Addition of TLR9 agonist immunotherapy to radiation improves systemic antitumor activity

Ahmed I Younes; Hampartsoum B Barsoumian; Duygu Sezen; Vivek Verma; Roshal Patel; Mark Wasley; Yun Hu; Joe D Dunn; Kewen He; Dawei Chen; Hari Menon; Fatemeh Masrorpour; Meidi Gu; Liangpeng Yang; Nahum Puebla-Osorio; Maria Angelica Cortez; James W Welsh

doi:10.1016/j.tranon.2020.100983

Addition of TLR9 agonist immunotherapy to radiation improves systemic antitumor activity

Transl Oncol. 2021 Feb;14(2):100983. doi: 10.1016/j.tranon.2020.100983. Epub 2020 Dec 16.

Authors

Ahmed I Younes¹, Hampartsoum B Barsoumian¹, Duygu Sezen¹, Vivek Verma¹, Roshal Patel¹, Mark Wasley¹, Yun Hu¹, Joe D Dunn¹, Kewen He², Dawei Chen², Hari Menon³, Fatemeh Masrorpour¹, Meidi Gu¹, Liangpeng Yang¹, Nahum Puebla-Osorio¹, Maria Angelica Cortez¹, James W Welsh⁴

Affiliations

¹ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
² Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Radiation Oncology, Shandong Cancer Hospital Affiliated to Shandong University, Jinan, China.
³ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Department of Radiation Oncology, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA.
⁴ Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: jwelsh@mdanderson.org.

Abstract

Radiotherapy (RT) has been used to control tumors by physically damaging DNA and inducing apoptosis; it also promotes antitumor immune responses via neoantigens release and augmenting immune-oncology agents to elicit systemic response. Tumor regression after RT can recruit inflammatory cells, such as tumor-associated macrophages and CD11b⁺ myeloid cell populations, a major subset of which may actually be immunosuppressive. However, these inflammatory cells also express Toll-like receptors (TLRs) that can be stimulated to reverse suppressive characteristics and promote systemic antitumor outcomes. Here, we investigated the effects of adding CMP-001, a CpG-A oligodeoxynucleotide TLR9 agonist delivered in a virus-like particle (VLP), to RT in two murine models (344SQ metastatic lung adenocarcinoma and CT26 colon carcinoma). High-dose RT (12Gy x 3 fractions) significantly increased the percentages of plasmacytoid dendritic cells within the tumor islets 3- and 5-days post-RT; adding CMP-001 after RT also enhanced adaptive immunity by increasing the proportion of CD4⁺ and CD8⁺ T cells. RT plus CMP-001-mediated activation of the immune system led to significant inhibition of tumor growth at both primary and abscopal tumor sites, thereby suggesting a new combinatorial treatment strategy for systemic disease.

Keywords: Abscopal effect; CMP-001; Cancer; Radiotherapy; TLR9 agonist.