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Abstract
Purpose: Radiation is used extensively to treat localized cancer, but improved understanding of its effects on the immune system has increased interest in its potential systemic (abscopal) effects, particularly in combination with checkpoint inhibitors such as anti-PD1. The majority of patients either do not respond or develop resistance to monotherapy over time. Here, we investigated the efficacy of OX40 (CD134) stimulation as an alternative immunotherapeutic approach in combination with radiotherapy (XRT) in a murine model of anti-PD1-resistant lung tumors.Experimental Design: We established a bilateral tumor model in 129Sv/Ev mice using an anti-PD1-resistant lung tumor cell line. Primary tumors were treated with intratumoral injection of an OX40 agonist antibody, given as adjuvant therapy after XRT (36 Gy in three 12-Gy fractions), whereas secondary tumors were left untreated to investigate abscopal outcomes.Results: The combination of XRT followed by OX40 stimulation effectively inhibited local and systemic antitumor growth, limited lung metastases, and improved survival rates. This treatment regimen augmented CD4+ and CD8+ T-cell expansion. XRT induced the expression of OX40 on T cells in tumors and spleens and increased the percentages of splenic CD103+ dendritic cells.Conclusions: Our data extend the benefits of radiation to systemic disease control, especially when combined with anti-OX40 agonist to promote immunologically mediated abscopal effects. Moreover, this study provides a rational treatment approach and sequence to overcome anti-PD1-resistant poorly immunogenic tumors.

Author information

Niknam S#1, Barsoumian HB#2, Schoenhals JE1, Jackson HL3, Yanamandra N3, Caetano MS2, Li A1, Younes AI2, Cadena A1, Cushman TR2, Chang JY2, Nguyen QN2, Gomez DR2, Diab A4, Heymach JV4, Hwu P5, Cortez MA1, Welsh JW6.
1
Department of Experimental Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
2
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
3
Immuno-oncology and combinations DPU, GlaxoSmithKline, Collegeville, Pennsylvania.
4
Department of Thoracic Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
5
Department of Melanoma Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
6
Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. jwelsh@mdanderson.org.
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Contributed equally