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

BACKGROUND: Stem-like progenitor exhausted CD8+ T cells (TPEX), 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 TPEX to the tumor microenvironment. We hypothesized that combining IL-15 stimulatory and TGF-β blocking activity would boost antitumor responses mediated by TPEX in the TDLN.

METHODS: 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.

RESULTS: HCW9218 was capable of localizing to the TDLNs and tumors after s.c. administration, neutralized TGF-β, expanded TPEX 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 TPEX 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.

CONCLUSIONS: 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.