Neoadjuvant BO-112 and hypofractionated radiation therapy with or without nivolumab in soft tissue sarcoma: preclinical and phase 1 results

Neoadjuvant immune checkpoint blockade (ICB) and radiation therapy (RT) improve disease-free survival in select patients with soft tissue sarcoma (STS). However, most STS are myeloid-rich and lack pre-existing T cells associated with ICB response. In preclinical models, we observed that intratumoral BO-112 (nanoplexed polyinosinic: polycytidylic acid (poly I:C)) engages myeloid cells that persist after RT, ultimately enhancing T cell-dependent tumor control. We evaluated BO-112 and hypofractionated RT, with or without nivolumab, in fourteen patients with high-risk STS in a phase 1 neoadjuvant trial. Consistent with its immunologic potency, the triple combination induced rare immune-related adverse events (myositis-myocarditis-myasthenia gravis spectrum), mitigated by BO-112 and nivolumab dose adjustment. BO-112 and RT reprogrammed tumor-associated myeloid cells toward antigen-presenting states, promoted clonal replacement by less exhausted T cells, and enhanced malignant cell depletion compared to standard RT. These immunologic changes coincided with encouraging disease control in a small, high-risk cohort, supporting further clinical development.

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Journal
Cancer Discovery
Published
2026-03-05
DOI
https://doi.org/10.1158/2159-8290.cd-25-1132
Primary Topic
Cancer Immunotherapy and Biomarkers
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article
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Neoadjuvant BO-112 and hypofractionated radiation therapy with or without nivolumab in soft tissue sarcoma: preclinical and phase 1 results

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Cancer Discovery
Cancer Immunotherapy and Biomarkers
article

Neoadjuvant BO-112 and hypofractionated radiation therapy with or without nivolumab in soft tissue sarcoma: preclinical and phase 1 results

Neda Nemat‐Gorgani, Dörthe Schaue, S. K. Nadia Rahman Silvia, Jillian R. Jaycox, A. Subramanian, Eilber Fc, Everett J. Moding, Aastha Pal, Kambiz Motamedi, Zuzana Jirakova Trnkova, Zinaida Good, Alvaro Chumpitaz Lavalle, Vishruth K. Reddy, J. Deng, Stefano Testa, Mito Tariveranmoshabad, Danielle S. Graham, Agnes Ewongwo, Sarah Kremer, Heather Ogana, Sam P. Limsuwannarot, S. Dubinett, Joseph G. Crompton, M. Quintero, Varand Ghazikhanian, Jingyu Xu, Carol Felix, Linh M. Tran, Katie M. Campbell, Aviv Hargil, Scott C. Chin, Scott D. Nelson, Anusha Kalbasi, Bartosz Chmielowski, Nicholas Bernthal, Arun S. Singh, Benjamin Levine
article en

Abstract

Neoadjuvant immune checkpoint blockade (ICB) and radiation therapy (RT) improve disease-free survival in select patients with soft tissue sarcoma (STS). However, most STS are myeloid-rich and lack pre-existing T cells associated with ICB response. In preclinical models, we observed that intratumoral BO-112 (nanoplexed polyinosinic: polycytidylic acid (poly I:C)) engages myeloid cells that persist after RT, ultimately enhancing T cell-dependent tumor control. We evaluated BO-112 and hypofractionated RT, with or without nivolumab, in fourteen patients with high-risk STS in a phase 1 neoadjuvant trial. Consistent with its immunologic potency, the triple combination induced rare immune-related adverse events (myositis-myocarditis-myasthenia gravis spectrum), mitigated by BO-112 and nivolumab dose adjustment. BO-112 and RT reprogrammed tumor-associated myeloid cells toward antigen-presenting states, promoted clonal replacement by less exhausted T cells, and enhanced malignant cell depletion compared to standard RT. These immunologic changes coincided with encouraging disease control in a small, high-risk cohort, supporting further clinical development.

Cancer Discovery
Beth Israel Deaconess Medical Center (US), University of California, Los Angeles (US), Yale University (US), University of Santa Monica (US), USC Norris Comprehensive Cancer Center (US), Comprehensive Cardiovascular (US), Stanford Medicine (US), Highlight Therapeutics (Spain) (ES), University of Pennsylvania Health System (US), Stanford University (US)
Good health and well-being
Openalex Percentile: Top 32%
Cancer Immunotherapy and Biomarkers
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