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

Stem-like progenitor exhausted CD8⁺ T cells (T_PEX), located within the tumor-draining lymph nodes (TDLNs), are responsible for maintaining tumor-specific responses in cancer. Although cytokines such as interleukin (IL)-15 are known to expand CD8⁺ T-cell subsets, transforming growth factor (TGF)-β in the TDLN is known to arrest the egress of these T_PEX to the tumor microenvironment. We hypothesized that combining IL-15 stimulatory and TGF-β blocking activity would boost antitumor responses mediated by T_PEX in the TDLN.

We developed a bifunctional TGF-βRII/IL-15 protein complex (HCW9218) and evaluated its antitumor activity in two murine models of melanoma and breast cancer. Peripheral blood, TDLN and tumor-infiltrating CD8⁺ T cells were characterized by flow cytometry following a single subcutaneous dose (s.c.) of HCW9218. Transcription profiling of CD8⁺ T cells in both murine models was performed. Synergistic activity of HCW9218 with immune-checkpoint inhibitors (ICIs) was evaluated. Finally, safety and immune profiling in patients with chemo-refractory/relapsed solid tumors was performed in a Phase 1 dose-escalating trial.

HCW9218 was capable of localizing to the TDLNs and tumors after s.c. administration, neutralized TGF-β, expanded T_PEX in TDLNs, increased chemokine-expressing effectors in peripheral circulation and promoted their infiltration into murine tumors. These data were corroborated in RNA sequencing analysis of TDLNs. ICIs significantly enhanced the effects of HCW9218 on T_PEX and synergistically improved HCW9218 antitumor efficacy in melanoma and reduced spontaneous lung metastasis in breast cancer models. In a Phase 1 clinical trial, HCW9218 monotherapy was well-tolerated, reduced serum TGF-β levels, promoted and sustained CD8⁺ T-cell expansion in peripheral blood and CD8⁺ T-cell infiltration in tumor biopsies. Stable disease was reported for four of six subjects (67%) with advanced ovarian cancer treated with HCW9218.

Our findings demonstrate that combination therapy targeting immune cells critical for antitumor responses and blocking immune-suppressive environment significantly improves antitumor therapeutic efficacy. These findings provide a strong basis for using HCW9218 to enhance the efficacy of ICIs against solid tumors in the clinical setting.