Abstract A052: Safety, immunogenicity and resistance of <i>in situ</i> Immunomodulation with CDX-301, radiotherapy, CDX-1140, and Poly-ICLC in patients with unresectable and metastatic solid tumors: a phase 1 trial

Abstract T-cell exclusion from the tumor microenvironment (TME) correlates with poor prognosis and is a significant obstacle in cancer treatment. Compelling evidence highlights critical roles of conventional type 1 dendritic cells (cDC1s) in eliciting potent antitumor T-cell responses. Our novel combinatorial in situ immunomodulation (ISIM) regimen comprised of in situ administration of FMS-like tyrosine kinase 3 ligand (Flt3L), radiotherapy (RT) and dual CD40/TLR3 stimulation promotes the recruitment and activation of tumor-residing cDC1s, mediating robust local and systemic antitumor T-cell immunity in orthotopic mouse tumor models. However, the safety, immunogenicity, and translatability of ISIM in human patients remain unknown. Here, we evaluated 6 patients with unresectable and metastatic solid tumors in the Cohort A of our phase I clinical study (NCT04616248). Patients received at least one cycle of ISIM, consisting of CDX-301, a recombinant human Flt3L (intratumoral injection, day 1-5), RT (9Gy, day 8), CDX-1140, human CD40 agonist and Poly-ICLC, human TLR3 agonist (intratumoral injection, day 9). All six patients tolerated treatment well with no severe adverse effects except for asymptomatic neutropenia (G3). One patient with metastatic myxofibrosarcoma exhibited a local response after 3-cycles of ISIM but limited abscopal effects were observed in all patients. Notably, we observed an inverse correlation between serum IFN-γ and IL-6 levels following vaccination with CDX-1140/Poly-ICLC, suggesting elevated IL-6 may represent a potential resistance mechanism to ISIM. At the tissue level, we found ISIM increased CD8+ tumor infiltrating lymphocytes (TILs) into the local site and upregulated PD-L1 expression by IHC in the patient who showed a local response. To better understand the localization and transcriptomic states of tumor-infiltrating immune cells and the broader spatial alterations induced by ISIM, we leveraged the Xenium In Situ Prime 5K platform on tumor biopsy specimens from the local responder. This analysis revealed that ISIM treatment recruited cDC1s into the human TME, along with additional DC subsets—including pDCs, cDC2s, and mRegDCs—as well as “chemokine-enriched” macrophages expressing CXCL9/10/11. Importantly, ISIM promoted the infiltration of GZMK + CXCR3 + CD8A + T cells, which are predominantly localized to DC-rich niches, and positioned themselves in close proximity to cancer cells. With ISIM, we found sarcoma-rich neighborhoods, dominated by cancer cells, endothelial cells and MRC1 + macrophages pre-treatment, were transformed into T-cell/DC-enriched niches post-treatment. Together, these findings demonstrate that ISIM is safe, promotes CD8+ T cell/DC infiltration into poorly-immune cell-inflamed human tumors, and remodels the TME into spatially organized immune neighborhoods conducive for DC-T-cell crosstalk. The Cohort B of this clinical trial combining ISIM with systemic anti-PD-1/IL-6 receptor blockade therapy is ongoing. (Grant support: NIH/NCI R01CA255240 and METAvivor) Citation Format: Steven V. Luong, Hisashi Kanemaru, Andrew S . Lim, Shelly X. Bian, Stella Yoo, Yukari Mizukami, Rowena Vergara, Maria E. Nelson, Stephen F. Sener, Andres M. Salazar, Tibor Keler, Diane Young, William D. Wallace, Ming Li, Yang Liu, Qiuyang Zhang, Chris X. Chen, Sheng Li, Evanthia Roussos Torres, Anastasia Martynova, Danielle Sterrenberg, Anthony El-Khoueiry, Daphne B. Stewart, Jason C. Ye, James S. Hu, Gino K. In, Fumito Ito. Safety, immunogenicity and resistance of in situ Immunomodulation with CDX-301, radiotherapy, CDX-1140, and Poly-ICLC in patients with unresectable and metastatic solid tumors: a phase 1 trial [abstract]. In: Proceedings of the AACR Immuno-Oncology Conference (AACR IO): Discovery and Innovation in Cancer Immunology: Revolutionizing Treatment through Immunotherapy; 2026 Feb 18-21; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Immunol Res 2026;14(2 Suppl):Abstract nr A052.