TGF-ßRII/IL-15 Immunotherapeutic complex targets exhausted CD8+ T cell subsets in lymph nodes and tumors

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-ßRII/IL-15 protein complex (HCW9218), with TGF-ß neutralization and IL-15 immunostimulatory activities, is capable of localizing to the TDLNs and tumors after subcutaneous administration, neutralizes TGF-ß, 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-ß 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. Overall design: B16F10 tumor bearing C57Bl6/J female mice received a single subcutaneous dose of HCW9218 (n=9) or saline (n=9) when tumors reached 50-100mm3, a single s.c. dose of HCW9218 (3mg/kg) was administered following which the mice were sacrificed on day 5 post treatment. Total CD8+ T cells were isolated from TDLN, sorted and pooled from 3 mice in each group (total 3 samples from each group) and subjected to single cell RNA Seq analysis.