TGF-βRII/IL-15 Immunotherapeutic complex targets exhausted CD8+ T cell subsets in lymph nodes and tumors [scRNA-Seq]

Exhausted CD8+ T cells, located within the tumor-draining lymph nodes (TDLNs) are responsible for maintaining tumor-specific responses in cancer. Here, we demonstrate that a bifunctional TGF-βRII/IL-15 protein complex (HCW9218), with TGF-β neutralization and IL-15 immunostimulatory activities, is capable of localizing to the TDLNs and tumors after subcutaneous administration, neutralizes TGF-β, expands progenitor stem-like exhausted T cells (TPEX) in TDLNs, and promotes their infiltration into tumors. Immune-checkpoint-inhibitors (ICIs) significantly enhanced the effects of HCW9218 on TPEX, and synergistically improved HCW9218 anti-tumor efficacy in melanoma and reduced spontaneous lung metastasis in breast cancer models. In a dose-escalating clinical trial in patients with chemo-refractory/relapsed solid tumors, HCW9218 monotherapy was well-tolerated, reduced serum TGF-β levels, promoted CD8+ T cell expansion in peripheral blood and CD8+ T cell infiltration in tumor biopsies. These findings provide a strong basis for using HCW9218 to enhance the efficacy of ICIs against solid tumors in the clinical setting. Lymph node biopsy from patient with ovarian cancer were collected pre and post treatment (cycle 3).