780 Targeting myeloid cells with BO-112 engages T cell immunity in combination with radiotherapy and checkpoint blockade in preclinical models and a phase 1 neoadjuvant clinical trial
Abstract
Background Immune checkpoint blockade (ICB) has demonstrated improvements in patients with soft tissue sarcoma (STS), however, response is limited to patients with pre-existing tumor-infiltrating T cells. Most STS harbor a myeloid-dominant infiltrate highlighting a therapeutic opportunity to leverage their ability to engage T cells. We hypothesized that BO-112, a nanoplexed poly I:C, will target myeloid cells to complement radiotherapy (RT) and ICB to generate T cell immunity in STS murine models and patients. Methods We tested combination hypofractionated RT ± intratumoral BO-112 ± anti-PD-1 in ICB-resistant murine models (autochthonous and transplantable KrasG12DP53-/- (KP) sarcoma). Tumor growth and survival were tracked. Target cells of BO-112 were identified using rhodamine-labeled BO-112. KP-bearing YFP-Cre mice were treated with intratumoral Cre-recombinase to track leukocytes. Tumor-infiltrating and peripheral immune cells were assessed longitudinally by flow cytometry. The contribution of lymphocyte subsets to anti-tumor effect was evaluated by antibody-mediated deletion. In a Phase I neoadjuvant trial, patients with STS received intratumoral BO-112, hypofractionated RT ± nivolumab followed by surgery. Longitudinal tumor (n=3–4 timepoints) and blood were evaluated by flow cytometry, IHC, TCR and whole exome DNA sequencing, and single cell and bulk RNA sequencing. Results Tumor control and survival were significantly improved with the local-only combination of RT and…
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