Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non–Small Cell Lung Cancer

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Abstract

<p class="first" id="d2420711e204">Many patients with advanced non-small cell lung cancer (NSCLC) receiving immunotherapy show primary resistance. High-dose radiotherapy can lead to increased tumor antigen release, improved antigen presentation, and T-cell infiltration. This radiotherapy may enhance the effects of checkpoint inhibition. </p>

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Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial.

Narek Shaverdian, Aaron Lisberg, Krikor Bornazyan … (2017)

Preclinical studies have found radiotherapy enhances antitumour immune responses. We aimed to assess disease control and pulmonary toxicity in patients who previously received radiotherapy for non-small-cell lung cancer (NSCLC) before receiving pembrolizumab.

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Maximizing tumor immunity with fractionated radiation.

Dörthe Schaue, Josephine A. Ratikan, Keisuke S. Iwamoto … (2012)

Technologic advances have led to increased clinical use of higher-sized fractions of radiation dose and higher total doses. How these modify the pathways involved in tumor cell death, normal tissue response, and signaling to the immune system has been inadequately explored. Here we ask how radiation dose and fraction size affect antitumor immunity, the suppression thereof, and how this might relate to tumor control. Mice bearing B16-OVA murine melanoma were treated with up to 15 Gy radiation given in various-size fractions, and tumor growth followed. The tumor-specific immune response in the spleen was assessed by interferon-γ enzyme-linked immunospot (ELISPOT) assay with ovalbumin (OVA) as the surrogate tumor antigen and the contribution of regulatory T cells (Tregs) determined by the proportion of CD4(+)CD25(hi)Foxp3(+) T cells. After single doses, tumor control increased with the size of radiation dose, as did the number of tumor-reactive T cells. This was offset at the highest dose by an increase in Treg representation. Fractionated treatment with medium-size radiation doses of 7.5 Gy/fraction gave the best tumor control and tumor immunity while maintaining low Treg numbers. Radiation can be an immune adjuvant, but the response varies with the size of dose per fraction. The ultimate challenge is to optimally integrate cancer immunotherapy into radiation therapy. Copyright © 2012 Elsevier Inc. All rights reserved.

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Fractionated radiation therapy stimulates anti-tumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD1 blockade.

Simon J Dovedi, Eleanor Cheadle, Amy Lee Popple … (2017)

Purpose: Radiotherapy (RT) is a highly effective anti-cancer treatment forming part of the standard of care for the majority of patients, but local and distal disease recurrence remains a major cause of mortality. RT is known to enhance tumor immunogenicity; however, the contribution and mechanisms of RT induced immune responses are unknown. Experimental Design: The impact of low-dose fractionated RT (5 x 2 Gy) alone and in combination with αPD-1 mAb on the tumor microenvironment was evaluated by flow cytometry and next-generation sequencing (NGS) of the T-cell receptor (TCR)-repertoire. A dual-tumor model was used, with fractionated RT delivered to a single tumor site to enable evaluation of the local and systemic response to treatment and ability to induce abscopal responses outside the radiation field. Results: We show that fractionated RT leads to T-cell infiltration at the irradiated site; however, the TCR landscape remains dominated by polyclonal expansion of pre-existing T-cell clones. Adaptive resistance via the PD-1/PD-L1 pathway restricts the generation of systemic anti-cancer immunity following RT which can be overcome through combination with αPD-1 mAb leading to improved local and distal tumor control. Moreover, we show that effective clearance of tumor following combination therapy is dependent on both T-cells resident in the tumor at the time of RT and infiltrating T-cells. Conclusions: These data provide evidence that RT can enhance T-cell trafficking to locally-treated tumor sites and augment pre-existing anti-cancer T-cell responses with the capacity to mediate regression of out-of-field tumor lesions when delivered in combination with αPD-1 mAb therapy.

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Author and article information

Journal

Title: JAMA Oncology

Abbreviated Title: JAMA Oncol

Publisher: American Medical Association (AMA)

ISSN (Print): 2374-2437

Publication date (Electronic): July 11 2019

Affiliations

[1 ]Department of Thoracic Oncology, Netherlands Cancer Institute, Amsterdam

[2 ]Department of Radiation Oncology, Netherlands Cancer Institute, Amsterdam

[3 ]Department of Radiation Oncology, Catharina Hospital, Eindhoven, the Netherlands

[4 ]Department of Radiology, Netherlands Cancer Institute, Amsterdam

[5 ]Department of Biometrics, Netherlands Cancer Institute, Amsterdam

[6 ]Department of Pulmonology, Erasmus Medical Center, Rotterdam, Amsterdam, the Netherlands

[7 ]Department of Pulmonology, VU Medical Center, Amsterdam, the Netherlands

[8 ]Department of Pathology, Netherlands Cancer Institute, Amsterdam

Article

DOI: 10.1001/jamaoncol.2019.1478

PMC ID: 6624814

PubMed ID: 31294749

SO-VID: d7e71c73-cafb-4dc6-a423-f5565e7a601a

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Effect of Pembrolizumab After Stereotactic Body Radiotherapy vs Pembrolizumab Alone on Tumor Response in Patients With Advanced Non–Small Cell Lung Cancer : Results of the PEMBRO-RT Phase 2 Randomized Clinical Trial

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Inflamed lung in vitro co-culture models

Most cited references 4

Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial.

Maximizing tumor immunity with fractionated radiation.

Fractionated radiation therapy stimulates anti-tumor immunity mediated by both resident and infiltrating polyclonal T-cell populations when combined with PD1 blockade.

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