RadScopal ™ response rate for checkpoint-resistant liver lesions was even higher at 71% by our (unpublished) post-hoc analysis.…”

Section: Low-dose Radiotherapy (Ldrt)mentioning

confidence: 99%

“…A multitude of therapeutic approaches have been levied in attempt to improve the outcomes of liver metastasis patients. Recently, several preclinical and clinical studies (6)(7)(8)(9)(10)(11) reported the outstanding safety, efficacy, and/or relating mechanisms of a novel non-ablative treatment termed low-dose radiotherapy (LDRT), which is defined as radiotherapy of 0.5-2 Gray (Gy) per fraction for up to 1-10 Gy total. These promising findings provide the rationale for the development of LDRT as a potential treatment alternative for patients with liver metastases.…”

Section: Introductionmentioning

confidence: 99%

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Novel Use of Low-Dose Radiotherapy to Modulate the Tumor Microenvironment of Liver Metastases

Barsoumian

Bertolet

et al. 2021

Front. Immunol.

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Despite multiple therapeutic approaches, the presence of liver metastases carries a guarded prognosis, urgently necessitating further clinical and scientific research to develop curative interventions. The liver is an immunoprivileged organ that suppresses the effectiveness of immunotherapies in patients with hepatic metastases. Cancer immunotherapies have been successfully bolstered by low-dose radiotherapy (LDRT), which is capable of reprogramming the tumor microenvironment (TME) from an immunosuppressive to an immunostimulatory one. Likewise, LDRT may be able to revoke the immune privilege enjoyed by the liver, permitting successful immunotherapies there. Here, we first review challenges that face the treatment of liver metastases. We next outline emerging preclinical and clinical evidence supporting enhanced systemic tumor control of LDRT in the context of cancer immunotherapy. Finally, we will discuss the rationale of combining liver-directed LDRT with immunostimulatory strategies to overcome immune resistance and achieve better clinical response. This notion is supported by a recent case study in which a patient who had progressed following T cell therapy experienced a complete response after LDRT to the liver.

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Section: Low-dose Radiotherapy (Ldrt)mentioning

confidence: 99%

Section: Low-dose Radiotherapy (Ldrt) For Liver Metastasesmentioning

confidence: 99%

Section: Low-dose Radiotherapy (Ldrt)mentioning

confidence: 99%

Section: Low-dose Radiotherapy (Ldrt)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Novel Use of Low-Dose Radiotherapy to Modulate the Tumor Microenvironment of Liver Metastases

Barsoumian

Bertolet

et al. 2021

Front. Immunol.

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Technical feasibility of novel immunostimulatory low‐dose radiation for polymetastatic disease with CBCT‐based online adaptive and conventional approaches

Nasser,

Perez,

Penagaricano

et al. 2024

J Applied Clin Med Phys

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PurposeA workflow/planning strategy delivering low‐dose radiation therapy (LDRT) (1 Gy) to all polymetastatic diseases using conventional planning/delivery (Raystation/Halcyon = “conventional”) and the AI‐based Ethos online adaptive RT (oART) platform is developed/evaluated.MethodsUsing retrospective data for ten polymetastatic non‐small cell lung cancer patients (5‐52 lesions each) with PET/CTs, gross tumor volumes (GTVs) were delineated using PET standardized‐uptake‐value (SUV) thresholding. A 1 cm uniform expansion of GTVs to account for setup/contour uncertainty and organ motion‐generated planning target volumes (PTVs). Dose optimization/calculation used the diagnostic CT from PET/CT. Dosimetric objectives were: Dmin,0.03cc ≥ 95% (acceptable variation (Δ) ≥ 90%), V100% ≥ 95% (Δ ≥ 90%), and D0.03cc ≤ 120% (Δ ≤ 125%). Additionally, online adaptation was simulated. When available, subsequent diagnostic CT was used to represent on‐treatment CBCT. Otherwise, the CT from PET/CT used for initial planning was deformed to simulate clinically representative changes.ResultsAll initial plans generated, both for Raystation and Ethos, achieved clinical goals within acceptable variation. For all patients, Dmin,0.03cc ≥ 95%, V100% ≥ 95%, and D0.03cc ≤ 120% goals were achieved for 84.8%/99.5%, 97.7%/98.7%, 97.4%/92.3%, in conventional/Ethos plans, respectively. The ratio of 50% isodose volume to PTV volume (R50%), maximum dose at 2 cm from PTV (D2cm), and the ratio of the 100% isodose volume to PTV volume (conformity index) in Raystation/Ethos plans were 7.9/5.9; 102.3%/88.44%; and 0.99/1.01, respectively. In Ethos, online adapted plans maintained PTV coverage whereas scheduled plans often resulted in geographic misses due to changes in tumor size, patient position, and body habitus. The average total duration of the oART workflow was 26:15 (min:sec) ranging from 6:43 to 57:30. The duration of each oART workflow step as a function of a number of targets showed a low correlation coefficient for influencer generation and editing (R2 = 0.04 and 0.02, respectively) and high correlation coefficient for target generation, target editing and plan generation (R2 = 0.68, 0.63 and 0.69, respectively).ConclusionsThis study demonstrates feasibility of conventional planning/treatment with Raystation/Halcyon and highlights efficiency gains when utilizing semi‐automated planning/online‐adaptive treatment with Ethos for immunostimulatory LDRT conformally delivered to all sites of polymetastatic disease.

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Combined treatment of non‐small cell lung cancer using radiotherapy and immunotherapy: challenges and updates

Shang

Liu

Verma

et al. 2021

Cancer Communications

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The efficacy of immunotherapy for advanced non-small cell lung cancer (NSCLC) remains unsatisfactory, as the majority of patients either do not experience an objective response or acquire secondary resistance. As a result, several methods to enhance the systemic efficacy of immunotherapy have been investigated, including a large area of active research by combining immunotherapy with radiation therapy (RT). Given the rapidly burgeoning concept of combining immunotherapy and RT for increasing therapeutic benefit, we review the progress in this field thus far and explore further avenues for enhancing this combination. This review commences with a discussion of the only two existing randomized trials (and a pooled analysis) showing that the addition of RT to immunotherapy improves the abscopal response rate, progression-free survival, and overall survival in metastatic NSCLC patients. We then discussed factors and biomarkers that may be associated with a proportionally greater benefit to additional RT, such as low programmed cell death protein ligand 1 (PD-L1) status, tumor mutational burden (TMB), and patient's immune function. Next, the implementation of RT to overcome immunotherapy resistance is discussed, including a mechanistic discussion and methods with which these mechanisms could be exploited. Lastly, the emerging role of low-dose RT is discussed, which

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High-dose irradiation in combination with non-ablative low-dose radiation to treat metastatic disease after progression on immunotherapy: Results of a phase II trial

Cited by 55 publications

References 69 publications

Novel Use of Low-Dose Radiotherapy to Modulate the Tumor Microenvironment of Liver Metastases

Novel Use of Low-Dose Radiotherapy to Modulate the Tumor Microenvironment of Liver Metastases

Technical feasibility of novel immunostimulatory low‐dose radiation for polymetastatic disease with CBCT‐based online adaptive and conventional approaches

Combined treatment of non‐small cell lung cancer using radiotherapy and immunotherapy: challenges and updates

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